Epilepsy (children) - newer drugs
Newer drugs for epilepsy in children (TA79)
4. Evidence and interpretation
The Appraisal Committee considered evidence from a number of sources (see Appendix B).
4.1. Clinical effectiveness
The evidence considered by the Committee included the Assessment Report, submissions by consultees and views put forward at the meeting by clinical experts and representatives of patient/carer organisations (see Appendix B).
4.1.1.1. Evidence from five randomised controlled trials including children was reviewed in the Assessment Report. These were: a placebo-controlled trial of lamotrigine adjunctive therapy in partial seizures (n = 199); a ‘response-mediated’ crossover trial of continued lamotrigine adjunctive therapy compared with withdrawal to adjunctive placebo in generalised seizures (n = 30 with 17 randomised); a placebo-controlled trial of lamotrigine adjunctive therapy in Lennox–Gastaut syndrome (n = 169); and a comparison of lamotrigine monotherapy with carbamazepine in newly diagnosed partial seizures (n = 417 randomised to lamotrigine or carbamazepine in a 2:1 ratio). The fifth study was a ‘responder-enriched’ trial of continued lamotrigine monotherapy compared with withdrawal to placebo in typical absence seizures; however, lamotrigine is not licensed for use in absence seizures.
4.1.1.2. As monotherapy in partial seizures, the comparison with carbamazepine found no statistically significant differences in terms of seizure outcomes between the two drugs. This was a mixed age study of patients aged 2 years and older, but results for the children 12 years and younger (n = 233) were reported separately. Although, in the whole trial population, more patients withdrew from the carbamazepine arm as a result of adverse events, this appeared to be mostly due to much worse treatment retention for carbamazepine in the elderly. In the paediatric subpopulation, there was a much smaller difference in withdrawals due to adverse effects (5% for lamotrigine and 7% for carbamazepine), which was not statistically significant. This study provides evidence for the effectiveness of lamotrigine monotherapy in partial seizures, but it cannot be concluded that lamotrigine and carbamazepine are equivalent.
4.1.1.3. The clinical trial of adjunctive lamotrigine in partial seizures included children between the ages of 2 and 16 years. This study provided evidence that lamotrigine was superior to placebo in suppressing seizures in patients who had not become seizure-free on their existing therapy. There was a greater reduction in median seizure frequency in the lamotrigine group than in the placebo group: a 36.1% reduction compared with a 6.7% reduction in the placebo group over the 18-week follow-up period (6 weeks’ dose titration plus a 12-week maintenance period). This was statistically significant, p = 0.008.
4.1.1.4. In Lennox–Gastaut syndrome, adjunctive lamotrigine was superior to adjunctive placebo in reducing the frequency of major motor seizures in one placebo-controlled study in people between the ages of 3 and 25 years. These results were to some extent supported by a small crossover trial in children and adolescents with refractory generalised seizures (two-thirds of whom had Lennox–Gastaut syndrome), although this trial’s unusual design makes comparison difficult. All participants initially received lamotrigine and the ‘responders’ (those experiencing a reduction of 50% or more in seizure frequency and/or a reduction in seizure severity) were randomised to continue lamotrigine or withdraw to placebo. After 12 weeks’ follow-up (plus a ‘wash-out’ period), the participants were ‘crossed over’, so that those who initially received lamotrigine withdrew to placebo, and lamotrigine was reintroduced in those who initially received placebo. The study initially included 30 patients (including 20 with Lennox–Gastaut syndrome), 17 of whom were randomised (2 later withdrew). No patients experienced more seizures on lamotrigine than on placebo and 9 of the 15 experienced a reduction of more than 50% in seizure frequency on lamotrigine compared with the placebo phase.
4.1.2.1. Two trials were considered: one placebo-controlled trial of oxcarbazepine adjunctive therapy in previously diagnosed seizures (n = 267) and one comparison of oxcarbazepine with phenytoin as monotherapy in a population of newly diagnosed patients with either partial seizures or generalised tonic-clonic seizures.
