Zonisamide add‐on therapy for focal epilepsy

Francesco Brigo; Simona Lattanzi; Stanley C Igwe; Masoud Behzadifar; Nicola Luigi Bragazzi

doi:10.1002/14651858.CD001416.pub5

Cochrane Database of Systematic Reviews

Zonisamide add‐on therapy for focal epilepsy

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DOI:

https://doi.org/10.1002/14651858.CD001416.pub5 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

24 julio 2020see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Epilepsia

Copyright:

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Francesco Brigo

Correspondencia a: Department of Neurology, Franz Tappeiner Hospital, Merano, Italy

[email protected]
Simona Lattanzi

Neurological Clinic, Marche Polytechnic University, Ancona, Italy
Stanley C Igwe

Department of Neuropsychiatry, Federal Teaching Hospital, Abakaliki, Nigeria
Masoud Behzadifar

Social Determinants of Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
Nicola Luigi Bragazzi

Department of Health Sciences, Postgraduate School of Public Health, Genoa, Italy

Contributions of authors

Francesco Brigo and Simona Lattanzi independently assessed trials for possible inclusion. Stanley C Igwe, Nicola L Bragazzi, and Masoud Behzadifar critically revised the text of the review and the accuracy of the analyses.

Sources of support

Internal sources

No sources of support supplied

External sources

National Institute for Health Research (NIHR), UK

This review update was funded by the National Institute for Health Research (NIHR) [Clinically effective treatments for central nervous system disorders in the NHS, with a focus on Epilepsy and Movement Disorders (SRPG project 16/114/26)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Declarations of interest

FB: Francesco Brigo received travel support and accomodation by Lusofarmaco to attend the annual Congress of the Italian Chapter of ILAE; he received fees for speaking from Lusofarmaco.
SL: none known
SI: none known
MB: none known
NLB: none known

Acknowledgements

We thank Dainippon, Elan Pharma, and Eisai for sharing unpublished and additional data for this review. We wish to acknowledge the hard work that went into the original version of this review by David Chadwick, Katie Carmichael, Shaheen Lakhan, Prachi Parikh, and Anthony G Marson. We are deeply grateful to Xuehan Liu who translated the two Chinese studies (Wu 2010; Zhang 2011).

Version history

Published

Title

Stage

Authors

Version

2020 Jul 24

Zonisamide add‐on therapy for focal epilepsy

Review

Francesco Brigo, Simona Lattanzi, Stanley C Igwe, Masoud Behzadifar, Nicola Luigi Bragazzi

https://doi.org/10.1002/14651858.CD001416.pub5

2018 Oct 18

Zonisamide add‐on therapy for focal epilepsy

Review

Francesco Brigo, Simona Lattanzi, Stanley C Igwe, Masoud Behzadifar, Nicola Luigi Bragazzi

https://doi.org/10.1002/14651858.CD001416.pub4

2013 Dec 19

Zonisamide add‐on for drug‐resistant partial epilepsy

Review

Katie Carmichael, Jennifer Pulman, Shaheen Emmanuel Lakhan, Prachi Parikh, Anthony G Marson

https://doi.org/10.1002/14651858.CD001416.pub3

2005 Oct 19

Zonisamide add‐on for drug‐resistant partial epilepsy

Review

David W Chadwick, Anthony G Marson

https://doi.org/10.1002/14651858.CD001416.pub2

2002 Apr 22

Zonisamide add‐on for drug‐resistant partial epilepsy

Review

David W Chadwick, A G Marson, Tony G Marson

https://doi.org/10.1002/14651858.CD001416

Differences between protocol and review

We considered head‐to‐head drug trials for inclusion in this review update. However, no such trials met the inclusion criteria. We also changed the title from 'Zonisamide add‐on for drug‐resistant partial epilepsy' to 'Zonisamide add‐on therapy for focal epilepsy'. We used the term 'focal', according to the most recent classification of epilepsies of the International League Against Epilepsy (ILAE; Kwan 2010). We also decided to avoid the term 'drug‐resistant epilepsy', because according to the current definition by the ILAE, it should be defined as the 'failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom'. However, some studies included in this review were conducted in participants receiving only one background antiepileptic drug; according to the ILAE definition, these participants would not be considered affected by drug‐resistant epilepsy.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

This diagram refers only to results of the updated searches for the current version of the review

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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

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Analysis 1.1

Comparison 1: Zonisamide versus placebo, Outcome 1: 50% responder rate ‐ whole treatment period

