Clobazam as an add‐on in the management of refractory epilepsy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective is to assess the effectiveness, efficacy and tolerability of clobazam as an add‐on therapy for refractory partial onset seizures and generalized onset tonic‐clonic seizures in adults and children.
Background
Epilepsy is an important medical condition affecting one per cent of the population. Although seizures will be easily controlled in many people, up to 30% of people with epilepsy will fail to respond to adequate doses of appropriate antiepileptic drugs (AEDs) (Cockerell 1995). In an attempt to achieve seizure control multiple AEDs are often used. However, in a review of 470 previously untreated adult patients with epilepsy in a major epilepsy centre, 47% of patients were controlled by the first AED, only 14% became seizure free on monotherapy with a second or third drug, and only 3% were controlled by polytherapy (Kwan 2000). For the purpose of this review drug resistance is defined as failure to respond to a minimum of two appropriately used AEDs.
Benzodiazepines have been developed for their anticonvulsant properties since the 1950s. The chemical composition of clobazam differs from all other classical benzodiazepines in general use. In animal studies, clobazam has a broader spectrum of antiepileptic properties inhibiting the spread of seizures and raising the seizure threshold, compared to the classical benzodiazepines. The sedative, behavioural and muscle relaxant effects, however, are less marked than with diazepam and the classical‐benzodiazepines (Kruse 1985). Animal studies have demonstrated that clobazam has more potent antiepileptic properties in chemically induced seizures than the standard antiepileptic medications (diazepam, phenobarbital or valproic acid) (Shenoy 1982).
Clobazam was first licensed for clinical use as a non‐sedating tranquilizer. The antiepileptic properties were only investigated after the drug was no longer protected by patent. Gastaut et al (Gastaut 1979) first investigated clobazam in intractable epilepsy. Since then clobazam has been reported to be effective in the treatment of partial, generalized and myoclonic seizures in both adults and children.
The effectiveness of clobazam used as polytherapy may be influenced by several factors. When clobazam is used as polytherapy there may be additive efficacy without additive toxicity (Guberman 1998). Such an effect could be due to a pharmacodynamic interaction between drugs or to a pharmacokinetic effect, in which the other drug influences the levels of clobazam or a clobazam metabolite. Drugs such as phenobarbital, phenytoin and carbamazepine that induce the hepatic microsomal enzymes increase the conversion of clobazam to N‐desmethylclobazam, an active metabolite with antiepileptic activity. Despite increases in the serum concentrations of this active metabolite, no increased toxicity is observed suggesting that N‐desmethylclobazam has a wide safety margin (Theis 1997).
The purpose of this review is to examine the effectiveness of clobazam as an add‐on therapy for refractory partial onset or generalized onset tonic‐clonic seizures in children and adults. We will also assess the rate of development of drug tolerance and adverse effects.
Objectives
The objective is to assess the effectiveness, efficacy and tolerability of clobazam as an add‐on therapy for refractory partial onset seizures and generalized onset tonic‐clonic seizures in adults and children.
Methods
Criteria for considering studies for this review
Types of studies
(1) Randomized studies with adequate or quasi (e.g. days of the week) methods of randomization.
(2) Studies may be single blinded, double blind or unblinded.
(3) Parallel group or crossover studies. For crossover studies, if the whole trial is well conducted and the data are clean then the whole data set will be used. For those studies with problems then only data from the first treatment period will be used.
(4) Minimum treatment period of eight weeks.
Types of participants
Children (less than 16 years) or adults with drug‐resistant partial onset (simple partial, complex partial or secondarily generalized tonic‐clonic seizures (with or without other generalized seizure types).
Types of interventions
(1) The active treatment group will receive therapy with clobazam in addition to their usual treatment.
(2) The control group will receive placebo in addition to their usual treatment. 'No treatment' controls will also be included.
Types of outcome measures
Effectiveness measures
The proportion of people having their treatment withdrawn during the course of the treatment period. Treatment may be withdrawn due to adverse effects, lack of efficacy, or a combination of both.
Efficacy measures
(1) The proportion of people with a 50% or greater reduction in seizure frequency in the treatment period compared to the prerandomized baseline period for the entire group and for each of partial onset and generalized onset tonic‐clonic seizure groups. This outcome was chosen as it is commonly reported in this type of study, and can be calculated for studies that do not report this outcome provided that baseline seizure data were recorded.
(2) The proportion of people who achieve total cessation of seizures.
Tolerability measures
(1) Proportion of individuals experiencing adverse events requiring medication withdrawal.
(2) The proportion of individuals experiencing any of the following adverse effects, considered by the review authors to be common and important adverse effects of antiepileptic drugs:
(a) skin rash;
(b) ataxia;
(c) cognitive/behavioural;
(d) sedation;
(e) weight gain;
(f) sleep disturbance;
(g) other.
Quality of life measures
Data on quality of life outcomes from any validated scale will be summarized in this review.
