Clonazepam monotherapy for treating people with newly diagnosed epilepsy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, when compared with placebo or a different anti‐seizure medication.
Background
Description of the condition
Epilepsy is "a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures" (Fisher 2005). According to the practical definition proposed by the International League Against Epilepsy (ILAE) in 2014, epilepsy can be diagnosed in "any of the following conditions: (1) at least two unprovoked (or reflex) seizures occurring > 24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome" (Fisher 2014).
Epilepsy is one of the most common neurological disorders worldwide, with an age‐adjusted prevalence in developed countries of 4 to 8 per 1000 population (Hauser 1991), and an age‐adjusted incidence of 44 per 100,000 person‐years (Hauser 1993). It affects people of any age, and in adulthood its incidence and prevalence increase with age (Hauser 1993).
Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy, and the choice of the initial antiepileptic drug should take into account the person's seizure type and epilepsy syndrome, age, childbearing potential, comorbidities, medical history, tolerability and risk of drug interactions (Perucca 2011).
In this review we will investigate the efficacy and tolerability of clonazepam used as monotherapy in people with newly diagnosed epilepsy.
Description of the intervention
Clonazepam, or 5‐(2‐chlorophenyl)‐7‐nitro‐1,3‐dihydro‐1,4‐benzodiazepin‐2‐one, is a drug with anxiolytic and antiepileptic properties. It is rapidly absorbed from the gastrointestinal tract, with an oral bioavailability almost complete (> 85%) and time to peak levels after a single oral dose of one to four hours (Trinka 2016). Clonazepam is extensively bound to plasma proteins (86%) and has no active metabolite. This drug is highly lipophilic, which enables a rapid cross of the blood‐brain barrier, resulting in a rapid onset of action. Clonazepam is eliminated by nitroreduction and has an elimination half‐life of 17 to 55 hours in healthy adults not taking enzyme inducing agents (Trinka 2016).
Clonazepam has a broad‐spectrum efficacy against many seizure types, both generalized and focal, including absences (Sato 1977; Trinka 2016; Wheless 2005). It is particularly effective against myoclonic seizures occurring in different epilepsy types, including progressive myoclonic epilepsies (Browne 1976; Livanainen 1982; Obeso 1995‐1996). Clonazepam is mainly used as add‐on treatment, but has been proven to be effective also when used in monotherapy. In particular, a paediatric study conducted in 60 children with epilepsy other than infantile spasms, showed that clonazepam monotherapy led to clinical seizure cessation in 71% of the participants with generalized seizures and 89% of focal seizures; the drug was well tolerated, with adverse effects (mainly drowsiness and ataxia) reported in 5% of children (Ishikawa 1985). Efficacy as monotherapy in adults has also been demonstrated in a randomized controlled trial (RCT) conducted in 36 participants with newly diagnosed complex focal seizures; in this study no significant difference was found in seizure control between clonazepam and carbamazepine (Mikkelsen 1981).
Common or clinically relevant adverse events related to clonazepam use include behavioural disorders (irritability, aggressive behaviour, hyperactivity), drowsiness, ataxia, sedation, cognitive dysfunction, and drooling (Browne 1978; Trinka 2016). Adverse effects occur in up to 50% of people treated with this drug (Browne 1978; Trinka 2016), and in some cases may improve after dose reduction and over time due to tolerance. Intolerable adverse effects have been reported in approximately 20% of people with epilepsy (Browne 1978; Keränen 1983).
How the intervention might work
Clonazepam belongs to the drug class of benzodiazepines. Benzodiazepines are drugs that enhance the binding of the gamma‐aminobutyric acid (GABA) to the GABA‐A receptors, increasing channel opening frequency; this leads to increased chloride conductance and neuronal hyperpolarization and eventually to enhanced inhibitory neurotransmission and antiepileptic action (Trinka 2016).
Why it is important to do this review
We plan to comprehensively search and critically assess the scientific literature on the clinical role of oral clonazepam used as monotherapy treatment for people with newly diagnosed epilepsy. In particular, it is important to evaluate whether high‐quality RCTs assessing the efficacy and tolerability of this drug are available.
Objectives
To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, when compared with placebo or a different anti‐seizure medication.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) or quasi‐RCTs comparing oral clonazepam used as monotherapy treatment (participants randomized to treatment with a single drug throughout the study period) versus placebo or a different anti‐seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the International League Against Epilepsy (ILAE) (Fisher 2014). We will not include RCTs assessing the role of clonazepam as treatment of status epilepticus.
We will include only RCTs of parallel or cross‐over designs, excluding uncontrolled and non‐randomized trials. We will not exclude trials on the basis of dose, duration of treatment, or length of follow‐up.
Types of participants
People with newly diagnosed epilepsy of any type (Scheffer 2016), defined as two or more unprovoked seizures or single unprovoked seizure and high risk of seizure recurrence (Fisher 2014), regardless of sex, age, or ethnicity.