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Analysis 1.2

Comparison 1: Zonisamide versus placebo, Outcome 2: 50% responder rate ‐ best‐case scenario

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Analysis 1.3

Comparison 1: Zonisamide versus placebo, Outcome 3: 50% responder rate ‐ worst‐case scenario

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Analysis 1.4

Comparison 1: Zonisamide versus placebo, Outcome 4: 50% responder rate ‐ dose‐effect for Brodie 2005

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Analysis 1.5

Comparison 1: Zonisamide versus placebo, Outcome 5: 50% responder rate ‐ dose effect for Faught 2001

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Analysis 1.6

Comparison 1: Zonisamide versus placebo, Outcome 6: Withdrawal rates

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Analysis 1.7

Comparison 1: Zonisamide versus placebo, Outcome 7: Adverse effects

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Summary of findings 1. Zonisamide compared to placebo for focal epilepsy

Zonisamide compared to placebo for focal epilepsy
Patient or population: patients with focal epilepsy Setting: hospital outpatients Intervention: add‐on zonisamide Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with zonisamide	Relative effect (CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
50% responder rate (whole treatment period; any dose)	Study population		RR 1.86 (95% CI 1.60 to 2.17)	1429 (7 RCTs)	⊕⊕⊕⊝ Moderate^a	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 (396 to 537)	RR 1.86 (95% CI 1.60 to 2.17)	1429 (7 RCTs)	⊕⊕⊕⊝ Moderate^a
Withdrawal rates (whole treatment period; any dose)	Study population		RR 1.44 (95% CI 1.08 to 1.93)	1156 (6 RCTs)	⊕⊕⊕⊝ Moderate^a	Zonisamide 300 mg to 500 mg/day (RR 1.59, 95% CI 1.18 to 2.13; moderate‐certainty evidence)
Withdrawal rates (whole treatment period; any dose)	110 per 1000	159 per 1000 (119 to 213)	RR 1.44 (95% CI 1.08 to 1.93)	1156 (6 RCTs)	⊕⊕⊕⊝ Moderate^a
Adverse effects: ataxia (whole treatment period; any dose)	Study population		RR 3.85 (99% CI 1.36 to 10.93)	734 (4 RCTs)	⊕⊕⊝⊝ Low^a,b	Note that for adverse events, we used a 99% CI.
	17 per 1000	67 per 1000 (24 to 189)	RR 3.85 (99% CI 1.36 to 10.93)	734 (4 RCTs)	⊕⊕⊝⊝ Low^a,b	Note that for adverse events, we used a 99% CI.
Adverse effects: dizziness (whole treatment period; any dose)	Study population		RR 1.40 (99% CI 0.90 to 2.18)	1429 (7 RCTs)	⊕⊕⊕⊝ Moderate^a
	75 per 1000	105 per 1000 (68 to 164)	RR 1.40 (99% CI 0.90 to 2.18)	1429 (7 RCTs)	⊕⊕⊕⊝ Moderate^a
Adverse effects: fatigue (whole treatment period; any dose)	Study population		RR 1.41 (99% CI 0.79 to 2.53)	1045 (6 RCTs)	⊕⊕⊕⊝ Moderate^a
	54 per 1000	76 per 1000 (43 to 137)	RR 1.41 (99% CI 0.79 to 2.53)	1045 (6 RCTs)	⊕⊕⊕⊝ Moderate^a
Adverse effects: nausea (whole treatment period; any dose)	Study population		RR 1.10 (99% CI 0.58 to 2.10)	805 (5 RCTs)	⊕⊕⊕⊝ Moderate^a
	66 per 1000	73 per 1000 (38 to 139)	RR 1.10 (99% CI 0.58 to 2.10)	805 (5 RCTs)	⊕⊕⊕⊝ Moderate^a
Adverse effects: somnolence (whole treatment period; any dose)	Study population		RR 1.52 (99% CI 1.00 to 2.31)	1636 (8 RCTs)	⊕⊕⊕⊝ Moderate^a
	72 per 1000	109 per 1000 (72 to 166)	RR 1.52 (99% CI 1.00 to 2.31)	1636 (8 RCTs)	⊕⊕⊕⊝ Moderate^a
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 High certainty. We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty. We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty. Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty. We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect
^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. ^bDowngraded once for imprecision

Summary of findings 1. Zonisamide compared to placebo for focal epilepsy

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Comparison 1. Zonisamide versus placebo

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]

Comparison 1. Zonisamide versus placebo

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Zonisamide add‐on therapy for focal epilepsy

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