Tratamiento complementario con zonisamida para la epilepsia focal
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en espera de evaluación
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group study | |
| Participants | Multicentre study, 49 centres in Europe and 5 in South Africa | |
| Interventions | Placebo, 100 mg, 300 mg, or 500 mg placebo, randomised in 2:1:1:2 ratio | |
| Outcomes | Reduction in seizure frequency, proportion with a 50% or greater reduction in seizure frequency | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were randomised sequentially in blocks of six" |
| Allocation concealment (selection bias) | Unclear risk | Insufficient details were provided |
| Blinding of participants and personnel (performance bias) | Low risk | "Treatments were blinded using a double dummy technique throughout the study" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Insufficient details about blinding of outcome assessors was provided |
| Incomplete outcome data (attrition bias) | Low risk | A modified ITT analysis was conducted as "all patients who received at least one dose of study drug were included in the safety analysis". 4 participants not included in the analysis were spread fairly evenly among groups (1 participant lost from 2 groups, 2 participants lost from 1 group) |
| Selective reporting (reporting bias) | Low risk | This study was deemed to be at a low risk of selective reporting |
| Funding Source | Low risk | Reported (sponsored by industry) |
| Conflicts of interest | Unclear risk | Not specified |
| Other bias | Low risk | Allocation to groups led to different durations of stable‐dose phase |
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group study. 2 treatment arms: 1 placebo and 1 zonisamide | |
| Participants | Multicentre (20) USA study | |
| Interventions | Zonisamide 400 mg/day or placebo (weeks 8 to 12) | |
| Outcomes | Primary: median percentage reduction from baseline of all focal seizures | |
| Notes | Of the randomised participants, 8 failed to complete week 5 in the placebo group, 15 in the zonisamide group | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Randomization codes were generated centrally, with separate randomization sequences for each site." |
| Allocation concealment (selection bias) | Low risk | "Each investigator had a sealed copy of the code to be opened in an emergency. Otherwise, assignments were not revealed until all patients at all sites had completed the study." |
| Blinding of participants and personnel (performance bias) | Unclear risk | Insufficient detail was provided about blinding of personnel |
| Blinding of outcome assessment (detection bias) | Unclear risk | Insufficient detail was provided about blinding of outcome assessors |
| Incomplete outcome data (attrition bias) | Unclear risk | The analysis for "the primary populations was a modified ITT" as it included participants who had received at least one dose of study medication |
| Selective reporting (reporting bias) | Low risk | No evidence of selective reporting |
| Funding Source | Low risk | Reported (sponsored by industry) |
| Conflicts of interest | Unclear risk | Not specified |
| Other bias | Low risk | No evidence of any other source of bias |
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group 2 treatment arms: 1 placebo and 1 zonisamide Computer‐generated, centrally performed randomisation (pseudo‐random number generator), allocation concealed by telephone randomisation service Method of blinding: identical appearance of active drug and placebo Baseline period: 8 weeks (4 weeks historical + 4 weeks screening) Treatment duration: 8 weeks titration + 12 weeks maintenance | |
| Participants | Number of participants: Zonisamide: 107; Placebo: 100 Age of participants, mean (SD); median (range): Zonisamide: 11.6 (3.3); 11.0 (6 to 17); Placebo: 11.2 (3.2); 11.0 (6 to 17). Gender of participants: Zonisamide: male 53 (49.5%); Placebo: male 55 (55.0%). Type of seizures: Zonisamide: simple focal with motor signs 40 (37.4%), simple focal without motor signs 11 (10.3%), complex focal 59 (55.1%), secondarily generalised tonic‐clonic 29 (27.1%) Placebo: simple focal with motor signs 34 (34.0%), simple focal without motor signs 10 (10.0%), complex focal 58 (58.0%), secondarily generalised tonic‐clonic 33 (33.0%) Seizure frequency during the baseline period, mean (SD); median (range): Zonisamide: 32.9 (50.3); 10.5 (4 to 261; (number of seizures per 28 days)) Placebo: 43.8 (126.4); 10.0 (4 to 882; (number of seizures per 28 days)) Number of background drugs: Zonisamide: 0 AED: 0; 1 AED: 44 (41.1%); 2 AEDs: 63 (58.9%) Placebo: 0 AED: 1 (1.0%); 1 AED: 39 (39.0%); 2 AEDs: 60 (60.0%) | |
| Interventions | Add‐on zonisamide versus add‐on placebo Zonisamide drug dose regimen (dosage and infusion rate): 1 mg/kg/day, titrated in weekly increments of 1 mg/kg over 8 weeks to a target dose of 8 mg/kg/day (max 500 mg/day), continued unchanged over the 12‐week maintenance period | |
