Description of the condition
Epilepsy is one of the more common chronic neurological disorders, affecting 1% of the population worldwide.
A large proportion of these patients (up to 30%) continue to have seizures despite adequate therapy with antiepileptic drugs (AEDs) used singularly or in combination (Cockerell 1995; Granata 2009). These individuals are regarded as having refractory epilepsy. Although there is no unifying definition of refractory epilepsy, most definitions refer to continued seizures despite AED treatment, and the generally employed definition is of continued seizures despite interminable medication changes (French 2006).
Various criteria have been used to define refractory epilepsy. In 2010 an internationally accepted definition of refractory epilepsy was proposed by a Task Force of the International League Against Epilepsy (ILAE), as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan 2010). Standard drugs (for example carbamazepine, phenytoin, valproate) do not control all patients’ seizures. However, over the past 15 to 20 years numerous new AEDs with a promising role in the treatment of refractory epilepsy have become available.
Seizures may occur in, and rapidly engage, bilaterally distributed networks (generalized seizures) or within networks limited to one hemisphere and either discretely localized or more widely distributed (focal seizures) (Berg 2010).
In this review we aimed to investigate the efficacy and tolerability of add-on stiripentol in people with focal refractory epilepsy.
Description of the intervention
Stiripentol is a new AED developed in France and was recently approved by the European Medicines Agency (EMEA) for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam, with a promising effect (Chiron 2007).
The safety profile of stiripentol is good with most adverse events being related to a significant increase in the plasma concentration of valproate and clobazam after the addition of stiripentol (Perez 1999). They include drowsiness, ataxia, nausea, abdominal pain, and loss of appetite with weight loss. Asymptomatic neutropenia is also occasionally observed (Chiron 2007).
How the intervention might work
Stiripentol is structurally unrelated to any other marketed AED. A gamma-aminobutyric acid (GABA)ergic effect of stiripentol has been demonstrated in vitro (Quilichini 2006) and is probably due to an allosteric modulation of the GABA-A receptor (Fisher 2009). The efficacy of stiripentol could therefore be secondary to a potentiation of GABAergic inhibitory neurotransmission (Quilichini 2006) and enhancement of the action of benzodiazepines (Fisher 2009). In humans, stiripentol also inhibits the cytochrome P450 enzymes (CYP) in the liver, resulting in an increased plasma concentration of concomitant AEDs metabolized by CYP (Chiron 2005). In patients affected by Severe Myoclonic Epilepsy in Infancy (SMEI), such a pharmacokinetic interaction particularly applies to clobazam (Giraud 2006).
Why it is important to do this review
To date, there have been no studies that have systematically reviewed the literature on the role of stiripentol as a treatment for focal refractory epilepsy, thus evaluating its use in conditions other than SMEI.
In this systematic review, we therefore aimed to assess and summarize the existing evidence regarding the efficacy and adverse effects of stiripentol as add-on treatment for people with focal refractory epilepsy.
To evaluate the efficacy and tolerability of stiripentol as add-on treatment for patients with focal refractory epilepsy taking any AEDs.
Criteria for considering studies for this review
Types of studies
We included studies meeting the following criteria:
- randomised controlled trials (RCTs);
- double, single or unblinded trials.
We decided to include only the above types of studies as they are considered the most effective means to evaluate the benefits and risks of treatments (Strauss 2005).
We excluded all other study designs, including cohort studies, cross-over studies, case-control studies, outcomes research, case studies, case series and expert opinion.
We analysed different treatment groups and controls separately.
No language restrictions were applied.
Types of participants
We considered people with focal epilepsy defined according to the ILAE criteria (International League Against Epilepsy 1989). We considered patients regardless of age, sex and ethnicity, including children with disabilities. As there is no internationally accepted definition of refractory epilepsy, for the purpose of this review we included any trial assessing stiripentol in refractory epilepsy however it was defined, but making note of what definition was used. If possible, based on rough data, we considered individuals to be affected by refractory epilepsy according to Kwan 2010. Patients affected by SMEI were excluded since another systematic review of ours (Antiepileptic drugs for the treatment of severe myoclonic epilepsy in infancy (Brigo 2013), protocol published in April 2013) will specifically assess the role of stiripentol in such a genetically determined disease.