Types of interventions
Clonazepam monotherapy at any dosage versus placebo or a different antiepileptic drug (active comparator). We will also include dose controlled studies (i.e. multiple‐arm trials assessing clonazepam at different dosages).
Types of outcome measures
Primary outcomes
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Proportion of participants seizure‐free at one, three, six, 12 and 24 months after randomization.
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Proportion of responders (at least 50% seizure frequency reduction from baseline to end of treatment).
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Proportion of participants with treatment‐emergent adverse events (TEAEs)
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during the treatment period;
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leading to discontinuation during the treatment period.
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We will assess seizure freedom and proportion of responders both for all seizure types and for specific seizure type (e.g. myoclonic, absence, tonic, atonic, tonic‐clonic, and focal seizures).
For each outcome, we will perform an intention‐to‐treat (ITT) primary analysis to include all participants in the treatment group to which they were allocated, irrespective of treatment actually received. We will use ITT data in the analysis for all randomly assigned participants recorded during the entire treatment period, including both titration and evaluation phases.
Secondary outcomes
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Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons; we will use this as a measure of global effectiveness.
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Improvement in quality of life, as assessed by validated and reliable rating scales.
Search methods for identification of studies
We will perform a comprehensive review of the literature to minimize publication bias.
Electronic searches
We will search the following databases.
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Cochrane Epilepsy Group Specialized Register.
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Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) via the Cochrane Register of Studies Online (CRSO).
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MEDLINE (Ovid) 1946 to date of search.
We will search the following trial registers.
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; to date of search).
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WHO ICTRP (World Health Organization International Clinical Trials Registry Platform; www.who.int/ictrp; to date of search).
The proposed search strategy for MEDLINE is set out in Appendix 1. We will modify this strategy for use with the other databases.
Searching other resources
We will also:
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handsearch the references quoted in the identified trials;
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contact pharmaceutical companies (Roche) to identify unpublished trials or data missing from articles;
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contact authors and known experts to identify any additional data;
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handsearch relevant conference proceedings (American Academy of Neurology (AAN), International League Against Epilepsy (ILAE)).
We will not impose any language restrictions on our searches, and we will attempt to obtain translations of retrieved articles where necessary.
Data collection and analysis
Selection of studies
The review authors (FB, SCI, and NLB) will independently screen all titles and abstracts to assess the eligibility of publications identified by the searches. We will exclude publications that did not meet the criteria at this stage. After screening, we will assess the full text of potentially eligible citations for inclusion. We will list studies that initially appeared to meet the inclusion criteria but that we later excluded in the 'Characteristics of excluded studies' table. We will collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will also provide any information we can obtain about ongoing studies. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Liberati 2009). We will resolve any disagreement through discussion.
Data extraction and management
Two review authors (FB and SCI) will independently extract data from trial reports onto standardized forms, and will cross‐check them for accuracy. We will resolve any disagreement regarding data extraction by consensus between the review authors.
We will extract the following trial data.
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Main study author and age of publication.
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Total number and demographics of participants for each group (age, sex, weight, height, body mass index, number of seizures in the past three months, number of seizures in the past 12 months, epilepsy duration, type of seizures).
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Intervention details (study design; inclusion and exclusion criteria; description of study phases with details on starting and target dose, titration, and length of each phase; primary and secondary endpoints).
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Trial methods (method of generation of random list; method of concealment of randomization; blinding methods).
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Definitions of ITT/full analysis, safety, and per‐protocol population adopted in each study.
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Proportion of participants achieving seizure freedom at one, three, six, 12 and 18 months after randomization in each group.
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Proportion of responders (at least 50% seizure frequency reduction from baseline to end of treatment).
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Proportion of participants with TEAEs during the treatment period in each group.
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Proportion of participants with TEAEs leading to discontinuation during the treatment period in each group.
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Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons.
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Improvement in quality of life.
Assessment of risk of bias in included studies
We will scrutinize trials and evaluate the methodological quality of all included studies. Two review authors (FB and SCI) will assess the risk of bias of each trial according to the approaches described in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement regarding data extraction by consensus between the review authors.
We will assess the risk of bias as: low, high or unclear risk of bias.
We will evaluate the following characteristics.
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Random sequence generation (selection bias).
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Allocation concealment (selection bias).
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Blinding of participants and personnel (performance bias).
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Blinding of outcome assessment (detection bias).
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Incomplete outcome data addressed.
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Selective reporting (reporting bias).
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Other bias, including outcome reporting bias.
Measures of treatment effect
We will use statistical methods in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), to measure treatment effect.
We will use mean differences (MDs) with 95% confidence intervals (CIs) for continuous data (improvement in quality of life, as assessed by validated and reliable rating scales) where we find data provided as means and standard deviations (SDs). Alternatively, if possible, we will calculate these data by using conventional statistical formulae. In the event of different quality of life scales, we will attempt to combine the different scales and present results as standardized mean differences (SMDs).
