Losigamone add‐on therapy for partial epilepsy

Yousheng Xiao; Man Luo; Jin Wang; Hongye Luo

doi:10.1002/14651858.CD009324.pub3

Losigamone add‐on therapy for partial epilepsy

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References

References to studies included in this review

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excluded studies
additional references
other published versions

Bauer J, Dienel A, Elger CE, Losigamone Study Group. Losigamone add‐on therapy in partial epilepsy: a placebo‐controlled study. Acta Neurologica Scandinavica 2001;103(4):226‐30.

Baulac M, Klement S, Losigamone Study Group. Efficacy and safety of losigamone in partial seizures: a randomized double‐blind study. Epilepsy Research 2003;55(3):177‐89.

References to studies excluded from this review

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included studies
additional references
other published versions

Morris III GL, Collins S, Bell W, Sahlroot JT, Matula M, Cereghino JJ. Losigamone a putative antiepileptic drug. Journal of Epilepsy 1997;10(2):62‐6.

Runge U, Rabending G, Röder H, Dienel A. Losigamone: first results in patients with drug resistant focal epilepsy (abstract). Epilepsia 1993;34(Suppl 2):6.

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Stefan H, Wang Y, Kerling F, Hopp P, Zhou D, Dienel A, et al. Therapeutic intensive seizure analysis (TISA) in presurgical evaluation of losigamone. Acta Neurologica Scandinavica 2001;104(4):195‐201.

Additional references

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excluded studies
other published versions

Banerjee PN, Filippi D, Hauser WA. The descriptive epidemiology of epilepsy ‐ a review. Epilepsy Research 2009;85(1):31‐45.

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005‐2009. Epilepsia 2010;51(4):676‐85.

De Boer HM, Mula M, Sander JW. The global burden and stigma of epilepsy. Epilepsy & Behavior 2008;12(4):540‐6.

Devinsky O. Patients with refractory seizures. New England Journal of Medicine 1999;340(20):1565‐70.

Dimpfel W, Chatterjee SS, Nöldner M, Ticku MK. Effects of the anticonvulsant losigamone and its isomers on the GABAA receptor system. Epilepsia 1995;36(10):983‐9.

Draguhn A, Jungclaus M, Sokolowa S, Heinemann U. Losigamone decreases spontaneous synaptic activity in cultured hippocampal neurons. European Journal of Pharmacology 1997;325(2‐3):245‐51.

Gebhardt C, Breustedt JM, Nöldner M, Chatterjee SS, Heinemann U. The antiepileptic drug losigamone decreases the persistent Na+ current in rat hippocampal neurons. Brain Research 2001;920(1‐2):27‐31.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Hong Z, Qu B, Wu XT, Yang TH, Zhang Q, Zhou D. Economic burden of epilepsy in a developing country: a retrospective cost analysis in China. Epilepsia 2009;50(10):2192‐8.

Hopewell S, Loudon K, Clarke MJ, Oxman AD, Dickersin K. Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.MR000006.pub3]

Kotsopoulos IA, van Merode T, Kessels FG, de Krom MC, Knottnerus JA. Systematic review and meta‐analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia 2002;43(11):1402‐9.

Kwan P, Arzimanoglou A, Berg A, Brodie M, Hauser WA, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069‐77.

Lefebvre C, Manheimer E, Glanville J . Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Luszczki JJ. Third‐generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacological Reports 2009;61(2):197‐216.

Pugliatti M, Beghi E, Forsgren L, Ekman M, Sobocki P. Estimating the cost of epilepsy in Europe: a review with economic modeling. Epilepsia 2007;48(12):2224‐33.

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Schuele SU, Luders HO. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurology 2008;7(6):514‐24.

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12.

World Health Organization. Public health principles and neurological disorders. www.who.int/mental_health/neurology/neurodiso/en/index.html) (accessed 23 April 2012).

