106 Chapter 3 The secondary aim is to estimate the percentage of patients with clinically relevant dexamethasone-induced sleeping problems and replicate our previous finding that addition of physiological doses of hydrocortisone to standard dexamethasone treatment reduces these sleeping problems. Sleeping difficulties are measured using the Sleep Disturbance Scale for Children (SDSC)28,29 at T3 + 4 and T7 + 8, i.e. before and after one course hydrocortisone and one course placebo. Sleep is measured through actigraphy as well.30 Patients wear a nonintrusive wrist actigraph for seven days.31 Parents are asked to keep a sleep log during the actigraphy measurement to interpret the data. These measurements take place twice: once when a patient receives hydrocortisone and once during placebo. We also evaluate whether hydrocortisone addition improves HRQoL in patients with dexamethasone-induced clinically relevant neurobehavioral problems. HRQoL is measured with the Pediatric Quality of Life questionnaire (PedsQL).32 The PedsQL is filled in before and after a hydrocortisone and placebo course, at T3+4 and T7+8. Randomization and blinding Patients are allocated to start with hydrocortisone or placebo using the method of a prefixed randomization list. This randomization list is prepared by the pharmacy, independent of the clinical investigators. The study is double blinded. Blinding of subject, researchers and physicians is ensured through use of the investigational medicinal product (IMP) and an identical placebo solution. In case of problems regarding study medication, the randomization list is available 24 hours per day through the pharmacy. Investigational treatment The IMP is hydrocortisone solution, given orally. The drug is administered in physiological dosages of 10 mg/m2/day. Patients use hydrocortisone (1 mg/ml) or placebo three times daily divided in a ratio of 5:3:2, following the physiological circadian rhythm. Patients receive hydrocortisone (two consecutive courses) or placebo (two consecutive courses) in a randomized order during a five-day dexamethasone treatment. A washout period of at least 2 weeks and 2 days is always present between courses to prevent carryover effect. After 2 courses cross-over takes place (Figure 1). The washout period renders the carry-over effect in the next period negligible. The idea is to use each patient as his own control by trying both regiments at different times and comparing the results. Pharmacovigilance is guaranteed by measuring the fluid volume in the medicine bottles after each 5-day course of study medication.
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