4.1.2.2. The placebo-controlled trial of combination therapy with oxcarbazepine was conducted in children and adolescents (age range 3–17 years) with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs. Oxcarbazepine led to a statistically significantly better response rate (proportion of patients with >50% reduction in seizures) and a significantly greater reduction from baseline in seizure frequency than placebo.
4.1.2.3. The monotherapy comparison with phenytoin was conducted in children and adolescents aged 5–18 years with newly diagnosed partial seizures or generalised tonic–clonic seizures. There was no statistically significant difference in the proportion of patients who remained seizure-free on oxcarbazepine monotherapy compared with phenytoin, although the premature discontinuation rate for phenytoin was higher.
4.1.2.4. The trials provided good evidence that oxcarbazepine adjunctive therapy was superior to placebo in partial seizures, and limited evidence for similar efficacy with better retention on therapy when oxcarbazepine monotherapy was compared with phenytoin in partial and generalised tonic–clonic seizures.
4.1.3.1. Two placebo-controlled trials of combination therapy with topiramate and one active controlled trial of topiramate as monotherapy were considered.
4.1.3.2. The first trial examined combination therapy with topiramate in 86 children (age range 2–16 years) with uncontrolled partial seizures. This study found that topiramate reduced the frequency of seizures from baseline to a significantly greater extent than placebo (median percentage reduction 33.1% compared with 10.5%, p = 0.03).
4.1.3.3. The second trial examined combination therapy with topiramate in 98 children and adults (age range 1–30 years) with Lennox–Gastaut syndrome. Topiramate was associated with a greater reduction from baseline in seizure frequency than placebo (median percentage reduction 20.6% compared with 8.8%) but this was not statistically significant. However, for atonic seizures (‘drop attacks’), the median percentage reduction from baseline in seizure rate was 14.8% for the topiramate group, compared with an increase of 5.1% for the placebo group (p = 0.041). This trial also reported improvements in parental global evaluation of seizure severity compared with placebo.
4.1.3.4. The monotherapy trial compared topiramate monotherapy with either carbamazepine or sodium valproate in the management of epilepsy in a mixed age population (6 years or older) with newly diagnosed partial or generalised tonic–clonic seizures (n = 613). The participants were recruited to either the carbamazepine or the valproate branch of the trial according to the investigator’s preferred treatment for that person. They were then randomised to one of two dose levels of topiramate (100 mg or 200 mg per day) or the chosen active control. For a small proportion of patients in this trial (about 2.5%) there was no epilepsy classification. This trial found that there was no statistically significant difference between the pooled topiramate groups and either carbamazepine or sodium valproate in any of the efficacy measures. An analysis of the paediatric subgroup of this trial (age range 6–16 years, n = 119), reported as a conference abstract only, found no statistically significant difference between topiramate and either carbamazepine or sodium valproate.
4.1.3.5. The trials provide evidence that topiramate is more effective than placebo in combination therapy in children with refractory partial seizures or people with Lennox–Gastaut syndrome. Topiramate appears to have similar effectiveness to carbamazepine and sodium valproate as monotherapy in newly diagnosed partial seizures or generalised tonic–clonic seizures.
4.1.4.1. Three randomised controlled trials of gabapentin were identified: two placebo-controlled trials of combination therapy with gabapentin in poorly controlled partial seizures and one placebo-controlled trial of gabapentin monotherapy in benign epilepsy with centrotemporal spikes (gabapentin is not licensed for use as monotherapy in this indication).
4.1.4.2. The larger of the two studies of combination therapy with gabapentin (n = 247) included children aged 3 to 12 years with refractory partial seizures. This study suggested a slight advantage in response rate for gabapentin compared with placebo, but this did not reach statistical significance. The smaller study (age range 1–36 months, n = 76) found no difference in response rates between the gabapentin and placebo groups. This was a very short trial in which seizure rate was monitored by continuous video-EEG recording over 72 hours.
4.1.4.3. The trials of gabapentin in children provided weak evidence of an advantage over no therapy (placebo). No evidence comparing gabapentin with alternative active therapies was identified.