Uppsala Monitoring Centre. WHO Adverse Reaction Terminology. Available from: http://www.umc‐products.com/DynPage.aspx?id=73589&mn1=1107&mn2=1664 (accessed most recently on 16 February 2015).

Willmore LJ. Losigamone. Dr Willmar Schwabe. Current Opinion In Investigational Drugs 2001;2(12):1763‐6.

References to other published versions of this review

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included studies
excluded studies
additional references

Xiao Y, Luo M, Wang J, Luo H. Losigamone add‐on therapy for partial epilepsy. Cochrane Database of Systematic Reviews 2011, Issue 9. [DOI: 10.1002/14651858.CD009324]

Xiao Y, Luo M, Wang J, Luo H. Losigamone add‐on therapy for partial epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 6. [DOI: 10.1002/14651858.CD009324.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies

Bauer 2001

Methods	Double‐blind, placebo‐controlled, add‐on study Random allocation of patients was mentioned in the original article but without details; allocation concealment was not mentioned. We could not obtain additional information after correspondence with the authors ITT analysis: yes
Participants	Setting: Germany 203 patients with partial epilepsy and had a stable co‐medication with no more than 3 AEDs Losigamone: 99 patients; F/M: 38/61; aged: 18 to 63 years; mean age: 36.1 years; disease duration: 23.5 years; mean seizure frequency: 8.77 seizures/28 days; number of other AEDs: 1 (28.7%), 2 (48.9%) or 3 (22.3%) Placebo: 104 patients; F/M: 46/58; aged: 19 to 74 years; mean age: 35.2 years; disease duration: 22.0 years; mean seizure frequency: 9.33 seizures/28 days; number of other AEDs: 1 (24.3%), 2 (55.3%) or 3 (20.4%) The baseline clinical characteristics were comparable between the 2 groups
Interventions	The study lasted for 16 weeks and consisted of an 8‐week baseline phase and an 8‐week double‐blind treatment phase Losigamone: administered 750 mg/day in the first 2 days after randomization and then maintained at 1500 mg/day from the third day during double‐blind treatment phase Placebo: during double‐blind treatment phase
Outcomes	Change in seizure frequency 50% or greater reduction in seizure frequency Adverse events
Notes	Of the 203 ITT population, 171 completed the study; 21 patients dropped out in the losigamone‐treated group, and 11 dropped out in the placebo group. The reasons for dropouts have been carefully recorded, adverse events were the main reason The study was sponsored by Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No description
Allocation concealment (selection bias)	Unclear risk	No description
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double blinded, but no additional information has been provided
Incomplete outcome data (attrition bias) All outcomes	High risk	The number of and the reasons for withdrawals were carefully reported but seem unbalanced across groups, the percentage of dropouts was 21.2% (21/99) in the losigamone group and 10.6% (11/104) in the placebo group; we classified the trial at a high risk of incomplete outcome data bias
Selective reporting (reporting bias)	Low risk	Favorable and unfavorable results were reported
Other bias	Low risk	Not identified

