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Zonisamide add‐on for drug‐resistant partial epilepsy

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Referencias

Brodie 2005a {published data only}

Brodie MJ, Duncan R, Vespignani H, Solyom A, Bitenskyy V, Lucas C. Dose‐dependent safety and efficacy of zonisamide: a randomized, double‐blind, placebo‐controlled study in patients with refractory partial seizures. Epilepsia 2005;46(1):31‐41.

Faught 2001 {published and unpublished data}

Faught E, Ayala R, Montouris G, Leppik IE. Randomized controlled trial of zonisamide for the treatment of refractory partial‐onset seizures. Neurology 2001;57(10):1774‐9.

Schmidt 1993 {published and unpublished data}

Schmidt D, Jacob R, Loiseau P, Deisenhammer E, Klinger D, Despland A, et al. Zonisamide for add‐on treatment of refractory partial epilepsy: a European double blind trial. Epilepsy Research 1993;15(1):67‐73.

Wilder 1986 {unpublished data only}

Wilder BJ, Ramsay RE, Guterman A. A double blind multicenter placebo controlled study of the efficacy of zonisamide in the treatment of complex partial seizures in medically refractory patients. Internal report of the Dainippon Pharmaceutical Company1986.

Anderson 1988 {published data only}

Anderson TJ, Donaldson IM, McConnell H, Pollock M, Dobbs BR. Zonisamide: comparison with sodium valproate as additional treatment in refractory seizures. New Zealand Medical Journal 1988;101(854):611.

References to studies awaiting assessment

Ir a:

Anonymous {published data only}

Anonymous. A double‐blind, randomized, multicenter, parallel group study to establish dose‐response, safety, and efficacy of Zonegran (zonisamide) as monotherapy in patients with newly diagnosed epilepsy. http://www.clinicaltrials.gov/ct/show/nct00056576.2004.

Brodie 2004a {published data only}

Brodie MJ, Duncan R, Vespignani H, Solyom A, Bitensky V. Zonisamide is an effective adjunctive therapy for patients with refractory partial epilepsy: results from a randomised, double‐blind, placebo‐controlled study. Epilepsia 2004;45(Suppl 3):155.

Brodie 2004b {published data only}

Brodie MJ, Vespignani H, Solyom A, Bitensky V. Dose‐dependent safety and efficacy of zonisamide in refractory, localization‐related epilepsy: a randomized, double‐blind, placebo‐controlled trial. Epilepsia 2004;45(Suppl 7):131.

Brodie 2005b {published data only}

Brodie MJ, Duncan R, Vespignani H, Solyom A, Bitenskyy V, Lucas C. Dose‐dependent safety and efficacy of zonisamide: a randomized, double‐blind, placebo‐controlled study in patients with refractory partial seizures. Epilepsia 2005;46(1):31‐41.

Brodie 2005c {published data only}

Brodie MJ, Vespignani H. Efficacy of zonisamide against refractory partial seizures in an evaluable patient population. Epilepsia 2005;46(Suppl 6):117‐8.

Brodie 2006 {published data only}

Brodie MJ. Zonisamide as adjunctive therapy for refractory partial seizures. Epilepsy Research 2006;68(Suppl 2):S11‐6.

Naritoku 2006 {published data only}

Narioku D. Dose responsive efficacy of zonisamide monotherapy during 40 weeks treatment of parital seizures in patients with newly diagnosed epilepsy. Epilepsia 2006;47(Suppl 3):138‐9.

Sackellares 2004 {published data only}

Sackellares JC, Ramsay RE, Wilder BJ, Browne TR, Shellenberger MK. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia 2004;45(6):610‐7.

Wroe 2005 {published data only}

Wroe S, Brodie MJ. Long‐term efficacy and safety with zonisamide: interim analysis of an open‐label study. Epilepsia 2005;46(Suppl 6):118.

Cockerell 1995

Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 1995;346:140‐4.

Hauser 1993

Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota 1935 ‐ 1984. Epilepsia 1993;34:453‐68.

McCullagh 1989

McCullagh P, Nelder JA. Generalized linear models. Second Edition. London: Chapman and Hall, 1989.

Sander 1996

Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology, Neurosurgery, and Psychiatry 1996;61(5):433‐43.

References to other published versions of this review

Ir a:

Marson 1996

Marson AG, Kadir ZA, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ 1996;313:1169‐74.