Types of interventions
- The active treatment group received stiripentol in addition to their conventional AED treatment.
- The control group received no treatment, matching add-on placebo or another AED (used as a comparator).
Types of outcome measures
For each outcome, an intention-to-treat primary analysis was made in order to include all patients in the treatment group to which they were allocated, irrespective of the treatment they actually received.
- Fifty per cent or greater reduction in seizure frequency: proportion of participants with at least a 50% reduction in seizure frequency at the end of the study compared to the pre-randomisation baseline period.
- Seizure freedom: proportion of participants achieving total cessation of seizures. We used the most current ILAE proposed definition of seizure freedom: no seizures of any type for either 12 months or three times the longest (pre-intervention) seizure-free interval, whichever is longest (Kwan 2010).
1. Adverse effects:
- proportion of patients that experienced at least one adverse effect;
- proportion of patients that experienced individual adverse effects (to be listed separately).
2. Proportion of dropouts or withdrawals due to side effects, lack of efficacy or other reasons.
3. Improvement in quality of life as assessed by validated and reliable rating scales (e.g. Quality Of Life In Epilepsy (QOLIE-31)).
Search methods for identification of studies
We searched the following databases:
- Cochrane Epilepsy Group Specialized Register (19 August 2013) using the search terms 'stiripentol' and 'diacomit';
- Cochrane Central Register of Controlled Trials (CENTRAL Issue 7, The Cochrane Library July 2013) using the search strategy set out in Appendix 1;
- MEDLINE (Ovid) (1946 to 19 August 2013) using the search strategy set out in Appendix 2;
- EMBASE (31 May 2012) using the search strategy set out in Appendix 3. (The last search in EMBASE was made on 31th May 2012. Since then we no longer have access to that database.)
We did not impose any language restrictions.
Searching other resources
We contacted the manufacturers of stiripentol (Biocodex) (contacted by mail on 31 May 2012) and experts in the field (contacted by mail on 31 May 2012) for information about any unpublished or ongoing studies. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also considered conference proceedings of the ILAE.
Data collection and analysis
In case future review updates identify more than one study, data analyses may be conducted referring to the methods reported in the previously published protocol of the present systematic review (Brigo 2012).
Selection of studies
Two review authors (FB and MS) independently screened all the titles and abstracts of publications identified by the searches to assess their eligibility. At this stage we excluded publications that did not meet the criteria. Following screening, we assessed the full texts of potentially eligible citations for inclusion. The review authors reached consensus on the selection of trials and the final list of studies. We discussed any disagreements and resolved them.
Data extraction and management
Two review authors (FB and MS) independently extracted the following characteristics of each included trial from the published reports, where possible. We used data extraction forms and any disagreements was resolved by mutual agreement. We recorded the rawest form of the data, when possible. In the case of missing or incomplete data, we contacted the principal investigators of included trials for the required additional information.
(c) Epileptic seizure type and epilepsy syndrome
(d) Etiology of epilepsy
(e) Duration of epilepsy
(f ) Number of seizures or seizure frequency prior to randomisation
(g) Presence of status epilepticus
(h) Number and types of AEDs previously taken
(i) Concomitant AEDs
(j) Presence of neurological deficit, signs
(k) Neuropsychological status
(l) Electroencephalography (EEG) findings
(m) Neuroradiologic findings (computed tomography (CT), magnetic resonance imaging (MRI))
(a) Criteria used to diagnose epilepsy
(b) Definition of drug-resistant or refractory epilepsy
(c) Trial design (i.e. RCT, parallel group or cross-over, single or double-blinded)
(d) Inclusion and exclusion criteria
(e) Method of randomisation
(f ) Method of allocation concealment
(g) Method of blinding
(h) Stratification factors
(i) Number of participants allocated to each group
(j) Duration of the different phases of the trial (baseline, titration, maintenance and optional open-label extension (if any))
Intervention and control
(a) Intervention given to controls
(b) Dosage of stiripentol
(c) Duration of treatment period
(a) Duration of follow up
(b) Reasons for incomplete outcome data
(c) Dropout or loss to follow-up rates
(d) Methods of analysis (e.g. intention-to-treat, per protocol, worst-case or best-case scenario analysis)
- Fifty per cent or greater reduction in seizure frequency: proportion of participants with at least 50% reduction in seizure frequency at the end of the study (numerator)/number of participants at pre-randomisation baseline period (denominator)
- Seizure freedom: proportion of participants achieving total cessation of seizures (numerator)/number of participants at pre-randomisation baseline period (denominator)
Incidence of adverse effects of any type: number of adverse effects (numerator)/total number of participants at pre-randomisation baseline period (denominator)
Assessment of risk of bias in included studies
Two review authors (FB and MS) assessed the risk of bias of each trial according to the approaches described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011) (Higgins 2011). We assessed the risk of bias as: yes (low risk of bias); no (high risk of bias); or unclear (uncertain risk of bias).
