107 Study protocol 3 Power calculation for the primary outcome parameter A sample size of 23 pairs with a correlation equal to 0 achieves 79% power to detect a difference of -5,2 between the null hypothesis mean difference of 0 and the actual mean difference of -5,2 at the 5% significance level (alpha) using a two-sided Wilcoxon SignedRank Test. These results are based on 3000 Monte Carlo samples from the null distribution: Normal with mean 3.4 and standard deviation 5.4 and the alternative distribution Normal with mean 8.6 and standard deviation equal to 6.3. Power computations are performed with PASS 2020 Power Analysis & Sample Size (https://www.ncss.com/software/pass/). We will include 50 patients in our RCT. Identification study The Identification study aims to select eligible patients for the RCT. Based on our previous study, we estimate that 40% of the included ALL patients experience clinically relevant neurobehavioral side effects.14 Estimating the probability of a 10% dropout rate, a 35% refusal rate and exclusion of 15% based on our exclusion criteria, a total of approximately 150 patients will be included in the Identification study course (Figure 2). The secondary aims for studies in the Identification cohort are to investigate possible factors associated to the inter-patient variability in dexamethasone-induced neurobehavioral problems, including pharmacokinetics, candidate single nucleotide polymorphisms (SNP) analyses and psychosocial and environmental factors. Patients with a rise of five or more points on the SDQ Total Difficulties score after five days of dexamethasone (T1-T2, Figure 1) will be compared with patients with a rise of four or less points. Dexamethasone kinetics are measured through peak levels (measured 2–3 hours after the first dexamethasone administration on day 1 of the dexamethasone course (T1)) and trough levels (measured on day 6 (T2), after the last dexamethasone dose the previous evening). To identify possible very slow metabolizers, an additional blood sample will be taken on day 8, i.e. two full days after the last dexamethasone dose (T2a). A blood sample to evaluate carrier status of several relevant candidate SNP is taken on T1. Germline DNA will be extracted and candidate SNP analysis of the GR gene (NR3C1), including Bcl1 polymorphism (rs41423247 variant), ER22/23EK polymorphism (rs6189) and N363S/A1220G polymorphism, and the AHSG gene (rs4918 variant) will be included. Psychosocial and environmental factors include parenting stress, measured with the NOSI-K (Nijmeegse Ouderlijke Stress Index),33 i.e. the adapted and shortened Dutch version of the Parental Stress Index (PSI)34 and the Distress Thermometer (DT).35,36 Several questions about received psychosocial support and education are filled in at T1 and T2. Eating and hunger satiety are measured using an Eating thermometer (a visual analogue scale to indicate hunger).
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