Aggregated n-of-1 trials of central nervous system stimulants versus placebo for paediatric traumatic brain injury – a pilot study

BACKGROUND: In 2006 there were 432,700 people in Australia who had acquired brain injury (ABI) with some limitation of activities; 90% of these were traumatic brain injuries (TBIs) and nearly a third sustained injury below age 15 years. One to four years post injury, 20% to 46% of children with traumatic brain injury (TBI) have clinically significant disorders of attention. There is controversy as to whether central nervous system (CNS) stimulants can be an effective method of treating these. Objectives were to determine the efficacy of CNS stimulants for children with TBI, and to calculate the sample size for a larger trial using the Conners’ 3 Parent Rating Scales Score as the primary endpoint. METHODS: Pilot series of aggregated prospective randomised, double-blind, n-of-1 trials of stimulant versus placebo within individual patients. Setting: tertiary children’s public hospital. Participants: ten children aged 6 to 16 years more than 12 months post TBI with attention, concentration and behavioral difficulties on stimulants. Interventions: Three cycles of methylphenidate or dexamphetamine orally at doses titrated by physician compared to placebo. Main Outcome Measures: Conners 3 Parent (Conners 3-P) and Teacher (Conners 3-T) Rating Scales (Global Index), Behaviour Rating Inventory of Executive Function (BRIEF) and Eyberg Child Behaviour Inventory (ECBI). RESULTS: Five of ten patients completed the study. Data from 18 completed cycles from seven patients were analysed. The posterior mean difference between stimulant and placebo scores for the Conners 3-PS (Global Index) was 2.3 (SD 6.2; 95% credible region -1.0 to 6.1; posterior probability that this mean difference was greater than zero was 0.92), and for the Conners 3-T (Global Index) the posterior mean difference was 5.9 (SD 4.5; 95% credible region -3.1 to 14.9; posterior probability 0.93). Posterior mean differences suggest improvement in behaviour and executive function and a decrease in number and intensity of child behaviour problems when taking stimulants compared to placebo. Taken together these data are suggestive of a small benefit at group level. CONCLUSIONS: In this pilot study, there was sufficient evidence that stimulants may be useful in management of behavioral and cognitive sequelae following TBI, to warrant a larger trial. TRIAL REGISTRATION: he trial was registered with the Australian and New Zealand Clinical Trials Registry: registration number ACTRN12609000873224.