We evaluated the following characteristics.
(a) Random sequence generation (selection bias).
(b) Allocation concealment (selection bias).
(c) Blinding of participants and personnel (performance bias).
(d) Blinding of outcome assessment (detection bias).
(e) Incomplete outcome data.
(f ) Selective reporting (reporting bias).
(g) Other bias (including outcome reporting bias).
Measures of treatment effect
For dichotomous outcomes, we abstracted the number of patients in each arm who experienced the outcome of interest. The data for our chosen outcomes were dichotomous and our preferred outcome statistic was the risk ratio (RR) calculated with the uncertainty in each trial being expressed using 95% confidence intervals (CIs).
Dealing with missing data
For each outcome, an intention-to-treat primary analysis was made in order to include all patients in the treatment group to which they were allocated, irrespective of the treatment they actually received.
Assessment of heterogeneity
Due to only one study satisfying our inclusion criteria, we have not performed an assessment of heterogeneity.
Assessment of reporting biases
Due to only one study satisfying our inclusion criteria, we have not carried out an analysis of reporting biases.
Due to only one study satisfying our inclusion criteria, we did not perform a meta-analysis.
Subgroup analysis and investigation of heterogeneity
Due to the limited eligible data, we did not perform subgroup analysis.
Due to the limited eligible data, we did not perform a sensitivity analysis.
Description of studies
The only included trial (Chiron 2006) used a 'responder enriched' design where participants responding to stiripentol during a pre-randomisation baseline phase were randomised to continue stiripentol or have it withdrawn. This trial therefore compared the effect of continuing versus withdrawing stiripentol. Only data from the randomised double-blind add-on placebo-controlled part of the trial were included in the present review.
Results of the search
The search strategy described above yielded 90 results (10 Cochrane Epilepsy Group Specialized Register, 14 CENTRAL, 27 MEDLINE, 48 EMBASE; one in reference lists; 14 by handsearching; no ongoing or unpublished trials; total 90 results after duplicates removed). No unpublished or ongoing trials were found.
After reading the abstracts, six studies were provisionally selected. Five studies were later excluded after reading the full texts as they did not meet our review criteria. Please see Characteristics of excluded studies for reasons of exclusion. We identified one study that met our inclusion criteria (Chiron 2006). See Figure 1.
|Figure 1. Study flow diagram.|
This study aimed to study stiripentol as an add-on therapy to carbamazepine in childhood partial epilepsy, adopting a 'responder enriched' design. Participants were 32 children with focal epilepsy. All included patients were defined as "refractory to the usual antiepileptic drugs (including valproate, carbamazepine, benzodiazepines, and phenytoin), as well as to vigabatrin". The presence of a refractory epilepsy was however not specified among the inclusion criteria. There were 18 male (seven in the stiripentol and 11 in the add-on placebo group) and 14 female (10 in the stiripentol and four in the add-on placebo group) participants. Mean age was 8 years ± 3 (mean ± standard deviation) among the participants in the stiripentol group and 10.4 years ± 3.4 in the add-on placebo group.
The first study period was a one-month baseline with a single-blind add-on placebo. The second period was a four-month open phase with open add-on stiripentol. These first two study periods adopted a non-randomised before-after design. At the end of this open phase, the responders (defined as those patients having at least a 50% decrease in seizure frequency during the open period compared with baseline) were randomised to either stiripentol or add-on placebo for a two-month double-blind period. Then all patients received long-term open stiripentol.