Marson 1997

Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38(8):859‐80.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

Brodie 2005a

Methods

Randomized double blind placebo controlled parallel group study.
Allocation concealment using telephone randomization.
Random permuted block of 6 per participating centre.
Blinded using identical tablets and packaging.
12 week pre‐randomization baseline period, 24 week treatment period including 6 week dose titration.

Participants

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

Interventions

Placebo, 100 mg, 300 mg or 500 mg placebo, randomized in 2:1:1:2 ratio.

Outcomes

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

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Low risk

A ‐ Adequate
Faught 2001

Methods

Randomized double blind placebo controlled parallel group study. 2 treatment arms: 1 placebo and 1 zonisamide.
Randomization 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 escalating dose of zonisamide for weeks 5 to 7 followed by 400 mg/day during weeks 8‐12.

Participants

Multi‐centre (20) US study.
Total randomized: 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 13‐68 years, 104 male, 99 female.
Median monthly seizure frequency for the randomized groups during baseline ranged between 11.2 and 13 seizures/month.

Interventions

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

Outcomes

Primary: 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.

Notes

Of the randomized 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

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Low risk

A ‐ Adequate
Schmidt 1993

Methods

Randomized 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 ug/ml. Median dosage in this group was 400 mg/day.
Randomization 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.

Participants

Participants from 10 European centres recruited between June 1984 and October 1986.
Total randomized: 144 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 73 were randomized 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.

Interventions

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

Outcomes

Primary: 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.

Notes

Because 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

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Low risk

A ‐ Adequate
Wilder 1986

Methods

Randomized 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 ug/ml. Median dosage in this group was 400 mg/day (range 200 to 600 mg/day).
Randomization 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.

Participants

Conducted at 4 US centres between August 1983 and July 1986.
Total randomized: 152 participants, all with 4 or more partial seizures/month while taking 1 or 2 AEDs. 78 were randomized 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.

Interventions

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

Outcomes

Primary: 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.

Notes

Because 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

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Low risk

A ‐ Adequate

AED: antiepileptic drug

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Anderson 1988

This trial did not compare zonisamide with placebo. The comparison was with valproate.

Data and analyses

Open in table viewer
Comparison 1. Zonisamide versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 50% responder rate ‐ post‐titration Show forest plot

4

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.1
Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate ‐ post‐titration.

Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate ‐ post‐titration.

1.1 Any dose

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

1.98 [1.51, 2.59]

1.2 300 ‐ 500 mg zonisamide

4

793

Risk Ratio (M‐H, Fixed, 95% CI)

2.04 [1.55, 2.67]

2 50% responder rate ‐ whole treatment period Show forest plot

4

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.2
Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate ‐ whole treatment period.

Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate ‐ whole treatment period.

2.1 Any dose

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

2.35 [1.74, 3.17]

2.2 300 ‐ 500 mg zonisamide

4

793

Risk Ratio (M‐H, Fixed, 95% CI)

2.44 [1.81, 3.30]

3 50% responder rate ‐ best case Show forest plot

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

2.57 [1.99, 3.31]
Analysis 1.3
Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate ‐ best case.

Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate ‐ best case.

4 50% responder rate ‐ worst case Show forest plot

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

1.43 [1.14, 1.81]
Analysis 1.4
Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate ‐ worst case.

Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate ‐ worst case.

5 50% responder rate ‐ dose effect Brodie 2005 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 Brodie 2005.

Comparison 1 Zonisamide versus placebo, Outcome 5 50% responder rate ‐ dose effect Brodie 2005.

5.1 100 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 300 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 500 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6 50% responder rate ‐ dose effect Faught 2001 Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Analysis 1.6
Comparison 1 Zonisamide versus placebo, Outcome 6 50% responder rate ‐ dose effect Faught 2001.

Comparison 1 Zonisamide versus placebo, Outcome 6 50% responder rate ‐ dose effect Faught 2001.

6.1 100 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 200 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 400 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Withdrawal rates Show forest plot

4

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.7
Comparison 1 Zonisamide versus placebo, Outcome 7 Withdrawal rates.

Comparison 1 Zonisamide versus placebo, Outcome 7 Withdrawal rates.

7.1 Any dose

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

1.47 [1.07, 2.02]

7.2 300 ‐ 500 mg zonisamide

4

793

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.20, 2.26]

8 Adverse events Show forest plot

4

Risk Ratio (M‐H, Fixed, 99% CI)

Subtotals only
Analysis 1.8
Comparison 1 Zonisamide versus placebo, Outcome 8 Adverse events.

