Melatonin in Youth: N-of-1 trials in a stimulant-treated ADHD Population (MYNAP): study protocol for a randomized controlled trial.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder affecting 5 % of children worldwide. A prevalent problem for children with ADHD is initial insomnia. The gold standard treatment to manage ADHD symptoms is stimulant medications, which may exacerbate the severity of existing initial insomnia. Currently, no gold standard treatment option exists for initial insomnia for these children. Melatonin, a hormone and a popular natural health product, is commonly provided to children by parents and recommended by healthcare providers, but high quality pediatric evidence is lacking. METHODS/DESIGN: This trial is a multicenter randomized triple-blind, placebo-controlled, parallel-group, randomized, controlled trial (RCT), in which each participant is offered an N-of-1 trial. An N-of-1 trial is a multiple-crossover, randomized, controlled trial conducted in a single individual. For the N-of-1 trial, each participant will undergo three pairs of treatment/placebo periods; each period is 1 week in length. Half the participants will have melatonin in the first period, the other half will start with placebo, and this will make up the parallel-group RCT. The primary outcome will be mean difference in sleep onset latency as measured by sleep diaries. A comparison of treatment effects yielded by the RCT data versus the aggregated N-of-1 trial data will also be assessed. DISCUSSION: This trial will provide rigorous evidence for the effectiveness of melatonin in children with ADHD on stimulants who experience initial insomnia. Further, this study will provide the first prospectively planned head-to-head comparison of RCT data with pooled data from a series of N-of-1 trials. Aggregated N-of-1 trials may be a powerful tool to produce high quality clinical trial evidence. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov, NCT02333149 . Registered on 16 December 2014. Australian New Zealand Clinical Trials Registry, ACTRN12614000542695 . Registered on 21 May 2014.

The Effect of Methylphenidate on Fatigue in Advanced Cancer: An Aggregated N-of-1 Trial.

CONTEXT: Fatigue is common in life-limiting cancer. Methylphenidate (MPH), a psychostimulant, may be a useful therapy. Gathering evidence in patients with advanced cancer can be challenging. OBJECTIVES: To determine if MPH improves cancer-related fatigue in people with advanced cancer. METHODS: N-of-1 trials are multicycle, double-blind, randomized, controlled crossover trials using standardized measures of effect in individuals. They are normally used to assess treatment effects in individuals. Aggregated N-of-1 trials from participants with end-stage cancer suffering fatigue were used to assess the group effect of MPH, producing an estimate of equivalent power to a parallel-group randomized controlled trial (RCT) but requiring less than half of the sample size. Up to three cycles of MPH 5 mg twice daily (three days) vs. identical placebo (three days) capsules were offered to participants. Primary outcome was improvement in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue Scale and the Wu Cancer Fatigue Scale. Analysis used Bayesian statistical methods using intention-to-treat principles. RESULTS: Forty-three participants completed 84 cycles of MPH and placebo in random order, exceeding sample size estimates. Overall, MPH did not improve fatigue (mean difference 3.2; 95% credible interval -2.0, 9.0; posterior probability of favorable effect 0.890). Eight participants showed important improvement, and one participant showed important worsening of fatigue on MPH. There were no features that distinguished participants whose fatigue responded to MPH compared with those who did not. CONCLUSION: MPH does not improve fatigue in the population of patients with end-stage cancer. Aggregated N-of-1 trial methodology is feasible and produces population-based sample estimates with less than half the sample size required for the equivalent parallel-group RCT. It also identified individuals who did and did not respond to MPH, which is a feature difficult to achieve in a standard RCT. The study was registered with the Australian Clinical Trials Registry (12609000794202).

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.