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Zonisamide add-on for drug-resistant partial epilepsy

  1. Katie Carmichael1,*,
  2. Jennifer Pulman1,
  3. Shaheen Emmanuel Lakhan2,
  4. Prachi Parikh3,
  5. Anthony G Marson1

Editorial Group: Cochrane Epilepsy Group

Published Online: 19 DEC 2013

Assessed as up-to-date: 12 FEB 2013

DOI: 10.1002/14651858.CD001416.pub3


How to Cite

Carmichael K, Pulman J, Lakhan SE, Parikh P, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD001416. DOI: 10.1002/14651858.CD001416.pub3.

Author Information

  1. 1

    Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, UK

  2. 2

    Global Neuroscience Initiative Foundation, Beverly Hills, CA, USA

  3. 3

    Cleveland Clinic, Department of Neurology, Cleveland, Ohio, USA

*Katie Carmichael, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Lower Lane, Fazakerley, Liverpool, L9 7LJ, UK. katie_carmichael@hotmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 19 DEC 2013

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Characteristics of included studies [ordered by study ID]
Brodie 2005

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
Allocation concealment using telephone randomisation
Random permuted blocks of 6 per participating centre
Blinded using identical tablets and packaging
12 week pre-randomisation baseline period, 24-week treatment period including 6-week dose titration


ParticipantsMulticentre study, 49 centres in Europe and 5 in South Africa
351 participants. At least 12 seizures during 12-week baseline period, with no period of more than 3 weeks seizure-free
Taking 1 to 3 AEDs
Aged 12 to 77
51% male


InterventionsPlacebo, 100 mg, 300 mg or 500 mg placebo, randomised in 2:1:1:2 ratio


OutcomesReduction in seizure frequency, proportion with a 50% or greater reduction in seizure frequency
Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomised sequentially in blocks of six"

Allocation concealment (selection bias)Unclear riskInsufficient details were provided

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Treatments were blinded using a double dummy technique throughout the study"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient details about blinding of outcome assessors was provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskA 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 riskThis study was deemed to be at a low risk of selective reporting

Other biasLow riskAllocation to groups led to different durations of stable-dose phase

Faught 2001

MethodsRandomised, double-blind, placebo-controlled, parallel-group study. 2 treatment arms: 1 placebo and 1 zonisamide
Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets
All participants received placebo during 28-day prospective baseline. Treatment period was 12 weeks. Participants receiving zonisamide were divided into 2 groups, 1 (group B1) of which received 100 mg/day during weeks 1 to 5, the second (group B2) of which received 100 mg/day during week 1 followed by 200 mg/day during weeks 2 to 5. Both groups received an escalating dose of zonisamide for weeks 5 to 7 followed by 400 mg/day during weeks 8 to 12


ParticipantsMulticentre (20) US study
Total randomised: 203 participants between April 1994 and March 1996 with at least 4 partial seizures/month taking 1 or 2 AEDs, 85 to placebo, 60 to group B1, 58 to group B2
Ages 13 to 68 years, 104 male, 99 female
Median monthly seizure frequency for the randomised groups during baseline ranged between 11.2 and 13 seizures/month


InterventionsZonisamide 400 mg/day or placebo (weeks 8 to 12)
Zonisamide 100 mg/day or 200 mg/day or placebo (weeks 1 to 5)
All treatments and packaging were identical


OutcomesPrimary: median percentage reduction from baseline of all partial seizures
Secondary: proportion of participants showing a 50% reduction in all partial seizures from baseline
Adverse events


NotesOf the randomised participants 8 failed to complete week 5 in the placebo group, 15 in the zonisamide group
By the end of week 12, 13 participants had withdrawn from the placebo group, 23 from zonisamide


Risk of bias

BiasAuthors' judgementSupport 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)
All outcomes
Unclear riskInsufficient detail was provided about blinding of personnel

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient detail was provided about blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe 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 riskNo evidence of selective reporting

Other biasLow riskNo evidence of any other source of bias

Lu 2011

MethodsRandomised, double-blind, placebo-controlled, parallel trial. 12-week baseline phase, 4-week titration phase, 12-week stable treatment phase. Placebo or zonisamide treatment interventions


ParticipantsSingle centre in China. 104 participants randomised, 53 received zonisamide (29 M:24 F) and 51 received placebo (32 M: 19 F). Mean age of zonisamide group = 36.83 years +/- 10.77 and mean age in placebo group = 29.81 years +/- 8.24. All participants had simple partial seizures, complex partial seizures or secondary generalised seizures


InterventionsPlacebo or zonisamide (titrated to 300 mg/day or 400 mg/day)


OutcomesThe following outcomes were measured:

1. Responder rate (50% or greater reduction in seizures frequency during treatment phase compared to baseline)

2. Seizure freedom

3. Adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information given other than "zonisamide and placebo were assigned to our centre in a ratio of 1:1" (page 223)