The following criteria were required for patients to be included in the baseline period: (1) children with partial seizures; (2) receiving carbamazepine as co-medication, a benzodiazepine (clobazam or clonazepam) or vigabatrin, or both, could also be administered in association; and (3) receiving at least 400 mg/day of carbamazepine. Patients had to be responders (that is experiencing at least a 50% decrease in seizure frequency during the third month of the open period compared with baseline) in the open phase to be eligible for randomisation. Patients receiving other drugs and those whose parents were unable to comply regularly with drug delivery and daily seizure diaries were not included.
Conflicts of interest or study sponsor were not reported.
Three studies were excluded as they were non-randomised trials (Loiseau 1988; Rascol 1989; Perez 1999). These studies adopted an uncontrolled before-after design. One study (Chiron 2000) (published as a conference proceeding) was excluded because it provided the preliminary results (interim analyses) of the study of Chiron 2006, which was published a few years later as an in-extenso paper presenting the definitive results and which was included in the present review. The other excluded study (Loiseau 1990) was a randomised double-blind parallel group trial which evaluated the efficacy of stiripentol as add-on therapy to carbamazepine versus carbamazepine monotherapy in patients with epilepsy uncontrolled by carbamazepine monotherapy. This study was excluded because it did not clearly specify whether it was conducted in patients with focal epilepsy. Moreover, it was conducted in patients with epilepsy "uncontrolled by carbamazepine monotherapy". Most definitions of drug refractory epilepsy that are available in the literature require the failure of at least two AEDs for such a diagnosis (Berg 2006). As a consequence, we did not consider patients of this study as affected by drug refractory epilepsy; this was also considering the internationally accepted definition of refractory epilepsy: failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan 2010).
Risk of bias in included studies
Patients were randomised using a computer-generated list, and the tablets were dosed by the pharmacist so that the investigator was blinded (low risk of selection bias). The second part of the trial was defined as double blinded (low risk of performance bias). Each patient received tablets of both stiripentol and 'placebo of stiripentol' and tablets of both carbamazepine and 'placebo of carbamazepine', and the individual tablets were prepared by the pharmacist (low risk of selection bias). However, part of the carbamazepine schedule was administered as 'open carbamazepine', the dose of which could be decreased whenever necessary. The study reported the number of dropouts, specifying the reasons. Although the reasons for dropouts were similar among the two groups, and the fact that strict escape criteria were specifically required for a 'responder enriched' design, the number of dropouts in both arms (add-on stiripentol and placebo) was high and far exceeded 20% (53.3 versus 35.3) (high risk of attrition bias). The published reports included all expected outcomes (low risk of reporting bias).
Due to its 'responder-enriched' design, this study resulted in a primary efficacy evaluation of an enriched population of patients. It was the result of randomising only patients who responded to open-label treatment (high risk of selection bias).
This trial used as a primary endpoint the number of patients meeting the escape criteria during the double-blind period, defined as: (1) an increase in seizure frequency during the double-blind period compared with the pre-randomisation period; (2) a significant increase in seizure severity during the double-blind period compared with the open period; and (3) status epilepticus occurring during the double-blind period. This study however provided the individual patient data for the randomised double-blind part of the trial, thus allowing us to include this information in the present review.
The length of follow up for the randomised double-blind study (only two months) was not adequate to evaluate a change in seizure frequency.
Effects of interventions
Add-on stiripentol versus add-on placebo
We found one study (Chiron 2006) comparing add-on stiripentol with add-on placebo, which recruited 32 participants. As outlined in Description of studies above, this trial used a 'responder enriched' design where participants responding to stiripentol during a pre-randomisation baseline phase were randomised to continue stiripentol or have it withdrawn. This trial therefore compared the effect of continuing versus withdrawing stiripentol.
See: Data and analyses
Fifty per cent or greater reduction in seizure frequency, and seizure freedom
There was no clear evidence of a reduction in seizure reduction (≥ 50% seizure reduction) (RR 1.51, 95% CI 0.81 to 2.82) or in seizure freedom (RR 1.18, 95% CI 0.31 to 4.43) with add on stiripentol compared with placebo, although a non-significant trend favouring add-on stiripentol was found for both outcomes. In the add-on placebo group 4/15 patients experienced a worsening in seizure frequency compared with the baseline period.