Baulac 2003

Methods	Multicenter, randomized, double‐blind, placebo‐controlled, add‐on study Random list generated using a random number generator‐based blocking method by a third party, who was not involved in the assignment, besides, all data collected were entered to a specified database that was not exposed until the study was finished Double blinded: the intervention drug and placebo were provided with identical appearance, shape, smell and taste ITT analysis: yes
Participants	264 patients aged 18 to 65 years with partial epilepsy who also had 1 to 3 AEDs Losigamone 1200 mg/day: 87 patients; F/M: 40/47; number of other AEDs: 1 (25.3%), 2 (55.2%) or 3 (19.5%) Losigamone 1500 mg/day: 92 patients; F/M: 29/63; number of other AEDs: 1 (29.3%), 2 (48.9%) or 3 (21.8%) Placebo: 85 patients; F/M: 39/46; number of other AEDs: 1 (23.5%), 2 (53.0%) or 3 (23.5%) The mean age of the study population was 35.7 years, the mean duration of the disease was 21 years and the mean seizure frequency per month before randomization was 9.2 seizures The baseline clinical characteristics were comparable across groups
Interventions	The study lasted for 28 weeks and consisted of a 12‐week baseline period, a 12‐week double‐blind treatment phase and a 4‐week post‐treatment period for safety observations Group 1: losigamone 1200 mg/day add‐on treatment during double‐blind treatment phase Group 2: losigamone 1500 mg/day add‐on treatment during double‐blind treatment phase Group 3: placebo during double‐blind treatment phase
Outcomes	The per cent reduction in seizure frequency 50% or greater reduction in seizure frequency Adverse events
Notes	Of the 264 ITT population, 228 patients completed the study, 11 were withdrawn in losigamone 1200 mg/day group, 19 in losigamone 1500 mg/day group, 6 in placebo group, while 28 (77.8%) of the withdrawals were due to adverse events The number of patients dropped out due to adverse events in the losigamone 1200 mg/day, 1500 mg/day and placebo groups were 10, 15 and 3, respectively The study was sponsored by Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random list generated using random permuted blocks
Allocation concealment (selection bias)	Low risk	Allocation sequence was conducted by a third party
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double blinded, but no additional information has been provided
Incomplete outcome data (attrition bias) All outcomes	High risk	The number of and the reasons for withdrawals were carefully reported but seems unbalanced across groups; the percentage of dropouts in losigamone 1200 mg/day was 12.6% (11/87), losigamone 1500 mg/day was 20.7% (19/92) and 7.1% (6/85) in the placebo group; we classified the trial at a high risk of incomplete outcome data bias
Selective reporting (reporting bias)	Low risk	Favorable and unfavorable results were reported
Other bias	Low risk	Not identified

AEDs: antiepileptic drugs
F/M: female/male
ITT: intention‐to‐treat

Characteristics of excluded studies [ordered by study ID]

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included studies

Study	Reason for exclusion
Morris 1997	A preliminary observational study without a control group
Runge 1993	Open‐label study without a control group
Stefan 2001	A randomized controlled trial assessed losigamone monotherapy in 16 patients with pharmacoresistant partial seizures undergoing presurgical evaluation

Data and analyses

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Comparison 1. Losigamone versus placebo: 50% or greater reduction in seizure frequency

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All doses Show forest plot	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.14, 2.72]
Open in figure viewer Analysis 1.1 Comparison 1 Losigamone versus placebo: 50% or greater reduction in seizure frequency, Outcome 1 All doses.
2 1500 mg/day Show forest plot	2	380	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.25, 3.01]
Open in figure viewer Analysis 1.2 Comparison 1 Losigamone versus placebo: 50% or greater reduction in seizure frequency, Outcome 2 1500 mg/day.
3 1200 mg/day Show forest plot	1	172	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.70, 3.08]
Open in figure viewer Analysis 1.3 Comparison 1 Losigamone versus placebo: 50% or greater reduction in seizure frequency, Outcome 3 1200 mg/day.

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Comparison 2. Losigamone versus placebo: treatment withdrawal

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All doses Show forest plot	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	2.16 [1.28, 3.67]
Open in figure viewer Analysis 2.1 Comparison 2 Losigamone versus placebo: treatment withdrawal, Outcome 1 All doses.
2 1500 mg/day Show forest plot	2	380	Risk Ratio (M‐H, Fixed, 95% CI)	2.34 [1.38, 3.99]
Open in figure viewer Analysis 2.2 Comparison 2 Losigamone versus placebo: treatment withdrawal, Outcome 2 1500 mg/day.
3 1200 mg/day Show forest plot	1	172	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [0.69, 4.63]
Open in figure viewer Analysis 2.3 Comparison 2 Losigamone versus placebo: treatment withdrawal, Outcome 3 1200 mg/day.