| Outcomes | Efficacy: Primary outcome: proportion of participants with a ≥ 50% reduction in seizure frequency during the 12‐week maintenance period compared to baseline (i.e. the 8 weeks preceding randomisation) Secondary outcomes: median percentage change from baseline in 28‐day seizure frequency; proportion of participants with ≥ 75% seizure frequency reduction; proportion of participants with an increase in seizure frequency of ≥ 25%, 25%, and 100%; proportion of participants achieving seizure freedom; percentage change from baseline in 28‐day seizure frequency by seizure type; relationship between zonisamide plasma level and responder rate Safety: incidence of treatment emergent AEs (TEAEs), serious TEAEs, and withdrawal due to TEAEs; clinical laboratory parameters; physical and neurologic evaluations; vital signs; height and weight; electrocardiography | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated, centrally performed randomisation (pseudo‐random number generator) |
| Allocation concealment (selection bias) | Low risk | Allocation concealed by telephone randomisation service |
| Blinding of participants and personnel (performance bias) | Low risk | Identical appearance of active drug and placebo |
| Blinding of outcome assessment (detection bias) | Unclear risk | Insufficient details about blinding of outcome assessors |
| Incomplete outcome data (attrition bias) | Low risk | No missing outcome data |
| Selective reporting (reporting bias) | Low risk | No evidence of selective reporting |
| Funding Source | Low risk | Reported (sponsored by industry) |
| Conflicts of interest | Low risk | Reported |
| Other bias | Low risk | No evidence of any other source of bias |
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, parallel trial. 12‐week baseline phase, 4‐week titration phase, 12‐week stable treatment phase. Placebo or zonisamide treatment interventions | |
| Participants | Single centre in China. 104 participants randomised, 53 received zonisamide (29 M:24 F) and 51 received placebo (32 M:19 F). Mean age in zonisamide group = 36.83 years ± 10.77, and mean age in placebo group = 29.81 years ± 8.24. All participants had simple focal seizures, complex focal seizures, or secondary generalised seizures | |
| Interventions | Placebo or zonisamide (titrated to 300 mg/day or 400 mg/day) | |
| Outcomes | The following outcomes were measured:
| |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No information given other than "zonisamide and placebo were assigned to our centre in a ratio of 1:1" |
| Allocation concealment (selection bias) | Low risk | "Random allocation of patients to their treatment group was concealed via the use of numbered containers" Comment: it was not explicitly stated whether the containers were opaque or not |
| Blinding of participants and personnel (performance bias) | Low risk | "Investigators were blind to treatment each patient received until the end of the study" and "Zonisamide and placebo tablets had the same size, colour and shape. The tablets were randomly numbered by the study sponsors" |
| Blinding of outcome assessment (detection bias) | Unclear risk | It is unclear whether the investigators, who were blinded, were also the outcome assessors |
| Incomplete outcome data (attrition bias) | Low risk | One participant was lost from each group, therefore, missing data were balanced between groups |
| Selective reporting (reporting bias) | Low risk | No evidence of selective reporting |
| Funding Source | Low risk | No sources of funding were used to assist in the conduct or preparation of this study, but the drug was provided for the trial by two different manufacturers of zonisamide (Eisai Co. Ltd and Shenzhen Zifu Co. Ltd) |
| Conflicts of interest | Unclear risk | Not specified |
| Other bias | Low risk | Both providers of zonisamide were manufacturers of the drug |
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group study | |
| Participants | Conducted at 4 USA centres between August 1983 and July 1986 | |
| Interventions | Zonisamide median dosage 400 mg/day (100 mg capsules) | |
| Outcomes | Primary: median percentage reduction in seizure frequency of all focal seizures from baseline | |
| Notes | Because of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Randomisation codes were generated by the study sponsor". "Each patient who qualified to receive double‐blind treatment was assigned a randomisation number and given zonisamide or placebo" |
| Allocation concealment (selection bias) | Low risk | "Random allocation of patients to their treatment groups was concealed via the use of numbered containers" |