See: Data and analyses
Add-on stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47) compared with placebo. When considered as specific adverse events, the confidence intervals are very wide and include the possibility of substantial increases and small reductions in the risk of neurological (RR 2.65, 95% CI 0.88 to 8.01) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36).
Proportion of dropouts or withdrawals due to side effects, lack of efficacy or other reasons
There was no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group). Eight patients in the add-on placebo group (35.3%) dropped out due to a loss of response (seven for an increase in seizure frequency and one for an increase in seizure severity); and four experienced worsening compared with baseline. Six patients in the stiripentol group (53.3%) dropped out (five because of an increase in seizure frequency and one for an increase in seizure severity).
Improvement in quality of life as assessed by validated and reliable rating scales
The included study did not assess this outcome.
This review aimed to assess the efficacy and tolerability of add-on stiripentol as add-on treatment for focal refractory epilepsy.
Only one study was included (Chiron 2006). This study adopted a 'responder enriched' design. Although all included patients were "refractory to the usual antiepileptic drugs (including valproate, carbamazepine, benzodiazepines, and phenytoin), as well as to vigabatrin as a new drug", the presence of a refractory epilepsy was not considered among the inclusion criteria. Furthermore, a definition of refractory epilepsy was not provided.
There was no statistically significant difference between add-on stiripentol and add-on placebo, neither in seizure reduction (≥ 50% seizure reduction) nor in seizure freedom, although a non-significant trend favouring add-on stiripentol was found for both outcomes. There was a statistically significant difference between add-on stiripentol and add-on placebo in adverse effects considered as a whole, with adverse effects being more frequent in the add-on stiripentol group. Conversely, there were no statistically significant differences in neurologic adverse effects and in gastrointestinal adverse effects, although a non-significant trend was found for adverse effects occurring more frequently after add-on stiripentol. There was no statistically significant difference between add-on stiripentol and add-on placebo in the proportion of dropouts, although a non-significant trend for more dropouts among add-on placebo participants was found.
Despite an overall 'low risk' of bias, the 'responder enriched' design used in the included trial raises several ethical and methodological concerns. This design shifts the focus to a patient subgroup when the accumulating data suggest greatest benefit for that subgroup. Only the second part of this study met the inclusion criteria of the systematic review (randomised add-on placebo-controlled double-blind trial) whereas the first part of this study adopted a non-randomised before-after design. The inclusion of responders to add-on stiripentol alone (that is patients experiencing at least a 50% decrease in seizure frequency during the third month of the open period compared with baseline) in the second part of the study may severely reduce the external validity of the results, limiting their generalization to a more widespread population. This study design results, therefore, in a primary efficacy evaluation of a highly selected 'enriched' population of patients as a result of randomising only patients who responded to open-label treatment (high risk of selection bias).
Furthermore, a 'responder enriched' design carries the risk of a carry-over effect in the add-on placebo-group. A carry-over effect occurs when the effects of an intervention given in one period persist into a subsequent period, thus interfering with the effects of a different subsequent intervention. The risk of a carry-over effect in the add-on placebo group of the included study seems to be high, since in the add-on placebo group the add-on stiripentol was withdrawn over three weeks (a long period, especially considering that the overall length of the randomised double-blind part of the trial was only two months). Furthermore, no washout period was included during the randomised double-blind phase to reduce the carry-over effect. As a consequence it is likely that a carry-over effect may have affected the outcome related to seizure frequency in the included study, with a possible reduction in seizure frequency in the add-on placebo group. Conversely, a 'responder enriched' design also carries the risk of a withdrawal effect secondary to the withdrawal of add-on stiripentol in the add-on placebo group during the randomised add-on placebo-controlled phase of the trial. The withdrawal effect may be responsible for an increase in seizure frequency (which, unlike reduction in seizure frequency, becomes a relevant endpoint within such a study design). Hence, it should be carefully taken into account to define strict escape criteria in order to prevent participants in the add-on placebo group from being exposed to seizures which may become more severe or more prolonged and may even evolve into status epilepticus. Regarding this last aspect, it is noteworthy to consider that in both arms (add-on stiripentol and add-on placebo), hence not only in the add-on placebo group, the percentage of dropouts was extremely high due to an increase in seizure frequency or severity.