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Comparison 3. Losigamone versus placebo: adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 The proportion of participants experiencing any adverse events (random model) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 3.1 Comparison 3 Losigamone versus placebo: adverse events, Outcome 1 The proportion of participants experiencing any adverse events (random model).
1.1 All doses	2	467	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.00, 1.80]
1.2 1200 mg/day	1	172	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.83, 1.34]
1.3 1500 mg/day	2	380	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.14, 1.71]
2 The proportion of participants experiencing any adverse events (fixed model) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 3.2 Comparison 3 Losigamone versus placebo: adverse events, Outcome 2 The proportion of participants experiencing any adverse events (fixed model).
2.1 All doses	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
3 Dizziness Show forest plot	2		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.3 Comparison 3 Losigamone versus placebo: adverse events, Outcome 3 Dizziness.
3.1 All doses	2	467	Risk Ratio (M‐H, Fixed, 99% CI)	3.82 [1.69, 8.64]
3.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	5.37 [0.77, 37.42]
3.3 1500 mg/day	2	380	Risk Ratio (M‐H, Fixed, 99% CI)	3.96 [1.79, 8.76]
4 Headache Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.4 Comparison 3 Losigamone versus placebo: adverse events, Outcome 4 Headache.
4.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	1.19 [0.43, 3.30]
4.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	0.85 [0.24, 3.06]
4.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	1.50 [0.50, 4.47]
5 Somnolence Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.5 Comparison 3 Losigamone versus placebo: adverse events, Outcome 5 Somnolence.
5.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.26 [0.57, 8.93]
5.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	1.71 [0.36, 8.19]
5.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	2.77 [0.66, 11.65]
6 Fatigue Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.6 Comparison 3 Losigamone versus placebo: adverse events, Outcome 6 Fatigue.
6.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.26 [0.57, 8.93]
6.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	1.71 [0.36, 8.19]
6.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	2.77 [0.66, 11.65]
7 Ataxia Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.7 Comparison 3 Losigamone versus placebo: adverse events, Outcome 7 Ataxia.
7.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	10.03 [0.24, 411.20]
7.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	10.75 [0.24, 473.22]
7.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	10.17 [0.23, 448.02]
8 Nausea Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.8 Comparison 3 Losigamone versus placebo: adverse events, Outcome 8 Nausea.
8.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	0.85 [0.21, 3.45]
8.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	0.39 [0.05, 3.25]
8.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	1.29 [0.30, 5.56]
9 Diplopia Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.9 Comparison 3 Losigamone versus placebo: adverse events, Outcome 9 Diplopia.
9.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.85 [0.59, 13.70]
9.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	2.28 [0.40, 12.90]
9.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	3.39 [0.66, 17.33]
10 Abnormal vision Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.10 Comparison 3 Losigamone versus placebo: adverse events, Outcome 10 Abnormal vision.
10.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.37 [0.48, 11.68]
10.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	1.63 [0.26, 10.25]
11 Vertigo Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.11 Comparison 3 Losigamone versus placebo: adverse events, Outcome 11 Vertigo.
11.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	6.17 [0.44, 87.50]
11.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	5.86 [0.37, 92.10]
11.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	6.47 [0.42, 98.79]
12 Depression Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 3.12 Comparison 3 Losigamone versus placebo: adverse events, Outcome 12 Depression.
12.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.09, 4.40]
12.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	0.98 [0.12, 7.71]
12.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	0.92 [0.12, 7.30]

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Losigamone versus placebo: 50% or greater reduction in seizure frequency, Outcome 1 All doses.

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Analysis 1.2

Comparison 1 Losigamone versus placebo: 50% or greater reduction in seizure frequency, Outcome 2 1500 mg/day.

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Analysis 1.3

Comparison 1 Losigamone versus placebo: 50% or greater reduction in seizure frequency, Outcome 3 1200 mg/day.

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Analysis 2.1

Comparison 2 Losigamone versus placebo: treatment withdrawal, Outcome 1 All doses.

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Analysis 2.2

Comparison 2 Losigamone versus placebo: treatment withdrawal, Outcome 2 1500 mg/day.

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Analysis 2.3

Comparison 2 Losigamone versus placebo: treatment withdrawal, Outcome 3 1200 mg/day.

