Sulthiame as add-on therapy for epilepsy

Review question

A team of Cochrane researchers investigated how well sulthiame worked when it was used as an add-on antiepileptic medicine (medicines that reduce seizures) in people with any type of epilepsy.

Background

Epilepsy is a common neurological (brain) condition that is characterised by repeated seizures. Most people respond well to conventional antiepileptic medicines, however, about 30% continue to have seizures. These people are said to have drug-resistant epilepsy.

Sulthiame is an antiepileptic drug that is used widely in some European countries and in Israel. Sometimes it is used as an additional (add-on) antiepileptic medicine for people with epilepsy, alongside an existing antiepileptic medicine.

Main results

Randomised controlled trials produce the most reliable evidence for medicines. The team searched the medical literature for randomised controlled trials that compared sulthiame as an add-on therapy to add-on placebo (an inactive, dummy drug), or another antiepileptic medicine.

The researchers found one relevant trial that included 37 infants, aged from three to 15 months, who had a diagnosis of West syndrome, a type of epilepsy. This trial was funded by DESITIN Pharma (Germany). All infants were started on an antiepileptic medicine, pyridoxine, three days before they added sulthiame or placebo. The infants' parents did not know which add-on therapy their children received. The trial lasted for nine days.

Very uncertain evidence from the trial suggests that sulthiame may stop seizures in people with West syndrome whose seizures do not stop with pyridoxine. Thirty per cent more infants had their seizures stop when they received add-on sulthiame (6/20 participants) compared to add-on placebo (0/17 participants). This difference was not statistically significant, mainly because there were so few infants included in the trial.

The same number of infants experienced one or more adverse effects in both groups (9 in each). More infants experienced somnolence (drowsiness) when they received add-on sulthiame (4/20), compared to those who received add-on placebo (1/17), but again, this was not statistically significant.

The small number of infants in the trial, and its short duration, means that we are not confident that the results are reliable.

Further randomised controlled trials are required before meaningful conclusions can be drawn about how well sulthiame works as an add-on therapy in West syndrome and other types of epilepsy, and to establish whether it produces any serious unwanted or harmful effects.

The evidence is current to January 2019.

Authors' conclusions: 

Sulthiame may lead to a cessation of seizures when used as an add-on therapy to pyridoxine in infants with West syndrome, however, we are very uncertain about the reliability of this finding. The included study was small and had a significant risk of bias, largely due to the lack of details regarding blinding and the incomplete reporting of outcomes. Both issues negatively impacted the certainty of the evidence. No conclusions can be drawn about the occurrence of adverse effects, change in quality of life, or mean reduction in seizure frequency. No evidence exists for the use of sulthiame as an add-on therapy in people with epilepsy outside West syndrome.

Large, multi-centre randomised controlled trials are needed to inform clinical practice, if sulthiame is to be used as an add-on therapy for epilepsy.

Read the full abstract...
Background: 

This is an updated version of the Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2015, Issue 10. Epilepsy is a common neurological condition, characterised by recurrent seizures. Most people respond to conventional antiepileptic drugs, however, around 30% will continue to experience seizures, despite treatment with multiple antiepileptic drugs. Sulthiame, also known as sultiame, is a widely used antiepileptic drug in Europe and Israel. We present a summary of the evidence for the use of sulthiame as add-on therapy in epilepsy.

Objectives: 

To assess the efficacy and tolerability of sulthiame as add-on therapy for people with epilepsy of any aetiology compared with placebo or another antiepileptic drug.

Search strategy: 

For the latest update, we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and CENTRAL (17 January 2019), MEDLINE Ovid (1946 to January 16, 2019), ClinicalTrials.gov and the WHO ICTRP Search Portal (17 January 2019). We imposed no language restrictions. We contacted the manufacturers of sulthiame, and researchers in the field to seek any ongoing or unpublished studies.

Selection criteria: 

Randomised controlled trials of add-on sulthiame, with any level of blinding (single, double or unblinded) in people of any age, with epilepsy of any aetiology.

Data collection and analysis: 

Two review authors independently selected trials for inclusion, and extracted relevant data. We assessed these outcomes: (1) 50% or greater reduction in seizure frequency between baseline and end of follow-up; (2) complete cessation of seizures during follow-up; (3) mean seizure frequency; (4) time-to-treatment withdrawal; (5) adverse effects; and (6) quality of life. We used intention-to-treat for primary analyses. We presented results as risk ratios (RR) with 95% confidence intervals (CIs). However, due to the paucity of trials, we mainly conducted a narrative analysis.

Main results: 

We included one placebo-controlled trial that recruited 37 infants with newly diagnosed West syndrome. This trial was funded by DESITIN Pharma, Germany. During the study, sulthiame was given as an add-on therapy to pyridoxine. No data were reported for the outcomes: 50% or greater reduction in seizure frequency between baseline and end of follow-up; mean seizure frequency; or quality of life. For complete cessation of seizures during a nine-day follow-up period for add-on sulthiame versus placebo, the RR was 11.14 (95% CI 0.67 to 184.47; very low-certainty evidence), however, this difference was not shown to be statistically significant (P = 0.09). The number of infants experiencing one or more adverse events was not significantly different between the two treatment groups (RR 0.85, 95% CI 0.44 to 1.64; very low-certainty evidence; P = 0.63). Somnolence was more prevalent amongst infants randomised to add-on sulthiame compared to placebo, but again, the difference was not statistically significant (RR 3.40, 95% CI 0.42 to 27.59; very low-certainty evidence; P = 0.25). We were unable to conduct meaningful analysis of time-to-treatment withdrawal and adverse effects due to incomplete data.

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