| Blinding of participants and personnel (performance bias) | Low risk | This study was deemed to be at low risk of performance bias |
| Blinding of outcome assessment (detection bias) | Low risk | This study was deemed to be at low risk of detection bias |
| Incomplete outcome data (attrition bias) | Unclear risk | Insufficient or unclear details were provided with regard to attrition bias |
| Selective reporting (reporting bias) | Low risk | No evidence of selective reporting |
| Funding Source | Low risk | Reported (sponsored by industry) |
| Conflicts of interest | Unclear risk | Not specified |
| Other bias | Low risk | Baseline period was extended if the frequency of seizures did not meet a prespecified threshold |
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, parallel group study | |
| Participants | Participants from 10 European centres recruited between June 1984 and October 1986 | |
| Interventions | Zonisamide median dosage 400 mg/day (100 mg capsules) | |
| Outcomes | Primary: median percentage reduction in seizure frequency of all focal seizures from baseline | |
| Notes | Because of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were randomised sequentially in blocks of four" |
| Allocation concealment (selection bias) | Unclear risk | Insufficient details provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | Insufficient details were provided about blinding of personnel |
| Blinding of outcome assessment (detection bias) | Unclear risk | Blinding of outcome assessors was not detailed |
| Incomplete outcome data (attrition bias) | Unclear risk | A modified ITT analysis was conducted including participants who had received "at least 7 days of treatment" |
| Selective reporting (reporting bias) | Low risk | This study was deemed to be at low risk of selective reporting |
| Funding Source | Low risk | Reported (sponsored by industry) |
| Conflicts of interest | Unclear risk | Not specified |
| Other bias | Low risk | Baseline period was extended if the frequency of seizures did not meet a prespecified threshold |
| Study characteristics | ||
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled study Duration of baseline: 12 weeks. Duration of study: increment, stabilisation, reduction = 4 weeks, 12 weeks, 4 weeks | |
| Participants | Participants with focal epilepsy Number of participants: Zonizamide: 120 Placebo: 120 Age of participants, mean ± SD: Zonisamide: 32.7 ± 12.2 Placebo: 30.7 ± 11.6 Gender of participants: Zonisamide: male/female = 57/54 Placebo: male/female = 63/43 Number of background drugs: 1 to 2 | |
| Interventions | Add‐on zonisamide versus add‐on placebo Zonisamide: increment: first two weeks 100 mg/day, third week 200 mg/day, forth week 300 mg/day. Stabilization: 300 mg/day. According to the participant's situation, doses could be increased to 400 mg/day. | |
| Outcomes | The median of the difference between the frequency of epileptic seizures and baseline value; in comparison with baseline period, the frequency of epileptic seizures decreased by more than 50%; safety index | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient details provided |
| Allocation concealment (selection bias) | Unclear risk | Insufficient details provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | Study defined as double‐blind. However, insufficient details were provided. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Insufficient details provided |
| Incomplete outcome data (attrition bias) | High risk | 12 participants who were seriously against the treatment program were excluded. FAS include 216 participants (zonisamide group:placebo group = 111:106), PPS include 201 participants (zonisamide group:placebo group = 102:99). No reasons for differences in the number of patients in ITT and in per protocol set (PPS) are provided. |
| Selective reporting (reporting bias) | Low risk | The study protocol was not available, but it was clear that the published reports included all expected outcomes |
| Funding Source | Unclear risk | Not reported |
| Conflicts of interest | Unclear risk | Not reported |
| Other bias | Low risk | No evidence of any other source of bias |
| Study characteristics | ||
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled study Stratified block randomisation and block randomisation Duration of baseline period: 12 weeks Duration of treatment: increment, stabilisation = 3 weeks, 13 weeks | |
| Participants | participants with focal epilepsy Number of participants: Zonizamide: 120 Placebo: 120 Age of participants, mean ± SD: Zonisamide: 30.83 ± 11.68 Placebo: 32.47 ± 11.92 Gender of participants: Zonisamide: male/female = 42/52 Placebo: male/female = 55/52 Number of background drugs: 1 to 2 | |
| Interventions | Add‐on zonisamide versus add‐on placebo Zonisamide: at the beginning, 100mg/day, increase to 300mg/day (100 mg, three times a day) within three weeks; stabilisation: 300mg/day | |