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Analysis 3.1

Comparison 3 Losigamone versus placebo: adverse events, Outcome 1 The proportion of participants experiencing any adverse events (random model).

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Analysis 3.2

Comparison 3 Losigamone versus placebo: adverse events, Outcome 2 The proportion of participants experiencing any adverse events (fixed model).

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Analysis 3.3

Comparison 3 Losigamone versus placebo: adverse events, Outcome 3 Dizziness.

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Analysis 3.4

Comparison 3 Losigamone versus placebo: adverse events, Outcome 4 Headache.

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Analysis 3.5

Comparison 3 Losigamone versus placebo: adverse events, Outcome 5 Somnolence.

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Analysis 3.6

Comparison 3 Losigamone versus placebo: adverse events, Outcome 6 Fatigue.

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Analysis 3.7

Comparison 3 Losigamone versus placebo: adverse events, Outcome 7 Ataxia.

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Analysis 3.8

Comparison 3 Losigamone versus placebo: adverse events, Outcome 8 Nausea.

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Analysis 3.9

Comparison 3 Losigamone versus placebo: adverse events, Outcome 9 Diplopia.

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Analysis 3.10

Comparison 3 Losigamone versus placebo: adverse events, Outcome 10 Abnormal vision.

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Analysis 3.11

Comparison 3 Losigamone versus placebo: adverse events, Outcome 11 Vertigo.

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Analysis 3.12

Comparison 3 Losigamone versus placebo: adverse events, Outcome 12 Depression.

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Summary of findings for the main comparison. Losigamone compared to placebo for partial epilepsy

Losigamone compared to placebo for partial epilepsy
Patient or population: partial epilepsy Settings: multicenter Intervention: losigamone Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Losigamone
50% or greater reduction in seizure frequency Follow‐up: mean 8 to 12 weeks	Study population		RR 1.76 (1.14 to 2.72)	467 (2 studies)	⊕⊕⊕⊝ moderate¹
	132 per 1000	233 per 1000 (151 to 360)
	Moderate
	131 per 1000	231 per 1000 (149 to 356)
Treatment withdrawal Follow‐up: mean 8 to 12 weeks	Study population		RR 2.16 (1.28 to 3.67)	467 (2 studies)	⊕⊕⊕⊝ moderate¹
	90 per 1000	194 per 1000 (115 to 330)
	Moderate
	88 per 1000	190 per 1000 (113 to 323)
The proportion of participants experiencing any adverse events Follow‐up: mean 8 to 12 weeks	Study population		RR 1.34 (1.00 to 1.80)	467 (2 studies)	⊕⊕⊕⊝ moderate¹
	471 per 1000	631 per 1000 (471 to 848)
	Moderate
	482 per 1000	646 per 1000 (482 to 868)
Adverse event (dizziness) Follow‐up: mean 8 to 12 weeks	Study population		RR 3.82 (1.69 to 8.64)	467 (2 studies)	⊕⊕⊕⊝ moderate¹
	63 per 1000	243 per 1000 (107 to 549)
	Moderate
	60 per 1000	229 per 1000 (101 to 518)
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.
¹ One of the two included trials did not describe the method used to generate the random list and did not mention allocation concealment

Summary of findings for the main comparison. Losigamone compared to placebo for partial epilepsy

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Table 1. Outcome reporting matrix

Study ID (author, date of publication)	Review's primary outcomes		Review's secondary outcomes		Other study outcomes
Study ID (author, date of publication)	50% or greater reduction in seizure frequency	Seizure freedom	Treatment withdrawal	Adverse events	Change in seizure frequency	The percentage reduction in seizure frequency
Bauer 2001	√	×	√	√	√	×
Baulac 2003	√	×	√	√	×	√
√Full reporting of outcomes for treatment comparison × No reporting of outcomes for treatment comparison

Table 1. Outcome reporting matrix

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Comparison 1. Losigamone versus placebo: 50% or greater reduction in seizure frequency