4.1.5.1. No studies of tiagabine conducted exclusively in children were found. Two placebo-controlled trials of adjunctive tiagabine primarily conducted in adults included some children (the inclusion criteria specified an age range of 12–75 years). Both found that the proportion of responders (those with a reduction of at least 50% in seizure frequency) was significantly greater in the tiagabine group. However, only one published any specific information on the paediatric subgroup and this was reported only in the form of an abstract, which did not reproduce results. Thus the Committee received no additional evidence on the efficacy or effectiveness of tiagabine in children rather than adults.
4.1.6.1. Seven randomised controlled trials were included in the assessment report: two placebo-controlled trials of combination therapy with vigabatrin in children with previously diagnosed partial seizures; one placebo-controlled trial of combination therapy with vigabatrin in a mixed seizure-type population; one trial of vigabatrin monotherapy compared with carbamazepine in children with newly diagnosed partial seizures; one placebo-controlled trial of vigabatrin monotherapy in infantile spasms; and two active-controlled trials of vigabatrin monotherapy in West’s syndrome.
4.1.6.2. There was no statistically significant difference in seizure control between vigabatrin monotherapy and carbamazepine monotherapy in children with newly diagnosed partial seizures. This is not a licensed indication for vigabatrin.
4.1.6.3. The evidence for vigabatrin adjunctive therapy in previously diagnosed partial seizures was limited but supported superior efficacy compared with placebo. Both studies are only published in abstract form, so details are limited. One study compared vigabatrin (dose 1.5–4 g daily) with placebo in 88 patients with uncontrolled complex partial seizures. More patients in the vigabatrin group had a 50% or greater reduction in their seizure rate than in the placebo group (55.8% compared with 26.7%, p = 0.009). The other study (n = 126) was a dose ranging study that reported a statistically significantly greater reduction in seizure frequency in the highest of the three vigabatrin dose-groups (100mg/kg/day) than in the placebo group (p = 0.014). However, the actual reduction in seizure frequency was not reported and it is not clear how many patients were randomised to each of the treatment groups.
4.1.6.4. The remaining placebo-controlled study of adjunctive vigabatrin recruited people who had been treated with vigabatrin in various clinical trials for a variable length of time and with limited effect (n = 18). The participants were randomised to continue vigabatrin or withdraw to placebo. Fewer patients in the continued vigabatrin group were withdrawn from the study because of a worsening of seizure frequency or severity (7% compared with 54% in the placebo group). This indicates that people who benefit to a modest extent from vigabatrin therapy initially may continue to benefit while they remain on therapy.
4.1.6.5. The placebo-controlled trial of vigabatrin monotherapy for West’s syndrome was well conducted and reported and provided strong evidence that vigabatrin is superior to placebo. This study was conducted in 40 infants (age 1 to 20 months) with newly diagnosed and previously untreated West’s syndrome. However, the short duration (5 days) gave limited opportunity to identify side effects.
4.1.6.6. The two active-controlled trials of vigabatrin monotherapy indicated that vigabatrin may be superior to adrenocorticotrophic hormone (ACTH) and hydrocortisone. Both studies used a ‘response-mediated’ cross-over design in which patients who did not respond well to the allocated treatment were switched to the alternative treatment. This design is not well suited to comparing drugs. Taking the results from the first (parallel) period of the studies allows comparisons to be drawn. In the comparison with ACTH (n = 42), ACTH abolished spasms in a marginally greater proportion of patients (difference not statistically significant) but vigabatrin appeared to be better tolerated. The comparison with hydrocortisone (n = 22) found that all the patients in the vigabatrin group were spasm-free at one month compared with 5 out of 11 in the hydrocortisone group (p < 0.01). Limitations in the design and analysis of these studies mean that they do not provide strong evidence.
4.1.6.7. The evidence suggests that vigabatrin is better than placebo in the treatment of partial seizures and West’s syndrome. However, there is no convincing evidence of its superiority to the alternative therapies in either of these patient groups. There is concern over the significant risk of visual field defects associated with its use. The licence for vigabatrin reflects this concern. However, the risk of visual field defects must be balanced against the adverse effects of alternative therapies. In the case of hormone (steroid) treatment for West’s syndrome, this includes a risk of serious infection and mortality.