| Outcomes | The clinical efficacy at 5 to 16 weeks; the average number of episodes per 4 weeks; drug safety evaluation | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Stratified random, segmented random, random distribution list |
| Allocation concealment (selection bias) | Low risk | Gave random distribution list to major leadership for safekeeping |
| Blinding of participants and personnel (performance bias) | Low risk | Study defined as double‐blind. However, insufficient details were provided. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Insufficient details provided |
| Incomplete outcome data (attrition bias) | High risk | ITT included 240 participants (zonisamide group:placebo group = 120:120); PPS included 201 participants (zonisamide group:placebo group = 94:107). No reasons for differences in the number of patients in ITT and in per protocol set (PPS) were provided. |
| Selective reporting (reporting bias) | Low risk | The study protocol was not available, but it was clear that the published reports included all expected outcomes |
| Funding Source | Unclear risk | Not reported |
| Conflicts of interest | Unclear risk | Not reported |
| Other bias | Low risk | No evidence of any other source of bias |
AED: antiepileptic drug
F: female
FAS: full analysis set
ITT: intention‐to‐treat
M: male
PPS: per‐protocol set
SD: standard deviation
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| No control group was used |
Characteristics of studies awaiting classification [ordered by study ID]
| Methods | Five‐month titration and stabilisation period followed by a three‐month treatment period Randomised controlled study (no further details on study design were provided) |
| Participants | 14 adult participants (9 males, 5 females); average age of 35 years At least 4 focal seizures |
| Interventions | Zonisamide add‐on versus sodium valproate add‐on |
| Outcomes | No details |
| Notes | No details |
| Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group 2 treatment arms: 1 placebo and 1 zonisamide Duration of baseline period: 12 weeks (retrospective, prior to entry) Duration of treatment period: 16 weeks (4‐week titration period + 12‐week fixed‐dose phase) |
| Participants | According to the International League Against Epilepsy (ILAE) classification of seizure type (1981) and international classification of epilepsies and epileptic syndromes (Kwan 2010), definite diagnosis of focal seizures (with or without secondary generalised seizures) refractory to current antiepileptic drug (AED) therapy Number of participants: Zonisamide: 120 Placebo: 120 Age of participants, mean (SD): Zonisamide: 32.72 (12.18) Placebo: 30.69 (11.59) Gender of participants: Zonisamide: male 57/111 Placebo: male 63/106 Number of background drugs: At least 1 to 2 concomitant AEDs on a stable dose (for 3 months prior to enrolment) |
| Interventions | Add‐on zonisamide versus add‐on placebo Zonisamide drug, dose regimen (dosage and infusion rate): During the 4‐week titration period, zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/day at the end of the titration period. The 300 mg/day was the target dose in the titration period, and must have been reached. Dose increment was continued to 400 mg/day if this was tolerated by the participant. |
| Outcomes | Efficacy Primary outcome: median percent change in seizure frequency from baseline during the fixed‐dose phase Secondary outcomes: mean percent change in complex focal seizure frequency from baseline during the fixed‐dose phase; mean percent change in simple focal seizure frequency from baseline during the fixed‐dose phase; mean percent change in focal with secondary generalisation seizure frequency from baseline during the fixed‐dose phase; responder rate as percentage of participants with ≥ 50% reduction in seizure frequency from baseline; mean number of seizure‐free days per 28 day period during fixed‐dose phase; mean percentage of change in seizure‐free days; mean time‐to‐first seizure during fixed dose phase; percentage of seizure‐free participants during fixed‐dose phase; drop‐out rate Safety drop‐out rate; incidence of treatment emergent AEs (TEAEs), serious TEAEs, and withdrawal due to TEAEs |
| Notes |
| Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group 2 treatment arms: 1 placebo and 1 zonisamide Duration of baseline period: 4 weeks Duration of treatment period: 16 weeks (8‐week titration period + 8‐week maintenance phase) |
| Participants | Number of participants: Zonisamide: 33 Placebo: 18 Age of participants, mean (SD): Zonisamide: 72.5 (5.63) Placebo: 71.1 (4.61) Gender of participants, mean (SD): Zonisamide: male 14/33 Placebo: male 7/18 Number of background drugs (active and control group): At least one, but not more than two concomitant AEDs |