We will analyze dichotomous data by calculating risk ratios (RRs) for each trial with the uncertainty in each trial being expressed using 95% CI. For individual adverse effects we will use 99% CIs to make allowance for multiple testing. The outcomes that we will analyze as dichotomous data are: (1) proportion of participants seizure free at one, three, six, 12 and 18 months after randomization; (2) proportion of responders (at least 50% seizure frequency reduction from baseline to end of treatment); (3) proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period; (4) proportion of participants with TEAEs leading to discontinuation during the treatment period; and (5) proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons.
Both for dichotomous and continuous data, we will calculate a pooled treatment effect across trials.
Unit of analysis issues
For any unit of analysis issues, we will deal with them according to theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).We will analyze multiple‐arm trials as follows: in the event of dose controlled studies with only one control group (i.e. two or more different doses of clonazepam versus control) we will "include each pair‐wise comparison separately, but with shared intervention groups divided out approximately evenly among the comparisons" (Higgins 2011). We will adopt this strategy to overcome a unit of analysis error. We will analyze randomized cross‐over studies in meta‐analyses using the results from paired analyses (Elbourne 2002).
Dealing with missing data
For individual missing data, such as information on dropout or loss to follow‐up, we will carry out an ITT analysis, using as the denominator the total number of people who underwent randomization.
Assessment of heterogeneity
We will visually inspect the forest plots to investigate the possibility of statistical heterogeneity.
We will evaluate statistical heterogeneity using the I2 statistic which provides an estimate of the percentage of variability due to heterogeneity rather than a sampling error (Higgins 2003).
We will interpret the level of heterogeneity using I2 according to theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), as follows: 0% to 40%: might not be important; 30% to 60%: moderate heterogeneity; 50% to 90%: substantial heterogeneity; 75% to 100%: considerable heterogeneity.
We will combine trial outcomes to obtain a summary estimate of effect (and the corresponding CI) using a fixed‐effect model, unless there is considerable heterogeneity (that is, I2 > 75%). If there is substantial heterogeneity we plan to explore the factors contributing to heterogeneity. If there is substantial heterogeneity that cannot readily be explained, we will use a random‐effects model. We will supplement homogeneity among trial results using a standard Chi2 test and we will reject the hypothesis of homogeneity if the P value is less than 0.10. We will assess possible sources of heterogeneity (for example, clinical, methodological or statistical heterogeneity) by using sensitivity analysis as described below.
Assessment of reporting biases
We will use a funnel plot to detect reporting biases if sufficient numbers of studies (> 10) are available. We will analyze possible sources of funnel plot asymmetry (e.g. publication bias, language bias, citation bias, poor methodological quality, true heterogeneity, etc.) according to the trials.
Data synthesis
Provided we think it clinically appropriate, and no considerable clinical and methodological heterogeneity is found, we plan to synthesize the trial results in a meta‐analysis. We will use the Mantel‐Haenszel method for analyzing dichotomous data and inverse variance for continuous data.
We will use the GRADE approach to interpret findings (Schunemann 2011). We will use GRADEpro software (GRADEpro GDT 2015), and import data from Review Manager 5 to create 'Summary of findings' tables for each comparison included in the review for the following primary outcomes (Review Manager 2014).
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Proportion of participants seizure‐free at 12 months after randomization.
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Proportion of participants seizure‐free at 24 months after randomization.
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Proportion of responders (at least 50% seizure frequency reduction from baseline to end of treatment).
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Proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period.
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Proportion of participants with TEAEs leading to discontinuation during the treatment period.
Subgroup analysis and investigation of heterogeneity
We plan to perform subgroup analysis separately assessing RCTs conducted in paediatric and adult populations, and according to dose and length of treatment.
Sensitivity analysis
In the case of residual unexplained heterogeneity, we will evaluate the robustness of the results of the meta‐analysis by comparing fixed‐effect and random‐effects model estimates, removing trials with low methodological quality (i.e. studies with inadequate allocation concealment or lack of blinded outcome assessor). If the conclusions we observe remain unchanged, then we will consider the evidence to be robust.
We will also use the worst‐case and best‐case scenarios for taking into account missing data.
Worst‐case analysis
We assumed participants randomized but excluded from analysis (e.g. for not completing follow‐up or with inadequate seizure data) were non‐responders in the clonazepam group and responders in the control group.
Best‐case analysis
We assumed participants randomized but excluded from analysis (e.g. for not completing follow‐up or with inadequate seizure data) were responders in the clonazepam group and non‐responders in the control group.
Summarizing and interpreting results
The 'Summary of findings' table for each comparison will include information on overall quality of the evidence from the trials and information of importance for healthcare decision‐making. The GRADE approach determines the quality of evidence on the basis of an evaluation of five criteria for RCTs (risk of bias, inconsistency, indirectness, imprecision, publication bias) (Schunemann 2011). We will use these to guide our conclusions and recommendations.