4.1.7. Newer antiepileptic drugs and childbearing potential
4.1.7.1. In selecting antiepileptic drugs for girls who are likely to need continued treatment into adulthood, safety in pregnancy needs to be considered. Few data are available on the use of newer antiepileptic drugs in pregnancy, and it is not yet possible to fully assess the risk of teratogenicity associated with them. Preliminary data from the UK Epilepsy and Pregnancy Register presented in 2002 (based on the outcomes of 2028 pregnancies) suggest that the crude rates for risk of major congenital malformation were 4% (95% confidence interval [CI], 3.2% to 5.3%) in women taking one antiepileptic drug and 6.3% (95% CI, 4.3% to 9.1%) in women taking more than one. There are also data for a small group of women with epilepsy (5.9% of the total) who were not exposed to antiepileptic drugs during pregnancy. The crude malformation rate in this group was 0.9% (95% CI, 0.2% to 4.7%). For the individual drugs, the risk in women taking carbamazepine was 2.3% (95% CI, 1.4% to 4.0%), the risk with sodium valproate was 7.2% (95% CI, 5.2% to 10.0%) and the risk with lamotrigine was 3% (95% CI, 1.5% to 5.7%). These data suggest that sodium valproate is associated with a significantly higher risk of malformations than carbamazepine. Although the crude rate for lamotrigine was lower than for sodium valproate, the difference was not statistically significant.
4.2. Cost effectiveness
4.2.1.1. The manufacturer submitted two economic analyses of lamotrigine in children. One was a simple decision tree with a 1-year time horizon comparing lamotrigine, carbamazepine and sodium valproate. The results indicated that the incremental cost-effectiveness ratio (ICER) for lamotrigine as first-line monotherapy was £13,045 per QALY gained. The second cost-effectiveness analysis considered lamotrigine as add-on therapy in children aged 2 years and over. The analysis did not consider a formal model of the management of epilepsy, but rather applied utility weights to outcomes observed in a placebo-controlled randomised controlled trial in order to produce cost–utility estimates. This approach estimated the ICER for lamotrigine add-on therapy to be £16,456 per QALY gained.
4.2.1.2. Neither of these analyses considered the chronic nature of epilepsy. In addition, the model for the monotherapy analysis considered first- and second-line therapy only, although significantly more therapeutic strategies are available; and the trial-based analysis had placebo as the comparator therapy.
4.2.1.3. The Assessment Group constructed a patient-level simulation model of the cost effectiveness of the newer anti-epileptic drugs in children. They used the model to examine the long-term cost effectiveness of adding lamotrigine to the portfolio of older antiepileptic drugs available. Patients were modelled as following a treatment algorithm starting with sequential monotherapy followed by adjunctive therapy, with progression based on the failure to achieve seizure freedom or the presence of unacceptable side effects. The analysis considered its cost effectiveness as first-line monotherapy, second-line monotherapy and first-line adjunctive therapy. The incremental costs were always positive, but the incremental benefits were sometimes negative and sometimes positive. The credible ranges for the ICERs on lamotrigine were: for first-line monotherapy, –£29,238 to + £44,118; for second-line monotherapy, –£41,628 to +£57,714; and for first-line adjunctive therapy, –£15,581 to +£22,500. These analyses indicated that there is significant uncertainty about the cost effectiveness of lamotrigine in each of these indications. Positive incremental costs were identified, as were a mixture of both positive and negative incremental QALYs.
4.2.1.4. It is plausible that lamotrigine is cost effective in all three indications. However, there is insufficient evidence for this to be stated with confidence.
4.2.2.1. Janssen-Cilag submitted three cost-effectiveness analyses of topiramate in children: combination therapy with topiramate compared with combination therapy with lamotrigine in partial seizures; monotherapy with topiramate compared with monotherapy with carbamazepine for partial seizures; and monotherapy with topiramate compared with monotherapy with sodium valproate in generalised seizures. The model reported that topiramate dominates lamotrigine as combination therapy; however, the comparison of topiramate with lamotrigine does not address the value of adding topiramate to the portfolio of older antiepileptic drugs.