| Interventions | Add‐on zonisamide versus add‐on placebo Zonisamide at targeted daily doses of 100 mg to 500 mg/day Subjects started the titration period on a total daily dose (TDD) of zonisamide 50 mg (25 mg twice daily) for a total of 8 weeks. Doses increased in 100 mg increments up to a targeted TDD of 300 mg, with a range of 100 mg to 500 mg. Participants entered the maintenance period on the same dose they were on at the end of the titration phase, taking the dose once daily (in the evening), or twice daily, for a total of 8 weeks. Participants were withdrawn if they required a TDD outside of the suggested range. |
| Outcomes | Primary outcome: change in mean reaction time in computer visual search task of the Ferrum Psyche test, and Bond‐Lader visual analogue scale mood sub‐scores from baseline, by visits during titration and maintenance period (weeks 4, 8, 12, 16). Secondary Outcome: percent change in seizure frequency from baseline to the last 28 days of the maintenance period; percentage of responders (≥ 50% reduction in seizure frequency) during the last 28 days of the maintenance period Safety: incidence of treatment emergent AEs (TEAEs), serious TEAEs, and withdrawal due to TEAEs |
| Notes |
AE ‐ adverse event; AED ‐ antiepileptic drug; SD ‐ standard deviation
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 50% responder rate ‐ whole treatment period Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.1  Comparison 1: Zonisamide versus placebo, Outcome 1: 50% responder rate ‐ whole treatment period | ||||
| 1.1.1 Any dose | 7 | 1429 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.86 [1.60, 2.17] |
| 1.1.2 300 mg to 500 mg/day | 7 | 1371 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.90 [1.63, 2.22] |
| 1.2 50% responder rate ‐ best‐case scenario Show forest plot | 7 | 1429 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.22 [1.92, 2.57] |
| Analysis 1.2  Comparison 1: Zonisamide versus placebo, Outcome 2: 50% responder rate ‐ best‐case scenario | ||||
| 1.3 50% responder rate ‐ worst‐case scenario Show forest plot | 7 | 1429 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.26, 1.64] |
| Analysis 1.3  Comparison 1: Zonisamide versus placebo, Outcome 3: 50% responder rate ‐ worst‐case scenario | ||||
| 1.4 50% responder rate ‐ dose‐effect for Brodie 2005 Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.4  Comparison 1: Zonisamide versus placebo, Outcome 4: 50% responder rate ‐ dose‐effect for Brodie 2005 | ||||
| 1.4.1 100 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.2 300 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.3 500 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 50% responder rate ‐ dose effect for Faught 2001 Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.5  Comparison 1: Zonisamide versus placebo, Outcome 5: 50% responder rate ‐ dose effect for Faught 2001 | ||||
| 1.5.1 100 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5.2 200 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5.3 400 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.6 Withdrawal rates Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.6  Comparison 1: Zonisamide versus placebo, Outcome 6: Withdrawal rates | ||||
| 1.6.1 Any dose | 6 | 1156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.08, 1.93] |
| 1.6.2 300 mg to 500 mg/day | 6 | 1099 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.59 [1.18, 2.13] |
| 1.7 Adverse effects Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 99% CI) | Subtotals only | |
| Analysis 1.7  Comparison 1: Zonisamide versus placebo, Outcome 7: Adverse effects | ||||
| 1.7.1 Ataxia | 4 | 734 | Risk Ratio (M‐H, Fixed, 99% CI) | 3.85 [1.36, 10.93] |
| 1.7.2 Dizziness | 7 | 1429 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.40 [0.90, 2.18] |
| 1.7.3 Fatigue | 6 | 1045 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.41 [0.79, 2.53] |
| 1.7.4 Nausea | 5 | 805 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.10 [0.58, 2.10] |
| 1.7.5 Somnolence | 8 | 1636 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.52 [1.00, 2.31] |
| 1.7.6 Agitation or irritability | 4 | 598 | Risk Ratio (M‐H, Fixed, 99% CI) | 2.35 [1.05, 5.27] |
| 1.7.7 Anorexia | 6 | 1181 | Risk Ratio (M‐H, Fixed, 99% CI) | 2.74 [1.64, 4.60] |
This diagram refers only to results of the updated searches for the current version of the review
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
Comparison 1: Zonisamide versus placebo, Outcome 1: 50% responder rate ‐ whole treatment period
Comparison 1: Zonisamide versus placebo, Outcome 2: 50% responder rate ‐ best‐case scenario
Comparison 1: Zonisamide versus placebo, Outcome 3: 50% responder rate ‐ worst‐case scenario
Comparison 1: Zonisamide versus placebo, Outcome 4: 50% responder rate ‐ dose‐effect for Brodie 2005
Comparison 1: Zonisamide versus placebo, Outcome 5: 50% responder rate ‐ dose effect for Faught 2001