Furthermore, the length of follow up for the randomised double-blind study (only two months) was probably not adequate to evaluate a change in seizure frequency.
More research is needed to assess the efficacy and tolerability of add-on stiripentol for the treatment of focal refractory epilepsy. Future studies should be randomised, double-blind, aim to recruit a sufficiently large number of participants, and should assess clinically meaningful outcome measures adopting the internationally accepted definition of refractory epilepsy (Kwan 2010).
Summary of main results
The only study included in the present review showed no statistically significant difference between add-on stiripentol and add-on placebo, neither in seizure reduction (≥ 50% seizure reduction) nor in seizure freedom. There was a statistically significant difference between add-on stiripentol and add-on placebo in adverse effects considered as a whole, with adverse effects occurring more frequently in the add-on stiripentol group.
Overall completeness and applicability of evidence
The generalization of study results to a more widespread population is prevented by the choice of a 'responder enriched' design, which results in a primary efficacy evaluation of a highly selected 'enriched' population of patients as a result of randomising only patients who responded to open-label treatment (high risk of selection bias).
Quality of the evidence
The generalization of study results to a more widespread population is prevented by the fact that only responders to add-on stiripentol (that is patients experiencing at least a 50% decrease in seizure frequency compared with baseline) were included in the randomised add-on placebo-controlled double-blind part of the study. Also, the very small sample size with correspondingly high dropout rate prevents generalization of the study results. Finally, because of the adopted design, a carry-over and a withdrawal effect probably affected the outcome related to seizure frequency.
Implications for practice
Currently, there is no evidence to support the use of add-on stiripentol for the treatment of focal refractory epilepsy. Although limited by the very limited information derived by only one included study, adverse effects considered as a whole seem to occur significantly more with add-on stiripentol compared with add-on placebo.
Implications for research
More research is needed to assess the efficacy and tolerability of add-on stiripentol for the treatment of focal refractory epilepsy. Future studies should be randomised, double-blind studies and should aim to recruit sufficiently large numbers of participants and assess clinically meaningful outcome measures. A 'responder enriched' design should be avoided because of the risk of a carry-over and withdrawal effect in the add-on placebo group and because of the reduced external validity of this study design. Furthermore, the internationally accepted definition of refractory epilepsy should be adopted.
We are indebted to the following epilepsy experts who were contacted for information about any unpublished or ongoing studies: Blaise Bourgeois, Barry Gidal, William H Theodore, Jacqueline French. We also thank Professor Anthony Marson, Cochrane Epilepsy Group, for his kind support. We do thank Marie-Emmanuelle le Guern (Biocodex) for providing us with some recent publications and for searching unpublished or ongoing trials related to the use of add-on stiripentol in epilepsy.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor Epilepsy explode all trees
#2 MeSH descriptor Seizures explode all trees
#3 (epilep* or seizure* or convuls*)
#4 (#1 OR #2 OR #3)
#5 (stiripentol) or (Diacomit)
#6 (#4 AND #5)
Appendix 2. MEDLINE search strategy
This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2011).
1. randomised controlled trial.pt.
2. controlled clinical trial.pt.
5. clinical trials as topic.sh.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. exp animals/ not humans.sh.
10. 8 not 9
11. (epilep$ or seizure$ or convuls$).tw.
12. exp Epilepsy/
13. exp Seizures/
14. 11 or 12 or 13
17.15 or 16
18. 10 and 14 and 17
Appendix 3. EMBASE search strategy
('stiripentol/exp OR stiripentol) AND ('epilepsy/exp OR epilepsy) AND 'controlled study/de'
Contributions of authors
Francesco Brigo conceived the idea and developed the project.
Francesco Brigo and Monica Storti designed the protocol.
Francesco Brigo and Monica Storti assessed the studies for inclusion and extracted the data from the individual studies.
Text of the final review was written by Francesco Brigo.
Declarations of interest
Sources of support
- None, Not specified.None
- None, Not specified.None
Differences between protocol and review
Intended methods for assessing heterogeneity, reporting biases, data synthesis, subgroup and sensitivity analyses that were not implemented due to the low number of studies can be found in the protocol of this systematic review (Brigo 2012). They may be used as the basis for future versions of the review should further studies be conducted.
Medical Subject Headings (MeSH)
MeSH check words