Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder

Clinical effectiveness

4.5 The Committee considered the relevance of the USA-based NCT00110461 trial to UK clinical practice. It discussed whether the population in the trial reflected that seen in UK clinical practice. The Committee noted that the trial recruited people who were aged between 10 and 17 years and that approximately 63% of the trial participants were aged 13 or older, and so were within the UK marketing authorisation. The Committee heard from the clinical specialists that the diagnosis criteria for bipolar I disorder in children and adolescents in the UK differed from those used in the USA and it is likely that some of the participants with bipolar I disorder comorbid with ADHD in the trial would not have been diagnosed with bipolar I disorder in the UK. The clinical specialists also confirmed that it was usual in clinical trials involving children and adolescents with bipolar I disorder to exclude people with learning disabilities and those at risk of suicide. The Committee discussed the concerns raised by the ERG that most of the participants recruited to the trial were treated as outpatients, whereas in UK clinical practice, they would be usually treated as inpatients. The Committee heard from the clinical specialists that a significant proportion of people in the NHS are managed as outpatients, especially outside the major cities where there is often limited availability of inpatient facilities for this age group. The Committee concluded that the results from the NCT00110461 trial were generalisable to UK clinical practice.

4.6 The Committee then considered the clinical-effectiveness results of the NCT00110461 trial, which showed that aripiprazole was associated with a statistically significant reduction in total YMRS score when compared with placebo throughout the 30-week study duration based on the last observation carried forward dataset. The Committee understood that the marketing authorisation is restricted to 12 weeks' treatment because of high discontinuation rates and the lack of a statistically significant difference in efficacy outcomes beyond 12 weeks when the analysis was based on the observed case dataset. The Committee discussed the usefulness of the YMRS score as the primary outcome and heard from the clinical specialists that this score is a well-recognised tool used in clinical trials for assessing symptoms of mania but that the tool is not routinely used by all clinicians in the UK. The clinical specialists explained that any changes in the YMRS are clearly evident in the change in severity of the symptoms of the individual. The Committee accepted that the YMRS is a valid tool for measuring the severity of symptoms of mania. It concluded that evidence from the trial demonstrated a reduction in manic symptoms in those receiving aripiprazole for 12 weeks compared with those receiving placebo.

4.7 The Committee considered the adverse event data from the NCT00110461 trial. Extrapyramidal disorder and somnolence were statistically significantly more common in those receiving either 10 mg or 30 mg aripiprazole compared with those receiving placebo. Akathisia was statistically significantly more common, but only in those receiving the 30 mg dose of aripiprazole compared with those receiving placebo. It noted there were no statistically significant increases in weight gain or BMI in those receiving aripiprazole compared with those receiving placebo at 4 weeks. The Committee heard from the clinical specialists that the patterns of adverse events seen in the trial were consistent with the use of aripiprazole in other indications. The clinical specialists also stated that for this group, in the short term, somnolence may help in the management of acute mania. The Committee noted the lack of long-term safety data for aripiprazole, but was aware that the risk management plan agreed with the EMA included a long-term (up to 2 years) study to evaluate the safety and tolerability of aripiprazole as maintenance treatment in adolescents with schizophrenia, and children and adolescents with bipolar disorder. The Committee concluded that current evidence suggests that the tolerability and range of adverse reactions associated with aripiprazole are acceptable. The Committee was aware that the population in the NCT00110461 trial was broader than that in the UK marketing authorisation, because the trial included children aged younger than 13 years and those with mixed episodes. The Committee understood that the EMA had restricted the licence for aripiprazole to adolescents aged 13 or older because of safety concerns in younger people. The Committee noted that the manufacturer had presented clinical efficacy and safety results in its submission by age group, that is, for ages 10–12 years and 13–17 years. The Committee noted that the subgroup analysis by age group suggested that there was no change in treatment effect between the age subgroups, but that the younger age group experienced a greater increase in mean weight and BMI changes from baseline at week 12. The Committee noted that the manufacturer provided baseline data on the current episode type (manic or mixed) but a subgroup analysis by age group and episode type was not presented. The Committee understood that these subgroups were post hoc subgroups. It was also aware that the subgroup analyses were based on small numbers of people in the groups, which increased the uncertainty in the results. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of NCT00110461.