4.2.2.2. The ICER for topiramate monotherapy was estimated to be £734 per QALY gained compared with carbamazepine and £635 per QALY gained compared with sodium valproate. The model used an efficacy estimate taken from an analysis of a small subgroup of children in one trial, which had only been published as a conference abstract. The sub-group analysis suggested a substantial efficacy advantage for topiramate monotherapy over sodium valproate and carbamazepine. The advantage is not consistent with the main trial results and the sensitivity analysis did not examine this issue.
4.2.2.3. The Assessment Group used the patient-level simulation model to examine the cost effectiveness of adding topiramate as a first-line adjunctive therapy to the portfolio of older antiepileptic drugs. These analyses indicated that there is significant uncertainty about the cost effectiveness of topiramate in children. The credible range for the incremental cost effectiveness ratio was –£48,431 to +£666,000. The Assessment Group did not examine the cost effectiveness of adding topiramate monotherapy to the portfolio of older antiepileptic drugs.
4.2.2.4. The assessment group also modelled the cost effectiveness of gabapentin and oxcarbazepine as first-choice adjunctive therapy. The model structure was the same as for the analyses of lamotrigine and topiramate. The incremental costs of gabapentin were always positive and the credible range for the ICER was –£273,000 to +£25,045 per QALY gained. The credible range for the incremental costs of oxcarbazepine included cost savings. The credible range for the ICER was –£22,352 to +£80,000.
4.3. Consideration of the evidence
4.3.1. The Appraisal Committee reviewed the evidence available on the clinical and cost effectiveness of newer antiepileptic drugs, having considered evidence on the nature of the condition and the value placed by children and/or their carers on the benefits of newer antiepileptic drugs from people with epilepsy, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the effective use of NHS resources.
4.3.2. The Committee considered that the evidence from randomised trials comparing newer and older antiepileptic drugs as monotherapy did not suggest differences in their overall effectiveness in seizure control. The Committee noted that most of the evidence on the effectiveness of newer antiepileptic drugs as monotherapy in children came from clinical trials in mixed age groups (that is, both adults and children were included in the same trial). There were very few data relating exclusively to children and to the types of epileptic disorder that commonly affect children. In coming to their conclusions, the Committee were persuaded that for the major licensed indications (generalised tonic–clonic seizures and/or partial seizures as appropriate to the individual drugs), the evidence from mixed-age trials could be considered alongside studies conducted principally or exclusively in adults.
4.3.3. Although side-effect profiles of newer and older drugs were different, the Committee considered that the evidence was inadequate to support a conclusion that the newer drugs were generally associated with improved quality of life. The Assessment Group’s cost-effectiveness analyses showed a high degree of uncertainty around the costs and benefits of these treatments.
4.3.4. The Assessment Group had not reported results for all possible comparisons and indications, as there was no evidence for superior efficacy of any of the therapies in any of the indications. However, the Committee considered that the model analyses provided useful insight into the cost effectiveness of all the newer antiepileptic drugs. The Committee considered that it was not possible to conclude that any of the newer anti-epileptic drugs were likely to be more cost effective than the older agents.
4.3.5. The Committee was also persuaded by the experts’ evidence that, before combination therapy is considered, children should be given a trial of all appropriate monotherapy regimens, with the changeover being carried out cautiously.
4.3.6. The experts and patient representatives stressed that the most important outcome for people with epilepsy is seizure freedom. The Committee reviewed the evidence for combination therapy with the newer antiepileptic drugs. While acknowledging that the evidence base on the use of these drugs in children was considerably sparser than that in adults, the Committee concluded that a significant proportion of children who do not achieve seizure freedom on monotherapy could derive worthwhile benefit from adjunctive therapy. The Committee noted that for some of the antiepileptic drugs used in combination therapy in children, there were few or no trials conducted exclusively in children demonstrating a benefit in terms of seizure control. The Committee accepted that, particularly for drugs used in combination therapy in older children and adolescents with partial seizures, it was appropriate to consider evidence from trials in adults and mixed-age populations alongside the evidence from studies in children. Other limitations in the evidence base include the relatively short duration of the studies of combination therapy (most were 3–6 months’ duration or less) and the limited number of direct comparisons between the newer drugs (none conducted in children). Because of these limitations, the Committee considered that it was not possible to determine whether any one drug was more likely to bring about seizure freedom over the longer term than any other.