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All doses Show forest plot	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.14, 2.72]

2 1500 mg/day Show forest plot	2	380	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.25, 3.01]

3 1200 mg/day Show forest plot	1	172	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.70, 3.08]

Comparison 1. Losigamone versus placebo: 50% or greater reduction in seizure frequency

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Comparison 2. Losigamone versus placebo: treatment withdrawal

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All doses Show forest plot	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	2.16 [1.28, 3.67]

2 1500 mg/day Show forest plot	2	380	Risk Ratio (M‐H, Fixed, 95% CI)	2.34 [1.38, 3.99]

3 1200 mg/day Show forest plot	1	172	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [0.69, 4.63]

Comparison 2. Losigamone versus placebo: treatment withdrawal

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Comparison 3. Losigamone versus placebo: adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 The proportion of participants experiencing any adverse events (random model) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 All doses	2	467	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.00, 1.80]
1.2 1200 mg/day	1	172	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.83, 1.34]
1.3 1500 mg/day	2	380	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.14, 1.71]
2 The proportion of participants experiencing any adverse events (fixed model) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 All doses	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
3 Dizziness Show forest plot	2		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

3.1 All doses	2	467	Risk Ratio (M‐H, Fixed, 99% CI)	3.82 [1.69, 8.64]
3.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	5.37 [0.77, 37.42]
3.3 1500 mg/day	2	380	Risk Ratio (M‐H, Fixed, 99% CI)	3.96 [1.79, 8.76]
4 Headache Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

4.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	1.19 [0.43, 3.30]
4.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	0.85 [0.24, 3.06]
4.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	1.50 [0.50, 4.47]
5 Somnolence Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

5.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.26 [0.57, 8.93]
5.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	1.71 [0.36, 8.19]
5.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	2.77 [0.66, 11.65]
6 Fatigue Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

6.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.26 [0.57, 8.93]
6.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	1.71 [0.36, 8.19]
6.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	2.77 [0.66, 11.65]
7 Ataxia Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

7.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	10.03 [0.24, 411.20]
7.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	10.75 [0.24, 473.22]
7.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	10.17 [0.23, 448.02]
8 Nausea Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

8.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	0.85 [0.21, 3.45]
8.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	0.39 [0.05, 3.25]
8.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	1.29 [0.30, 5.56]
9 Diplopia Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

9.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.85 [0.59, 13.70]
9.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	2.28 [0.40, 12.90]
9.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	3.39 [0.66, 17.33]
10 Abnormal vision Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

10.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	2.37 [0.48, 11.68]
10.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	1.63 [0.26, 10.25]
11 Vertigo Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

11.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	6.17 [0.44, 87.50]
11.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	5.86 [0.37, 92.10]
11.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	6.47 [0.42, 98.79]
12 Depression Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

12.1 All doses	1	264	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.09, 4.40]
12.2 1200 mg/day	1	172	Risk Ratio (M‐H, Fixed, 99% CI)	0.98 [0.12, 7.71]
12.3 1500 mg/day	1	177	Risk Ratio (M‐H, Fixed, 99% CI)	0.92 [0.12, 7.30]

Comparison 3. Losigamone versus placebo: adverse events

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References

References to studies included in this review

Bauer 2001 {published data only}

Baulac 2003 {published data only}

References to studies excluded from this review

Morris 1997 {published data only}

Runge 1993 {published data only}

Stefan 2001 {published data only}

Additional references

Banerjee 2009

Berg 2010

De Boer 2008

Devinsky 1999

Dimpfel 1995

Draguhn 1997

Gebhardt 2001

Higgins 2011

Hong 2009

Hopewell 2009

Kotsopoulos 2002

Kwan 2010

Lefebvre 2011

Luszczki 2009

Pugliatti 2007

RevMan 2012 [Computer program]

Schuele 2008

Schulz 1995

WHO 2006

WHO‐ART

Willmore 2001

References to other published versions of this review

Xiao 2011

Xiao 2012

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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