Comparison 1 Zonisamide versus placebo, Outcome 8 Adverse events.

8.1 Ataxia

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

4.50 [1.05, 19.22]

8.2 Dizziness

4

850

Risk Ratio (M‐H, Fixed, 99% CI)

1.77 [1.00, 3.12]

8.3 Nausea

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

1.50 [0.69, 3.28]

8.4 Fatigue

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

1.32 [0.69, 2.50]

8.5 Somnolence

4

850

Risk Ratio (M‐H, Fixed, 99% CI)

1.96 [1.12, 3.44]

8.6 Agitation/irritability

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

2.37 [1.00, 5.64]

8.7 Anorexia

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

3.00 [1.31, 6.88]

Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate ‐ post‐titration.
Figuras y tablas -
Analysis 1.1

Comparison 1 Zonisamide versus placebo, Outcome 1 50% responder rate ‐ post‐titration.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate ‐ whole treatment period.
Figuras y tablas -
Analysis 1.2

Comparison 1 Zonisamide versus placebo, Outcome 2 50% responder rate ‐ whole treatment period.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate ‐ best case.
Figuras y tablas -
Analysis 1.3

Comparison 1 Zonisamide versus placebo, Outcome 3 50% responder rate ‐ best case.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate ‐ worst case.
Figuras y tablas -
Analysis 1.4

Comparison 1 Zonisamide versus placebo, Outcome 4 50% responder rate ‐ worst case.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 5 50% responder rate ‐ dose effect Brodie 2005.
Figuras y tablas -
Analysis 1.5

Comparison 1 Zonisamide versus placebo, Outcome 5 50% responder rate ‐ dose effect Brodie 2005.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 6 50% responder rate ‐ dose effect Faught 2001.
Figuras y tablas -
Analysis 1.6

Comparison 1 Zonisamide versus placebo, Outcome 6 50% responder rate ‐ dose effect Faught 2001.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 7 Withdrawal rates.
Figuras y tablas -
Analysis 1.7

Comparison 1 Zonisamide versus placebo, Outcome 7 Withdrawal rates.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Zonisamide versus placebo, Outcome 8 Adverse events.
Figuras y tablas -
Analysis 1.8

Comparison 1 Zonisamide versus placebo, Outcome 8 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva
Comparison 1. Zonisamide versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 50% responder rate ‐ post‐titration Show forest plot

4

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Any dose

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

1.98 [1.51, 2.59]

1.2 300 ‐ 500 mg zonisamide

4

793

Risk Ratio (M‐H, Fixed, 95% CI)

2.04 [1.55, 2.67]

2 50% responder rate ‐ whole treatment period Show forest plot

4

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Any dose

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

2.35 [1.74, 3.17]

2.2 300 ‐ 500 mg zonisamide

4

793

Risk Ratio (M‐H, Fixed, 95% CI)

2.44 [1.81, 3.30]

3 50% responder rate ‐ best case Show forest plot

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

2.57 [1.99, 3.31]

4 50% responder rate ‐ worst case Show forest plot

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

1.43 [1.14, 1.81]

5 50% responder rate ‐ dose effect Brodie 2005 Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.1 100 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 300 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 500 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6 50% responder rate ‐ dose effect Faught 2001 Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

6.1 100 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 200 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.3 400 mg per day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Withdrawal rates Show forest plot

4

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.1 Any dose

4

850

Risk Ratio (M‐H, Fixed, 95% CI)

1.47 [1.07, 2.02]

7.2 300 ‐ 500 mg zonisamide

4

793

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.20, 2.26]

8 Adverse events Show forest plot

4

Risk Ratio (M‐H, Fixed, 99% CI)

Subtotals only

8.1 Ataxia

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

4.50 [1.05, 19.22]

8.2 Dizziness

4

850

Risk Ratio (M‐H, Fixed, 99% CI)

1.77 [1.00, 3.12]

8.3 Nausea

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

1.50 [0.69, 3.28]

8.4 Fatigue

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

1.32 [0.69, 2.50]

8.5 Somnolence

4

850

Risk Ratio (M‐H, Fixed, 99% CI)

1.96 [1.12, 3.44]

8.6 Agitation/irritability

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

2.37 [1.00, 5.64]

8.7 Anorexia

3

499

Risk Ratio (M‐H, Fixed, 99% CI)

3.00 [1.31, 6.88]
Figuras y tablas -
Comparison 1. Zonisamide versus placebo
Ir a la tabla de la revisión