4.8 The Committee noted that there were no head-to-head comparisons of aripiprazole with the other comparator antipsychotics. The Committee considered the manufacturer's approach to conducting a network meta-analysis to determine the relative efficacy and tolerability of aripiprazole, risperidone, olanzapine and quetiapine. The Committee noted and accepted the ERG's concerns about the network meta-analysis (see sections 3.37–3.39). The Committee was aware that using a random-effects model in the network meta-analysis as suggested by the ERG produced results similar to those obtained by the manufacturer. The Committee therefore accepted the results of the network meta-analysis as a reasonable basis for the economic model given the evidence available.

4.9 The Committee considered the clinical effectiveness evidence of aripiprazole compared with risperidone, olanzapine and quetiapine obtained from the network meta-analysis. It noted that the results suggested that aripiprazole and the other antipsychotics showed greater efficacy than placebo but that no statistically significant differences in efficacy were found between aripiprazole and the other antipsychotics. It then considered the adverse-event profile of aripiprazole compared with risperidone, olanzapine and quetiapine. It was aware that the results suggested that the extrapyramidal symptoms and somnolence occurred more frequently with aripiprazole than with risperidone or quetiapine but that these results were not statistically significant. The Committee also noted that the results suggested that clinically significant weight gain was statistically significantly less likely with aripiprazole than with olanzapine or quetiapine. The Committee was aware of the testimony from the clinical specialists about the importance of having a range of treatments available in order to individualise treatment, minimise adverse treatment effects and therefore increase adherence to medication. The Committee heard from the clinical specialists that avoiding weight gain may be of considerable importance to adolescents. The Committee concluded that based on the evidence available, aripiprazole was as effective as other antipsychotics for treating acute mania and had a comparable and acceptable adverse reaction profile.

Cost effectiveness

4.10 The Committee considered the manufacturer's economic model and the ERG's critique and exploratory analysis. It noted that the ERG considered the manufacturer's model to be transparent, robust, and well structured. The Committee agreed that the model structure was appropriate.

4.11 The Committee considered the manufacturer's base case in which strategies with aripiprazole used at any stage of the treatment pathway (that is, strategies 2 to 4) were compared with a treatment strategy without aripiprazole (strategy 1). The Committee noted that the manufacturer had undertaken a number of deterministic sensitivity analyses (see section 3.32). The Committee was aware that the main parameters that could make the strategies including aripiprazole become less cost effective were the rates of response applied during the treatment phase. The Committee noted that a higher response rate during the treatment phase resulted in people leaving hospital earlier, which had both cost and health-related quality-of-life benefits. The Committee was also aware that the manufacturer's probabilistic sensitivity analyses suggested that there was uncertainty surrounding the ICERs and it understood that this may be a result of the lack of statistically significant differences in response rates obtained from the network meta-analysis for the 4 antipsychotics. The Committee noted that the results from the manufacturer's probabilistic sensitivity analyses indicated that for the 3 strategies that include aripiprazole, the majority of the probabilistic sensitivity iterations indicated cost effectiveness or dominance. The Committee therefore agreed that the base-case results suggested that a treatment strategy that includes aripiprazole is a cost-effective option when compared with a treatment strategy without it.

4.12 The Committee then considered the impact of the position of aripiprazole within the treatment pathway on the cost effectiveness results. The Committee discussed the results of the manufacturer's base case as presented in the incremental analysis. The Committee noted that the pathway in which aripiprazole was positioned second, that is strategy 2, dominated all of the other strategies. The Committee also noted that a comparison of the ranges of costs and QALYs (in the base case, costs ranged from £74,133 to £75,066, and QALYs ranged from 2.516 to 2.525) across the strategies showed that they were similar. The Committee noted that the treatment pathway without aripiprazole (strategy 1) was dominated by each of the other treatment pathways including aripiprazole in over half of the probabilistic sensitivity analysis iterations, and that the probability of strategy 1 being the most cost-effective strategy was half the probabilities for strategy 2 and strategy 3 for all of the thresholds explored by the ERG (see section 3.41). Given that each of the strategies was dominated by every other strategy in at least some of the probabilistic iterations, the Committee agreed that the results were not sufficiently robust to make a recommendation on the position of aripiprazole in the treatment pathway. The Committee concluded that aripiprazole should be recommended as an option for the treatment of moderate to severe manic episodes in bipolar I disorder in adolescents.

Summary of Appraisal Committee's key conclusions