Allocation concealment (selection bias)Low risk"Random allocation of patients to their treatment group was concealed via the use of numbered containers" Comment: it is not explicitly stated whether the containers were opaque or not

Blinding of participants and personnel (performance bias)
All outcomes
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)
All outcomes
Unclear riskIt is unclear whether the investigators who were blinded were also the outcome assessors or not

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient was lost from each group, therefore missing data were balanced between groups

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskBoth providers of zonisamide were manufacturers of the drug

Sackellares 2004

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
2 treatment arms, 1 placebo, 1 zonisamide. The initial target dose of zonisamide was 7 mg/kg/day, but when it became apparent that this was associated with a significant incidence of adverse effects, it was titrated over the first 4 weeks to 400 mg/day. Thereafter a non-blinded observer recommended dose adjustments to obtain plasma levels of 20 to 30 µg/ml. Median dosage in this group was 400 mg/day (range 200 to 600 mg/day)
Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets
Baseline was variable, between 8 and 12 weeks, being extended if frequency was below 4 partial seizures/month
Treatment period was 12 weeks


ParticipantsConducted at 4 US centres between August 1983 and July 1986
Total randomised: 152 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 78 were randomised to zonisamide, 74 to placebo
Age 17 to 67 years, 101 male 51 female
Median monthly seizure frequency pre-baseline: 7.5 zonisamide, 11.1 placebo


InterventionsZonisamide median dosage 400 mg/day (100 mg capsules)
Placebo
Treatments and packaging were identical


OutcomesPrimary: median percentage reduction in seizure frequency of all partial seizures from baseline
Secondary: proportion of participants with a 50% reduction in all partial seizures from baseline


NotesBecause of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period
14 people failed to complete the 12-week treatment period in the zonisamide group, 7 in the placebo group


Risk of bias

BiasAuthors' judgementSupport 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)
All outcomes
Low riskThis study was deemed to be at low risk of performance bias

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThis study was deemed to be at low risk of detection bias

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient or unclear details were provided with regard to attrition bias

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskBaseline period was extended if the frequency of seizures did not meet a prespecified threshold

Schmidt 1993

MethodsRandomised, double-blind, placebo-controlled, parallel group study
2 treatment arms, 1 placebo, 1 zonisamide. The initial target dose of zonisamide was 7 mg/kg/day, but when it became apparent that this was associated with a significant incidence of adverse effects, it was titrated over the first 4 weeks to 400 mg/day. Thereafter a non-blinded observer recommended dose adjustments to obtain plasma levels of 20 to 30 µg/ml. Median dosage in this group was 400 mg/day
Randomisation concealment by allocated sequentially numbered, sealed packages. Random list generated by random permuted blocks. Blinding by identical packing and tablets
Baseline was variable, between 8 and 12 weeks, being extended if frequency was below 4 partial seizures/month
Treatment period was 12 weeks


ParticipantsParticipants from 10 European centres recruited between June 1984 and October 1986
Total randomised: 144 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 73 were randomised to zonisamide, 71 to placebo
Age 17 to 60 years, 85 male 59 female
Median monthly seizure frequency pre-baseline: 11.3 zonisamide, 11.0 placebo


InterventionsZonisamide median dosage 400 mg/day (100 mg capsules)
Placebo
Treatments and packaging were identical


OutcomesPrimary: median percentage reduction in seizure frequency of all partial seizures from baseline
Secondary: proportion of participants with a 50% reduction in all partial seizures from baseline


NotesBecause of the variable baseline periods, baseline seizure frequency was recalculated for the 8 weeks immediately before entry into the treatment period
7 people failed to complete the 12-week treatment period in the zonisamide group, 2 in the placebo group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomised sequentially in blocks of four"

Allocation concealment (selection bias)Unclear riskInsufficient details provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient details were provided about blinding of personnel

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors was not detailed

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskA modified ITT analysis was conducted including patients who had received "at least 7 days of treatment"

Selective reporting (reporting bias)Low riskThis study was deemed to be at low risk of selective reporting

Other biasLow riskBaseline period was extended if the frequency of seizures did not meet a prespecified threshold

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Shimizu 1988No control group was used

 
Characteristics of studies awaiting assessment [ordered by study ID]
Anderson 1988

MethodsNo details

ParticipantsNo details

InterventionsZonisamide add-on versus sodium valproate add-on

OutcomesNo details

NotesNo details

 
Comparison 1. Zonisamide versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 50% responder rate - whole treatment period5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Any dose
5949Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.52, 2.42]

    1.2 300 to 500 mg zonisamide
5891Risk Ratio (M-H, Fixed, 95% CI)2.00 [1.58, 2.54]