Comparison 1: Zonisamide versus placebo, Outcome 6: Withdrawal rates
Comparison 1: Zonisamide versus placebo, Outcome 7: Adverse effects
| Zonisamide compared to placebo for focal epilepsy | ||||||
|---|---|---|---|---|---|---|
| Patient or population: patients with focal epilepsy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with zonisamide | |||||
| 50% responder rate (whole treatment period; any dose) | Study population | RR 1.86 | 1429 | ⊕⊕⊕⊝ | Zonisamide 300 mg to 500 mg/day (RR 1.90, 95% CI 1.63 to 2.22; moderate‐certainty evidence) | |
| 248 per 1000 | 461 per 1000 | |||||
| Withdrawal rates (whole treatment period; any dose) | Study population | RR 1.44 | 1156 | ⊕⊕⊕⊝ Moderatea | Zonisamide 300 mg to 500 mg/day (RR 1.59, 95% CI 1.18 to 2.13; moderate‐certainty evidence) | |
| 110 per 1000 | 159 per 1000 | |||||
| Adverse effects: ataxia (whole treatment period; any dose) | Study population | RR 3.85 | 734 | ⊕⊕⊝⊝ | Note that for adverse events, we used a 99% CI. | |
| 17 per 1000 | 67 per 1000 | |||||
| Adverse effects: dizziness (whole treatment period; any dose) | Study population | RR 1.40 | 1429 | ⊕⊕⊕⊝ Moderatea | ||
| 75 per 1000 | 105 per 1000 | |||||
| Adverse effects: fatigue (whole treatment period; any dose) | Study population | RR 1.41 | 1045 | ⊕⊕⊕⊝ Moderatea | ||
| 54 per 1000 | 76 per 1000 | |||||
| Adverse effects: nausea (whole treatment period; any dose) | Study population | RR 1.10 | 805 | ⊕⊕⊕⊝ Moderatea | ||
| 66 per 1000 | 73 per 1000 | |||||
| Adverse effects: somnolence (whole treatment period; any dose) | Study population | RR 1.52 | 1636 | ⊕⊕⊕⊝ Moderatea | ||
| 72 per 1000 | 109 per 1000 | |||||
| *The assumed control risk (ACR) was calculated using median control group risk across the studies that provided data for that outcome.. The corresponding intervention risk in the zonisamide group (and its 95% CI) was based on the assumed risk in the comparison group (ACR) and the relative effect of the intervention (and its 95% CI) and is calculated according to following formula: corresponding intervention risk, per 100 = 100 * ACR * RR. CI: confidence interval; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded once for methodological uncertainties in included studies (unclear risk of bias). Some studies were at high risk of attrition bias; they did not provide reasons for differences between the number of patients in ITT and in per protocol set (PPS). However, the conclusions were unchanged following best‐case (RR 2.22, 95% CI 1.92 to 2.57) and worst‐case (RR 1.44, 95% CI 1.26 to 1.64) scenario analysis. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 50% responder rate ‐ whole treatment period Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Any dose | 7 | 1429 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.86 [1.60, 2.17] |
| 1.1.2 300 mg to 500 mg/day | 7 | 1371 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.90 [1.63, 2.22] |
| 1.2 50% responder rate ‐ best‐case scenario Show forest plot | 7 | 1429 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.22 [1.92, 2.57] |
| 1.3 50% responder rate ‐ worst‐case scenario Show forest plot | 7 | 1429 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.26, 1.64] |
| 1.4 50% responder rate ‐ dose‐effect for Brodie 2005 Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.1 100 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.2 300 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.3 500 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 50% responder rate ‐ dose effect for Faught 2001 Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5.1 100 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5.2 200 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5.3 400 mg/day | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.6 Withdrawal rates Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 Any dose | 6 | 1156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [1.08, 1.93] |
| 1.6.2 300 mg to 500 mg/day | 6 | 1099 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.59 [1.18, 2.13] |
| 1.7 Adverse effects Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 99% CI) | Subtotals only | |
| 1.7.1 Ataxia | 4 | 734 | Risk Ratio (M‐H, Fixed, 99% CI) | 3.85 [1.36, 10.93] |
| 1.7.2 Dizziness | 7 | 1429 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.40 [0.90, 2.18] |
| 1.7.3 Fatigue | 6 | 1045 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.41 [0.79, 2.53] |
| 1.7.4 Nausea | 5 | 805 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.10 [0.58, 2.10] |
| 1.7.5 Somnolence | 8 | 1636 | Risk Ratio (M‐H, Fixed, 99% CI) | 1.52 [1.00, 2.31] |
| 1.7.6 Agitation or irritability | 4 | 598 | Risk Ratio (M‐H, Fixed, 99% CI) | 2.35 [1.05, 5.27] |
| 1.7.7 Anorexia | 6 | 1181 | Risk Ratio (M‐H, Fixed, 99% CI) | 2.74 [1.64, 4.60] |