4.3.7. The Committee was persuaded that, irrespective of which adjunctive therapy was used, children who do not derive worthwhile benefits in terms of significant seizure reduction or improvement in quality of life should not continue with that regimen in the long term. After sequential trials of combination therapies, if none of the combinations proves to be beneficial, then after discussion with the child and/or their carer, the child should revert to treatment with the regimen that proved most effective for him or her and had least side effects.
4.3.8. The Committee noted that, in addition to the general scarcity of well-conducted clinical studies of antiepileptic drugs in children, clinical experts were concerned that the available studies did not take account of the heterogeneity of the epilepsies. There were particular difficulties in assessing the effectiveness of antiepileptic drugs in children with defined seizure syndromes because entry to the studies was usually determined by seizure type (partial or generalised seizures or multiple seizure types). This could have meant that the studies inappropriately mixed patients with different epilepsy disorders and varied prognoses. These studies are not helpful when tailoring antiepileptic drug treatment to the needs of the child, and often decisions are based on less robust sources of evidence and individual clinician’s opinions and experience. However, the Committee recognised the importance of having a range of therapies available for the treatment of epilepsies in the light of variation in children’s responses.
4.3.9. The Committee noted the lack of high-quality evidence on which to base decisions on the most appropriate treatments for children with learning disabilities. The Committee decided the considerations surrounding choice of treatment and the importance of regular monitoring of effectiveness and tolerability were largely the same as for the general population.
4.3.10. The Committee heard from the experts that some people may be maintained for long periods on ineffective medication, or therapy that is not well tolerated. The experts highlighted the importance of regular monitoring of patients to review and optimise their treatment.
4.3.11. The experts stressed to the Committee the value of vigabatrin in the management of West’s syndrome. Their opinion was based on the balance of the known risks and benefits for the use of vigabatrin in this clinical situation
4.3.12. The Committee noted that the issue of whether antiepileptic drugs may be harmful to the unborn child is a matter of major concern and should be considered in the treatment of girls of childbearing potential (and younger girls who are likely to need continued treatment into adolescence and adulthood). The Committee took specific note of the particular concern regarding the risks to the unborn child associated with sodium valproate and that, because of this, the Summary of Product Characteristics for sodium valproate (Epilim) warns that, for partial seizures, it should be used in women and girls only if they are resistant to other treatments. The experts advised the Committee that despite the concerns highlighted in the Summary of Product Characteristics, sodium valproate may be an appropriate choice for women or girls with some types of generalised seizures. However, when considering the use of sodium valproate in girls of childbearing potential, the risks and benefits must be clearly communicated with both the child and her carer as appropriate to ensure that an informed choice is made. The Committee were persuaded that, as yet, there are few data upon which to base an assessment of the potential risks of teratogenicity associated with newer drugs.
4.3.13. Additionally, the Committee took note of the potential for drug interactions with the use of the antiepileptic drugs and, in particular, interaction with oral contraceptives, which may be of relevance in girls of childbearing potential. They concluded that this aspect of therapy should be taken into account in determining the most suitable treatment for any individual patient.
4.3.14. The Committee discussed the issue of generic prescribing in relation to antiepileptic drugs. They noted that the experts had particular concerns about the use of generic products, particularly in relation to some of the older drugs, such as phenytoin, where the pharmacokinetics are such that small differences in absorption can result in large differences in therapeutic effect. However, the Committee did not consider that it had adequate evidence to make recommendations on the use of generic products in the treatment of epilepsy.
4.3.15. The Committee were aware of the importance of investigation and early accurate diagnosis for children experiencing a first seizure so that an appropriate pathway of care including drug therapy can be put in place efficiently. In addition, the experts emphasised the importance of appropriate follow-up arrangements including, where necessary, shared care arrangements for all children with epilepsy, in order to ensure they were on the most appropriate treatment regimen.