 2 50% responder rate - best-case5949Risk Ratio (M-H, Fixed, 95% CI)2.23 [1.78, 2.79]

 3 50% responder rate - worst-case5949Risk Ratio (M-H, Fixed, 95% CI)1.42 [1.16, 1.75]

 4 50% responder rate - dose effect Brodie 20051Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    4.1 100 mg per day
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 300 mg per day
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 500 mg per day
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 50% responder rate - dose effect Faught 20011Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    5.1 100 mg per day
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 200 mg per day
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.3 400 mg per day
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Withdrawal rates5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Any dose
5949Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.07, 2.01]

    6.2 300 to 500 mg zonisamide
5892Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.20, 2.25]

 7 Adverse effects5Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    7.1 Ataxia
3494Risk Ratio (M-H, Fixed, 99% CI)3.77 [1.28, 11.11]

    7.2 Dizziness
5949Risk Ratio (M-H, Fixed, 99% CI)1.46 [0.88, 2.44]

    7.3 Nausea
4598Risk Ratio (M-H, Fixed, 99% CI)1.21 [0.61, 2.40]

    7.4 Fatigue
4598Risk Ratio (M-H, Fixed, 99% CI)1.41 [0.76, 2.62]

    7.5 Somnolence
5949Risk Ratio (M-H, Fixed, 99% CI)1.83 [1.08, 3.11]

    7.6 Agitation/irritability
4598Risk Ratio (M-H, Fixed, 99% CI)2.35 [1.05, 5.27]

    7.7 Anorexia
3494Risk Ratio (M-H, Fixed, 99% CI)2.71 [1.29, 5.69]

 
Summary of findings for the main comparison. Zonisamide versus placebo for drug-resistant partial epilepsy

Zonisamide versus placebo for drug-resistant partial epilepsy

Patient or population: patients with drug-resistant partial epilepsy
Settings: hospital out-patient setting
Intervention: zonisamide versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlZonisamide versus placebo

50% responder rate - whole treatment period - any doseStudy populationRR 1.92
(1.52 to 2.42)
949
(5 studies)
⊕⊕⊕⊕
high
3 out of 5 studies found a non-significant effect of zonisamide on responder rate but the combined overall effect was statistically significant

191 per 1000367 per 1000
(290 to 462)

Moderate

175 per 1000336 per 1000
(266 to 424)

Withdrawal rates - any doseStudy populationRR 1.47
(1.07 to 2.01)
949
(5 studies)
⊕⊕⊕⊕
high
No study produced a statistically significant effect of zonisamide on withdrawal rates independently but a statistically significant effect was found overall

113 per 1000166 per 1000
(121 to 227)

Moderate

95 per 1000140 per 1000
(102 to 191)

Adverse effects - ataxiaStudy population3.77
(1.28 to 11.11)
494
(3 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on ataxia independently, but there was a significant effect when study data were combined

26 per 1000100 per 1000
(34 to 294)

Moderate

24 per 100090 per 1000
(31 to 267)

Adverse effects - dizzinessStudy population1.46
(0.88 to 2.44)
949
(5 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on dizziness independently

88 per 1000128 per 1000
(77 to 215)

Moderate

118 per 1000172 per 1000
(104 to 288)

Adverse effects - nauseaStudy population1.21
(0.61 to 2.4)
598
(4 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on nausea independently

76 per 100091 per 1000
(46 to 181)

Moderate

69 per 100083 per 1000
(42 to 166)

Adverse effects - fatigueStudy population1.41
(0.76 to 2.62)
598
(4 studies)
⊕⊕⊕⊕
high
No study found a statistically significant effect of zonisamide on fatigue independently

86 per 1000122 per 1000
(66 to 226)

Moderate

79 per 1000111 per 1000
(60 to 207)

Adverse effects - somnolenceStudy population1.83
(1.08 to 3.11)
949
(5 studies)
⊕⊕⊕⊕
high
4 out of 5 studies found no statistically significant difference in the occurrence of somnolence between the zonisamide group and the control group

75 per 1000138 per 1000
(81 to 234)

Moderate

118 per 1000216 per 1000
(127 to 367)

Adverse effects - agitation/irritabilityStudy population2.35
(1.05 to 5.27)
598
(4 studies)
⊕⊕⊕⊕
high
1 out of 4 studies found a significant effect of zonisamide on agitation/irritability and there was a statistically significant effect overall

43 per 1000101 per 1000
(45 to 227)

Moderate

44 per 1000103 per 1000
(46 to 232)

Adverse effects - anorexiaStudy population2.71
(1.29 to 5.69)
494
(3 studies)
⊕⊕⊕⊕
high
None of 3 studies found significant effects of zonisamide on anorexia, but overall there was a significant effect when data were combined

62 per 1000167 per 1000
(80 to 351)

Moderate

81 per 1000220 per 1000
(104 to 461)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.