Tolerance measures
Data on the development of antiepileptic drug tolerance, and the definitions used in each study, will be summarized in this review.
Search methods for identification of studies
We will search the following databases for randomized trials using the search terms "clobazam", "seizure" and "epilepsy":
(a) Cochrane Epilepsy Group Specialized Register;
(b) Cochrane Central Register of Controlled Trials (CENTRAL);
(c) MEDLINE;
(d) EMBASE;
(e) Database of Abstracts of Reviews of Effectiveness (DARE);
(f) American College of Physicians Journals;
(g) BIOSIS.
In addition, we will handsearch any reference lists from identified trials for other relevant articles. We will also contact Hoechst Marion Roussel (manufacturers of clobazam) for information on unpublished or ongoing trials.
Data collection and analysis
Trial assessment and data collection
Trials will be independently assessed for inclusion by two review authors (BM and AGM). Results will be compared and any disagreements resolved by discussion.
We plan to obtain the following information for each trial meeting our inclusion criteria. If the information is not available in the published manuscript we will contact the original investigators for further data.
Trial design
(1) Method of randomization.
(2) Method of concealment of randomization.
(3) Method of blinding.
(4) Stratification factors.
(5) Duration of baseline period.
(6) Duration of treatment period.
(7) Description of withdrawals and dropouts.
Patient factors
(1) Age.
(2) Sex.
(3) Seizure type(s).
(4) Number and description of background drugs.
(5) Number of seizures prior to randomization.
(6) Presence of neurological deficit/signs at baseline.
(7) EEG results at baseline.
(8) Neuroimaging CT/MRI scans.
Treatment data
(1) Medication dose per treatment group.
(2) Total number of individuals allocated to each group.
Follow‐up data
(1) The number of individuals in each group achieving a 50% or greater reduction in seizures per treatment group.
(2) The number of individuals in each group achieving a total cessation of seizures.
(3) The number of individuals having treatment withdrawn and reasons for treatment withdrawal per treatment group.
(4) For those excluded; the reason for exclusion, whether any of those excluded completed the treatment phase, whether any of those excluded had a 50% or greater reduction in seizure frequency during the treatment phase.
Outcomes
Efficacy, tolerability and adverse events and tolerance, as listed above per randomized group.
Quality assessment
We will use the Jadad validated quality scale (Jadad 1996) to rate the quality of the studies including the following items.
(a) Was the study described as randomized? Yes = one point, No = zero points.
(b) Was the study described as double blind? Yes = one point, No = zero points.
(c) Was there a description of withdrawals and dropouts? Yes = one point, No = zero points.
(d) Was the blinding appropriate? Yes = one point, No = deduct one point.
(e) Was the randomization appropriate? Yes = one point, No = deduct one point.
Each study will be given a total score between zero and five points, with higher scores corresponding to higher quality studies (Jadad 1996). The Jadad score for each study will be reported.
Data analysis
(1) We will extract data from the trials or calculate it from the primary data supplied by the authors.
(2) Our primary analysis will be an intention‐to‐treat analysis of patients according to the treatment allocation regardless of the final treatments. Where possible we will analyze patients according to seizure type. We will assume patients not completing follow‐up or with inadequate seizure data as non responders.
(3) Where possible we will undertake a subgroup analysis according to age groups (children versus adults), seizure type (partial versus generalized onset seizures) and by baseline severity.
(4) We will assess clinical heterogeneity by comparing the distribution of important patient factors between trials (age, seizure type, duration of epilepsy, number of antiepileptic drugs taken at time of randomization) and trial factors (randomization concealment, blinding and losses to follow‐up).
(5) We will assess statistical heterogeneity by using a Chi‐squared test where p>0.05 indicates significant heterogeneity. If heterogeneity is found, potential causes will be explored. If heterogeneity is not found, we will synthesize data using a fixed effects model. Our preferred estimator is the Peto odds ratio. For the outcomes 50% reduction in seizure frequency and treatment withdrawal we will use 95% confidence intervals. For individual adverse effects we will use 99% confidence intervals to allow for multiple testing.
(6) Worst case: we will assume that participants not completing follow‐up or with inadequate seizure data to be non responders in the clobazam group, and responders in the placebo group.
(7) Best case: we will assume that participants not completing follow‐up or with inadequate seizure data to be responders in the clobazam group, and non responders in the placebo group.
(8) We will use stratified logrank tests and regression modelling to analyze 'time to event' measures (eg time to treatment withdrawal).
(9) We will examine dose response relationships using logistic regression and calculate the following for the differing doses:
(a) the percentage of individuals having a 50% response;
(b) the difference in percentage of individuals responding to each dose compared to placebo.
A binary variable will be defined with the value 0 if the response is less than 50% and with the value 1 if the response is 50% or greater. Dose regression relationships will be examined using logistic regression with this binary variable as the outcome variable.
(10) We will summarize tolerance data narratively.
(11) We will document the incidence of individual adverse effects.
(12) We will summarize quality of life data narratively.
