The 'how to survive my dex days' study.

Rationale:

The use of dexamethasone (a synthetic corticosteroid) is an essential component for effective treatment of childhood acute lymphoblastic leukemia (ALL). However, it has been reported that in 5-75% of children, treatment with dexamethasone, is accompanied by serious side-effects on mood, cognition and behaviour leading to major effects on wellbeing of children and their parents. In addition, these side-effects often induce therapy adjustments with the risk of decreased effect and subsequent outcome. The exact pathophysiology of the dexamethasone-induced cerebral side-effects is unknown but has been presumed to be mediated by its effect on the glucocorticoid receptor. Dexamethasone suppresses endogenous production of cortisol. Recent findings show that lack of endogenous cortisol can lead to such side-effects by lack of stimulation of the mineralocorticoid receptor (MR) in the brain. Cortisol dependent mineralocorticoid receptor effects in the brain have been shown to be involved in emotion, memory and sleep. These recent findings led to our novel hypothesis: During treatment with dexamethasone, the deprived mineralocorticoid receptor may cause serious cerebral side effects. Hence, it is feasible that these side effects on mood, behaviour and cognition could be prevented, by an intervention with a natural occurring hormone that stimulates the mineralocorticoid receptor in the brain in a physiological way. This can be done by adding physiological dosages of cortisol during dexamethasone treatment. To ensure the safety of this study, we performed a preclinical study, in which we found that adding cortisol to both in vitro cultured leukemic cell lines and ex vivo cultured primary patients¡¦ cells, did not influence the anti-leukemic effect of dexamethasone. Previously, we and others have shown that in vitro dexamethasone sensitivity is strongly associated with clinical steroid response and with clinical outcome.



Objective:

The primary aim of the study is to reduce dexamethasone induced cerebral side-effects on mood, behaviour, and cognition by adding physiological doses of cortisol to standard treatment.

The secondary aim of the study is to analyse the effect of the intervention on other side-effects of dexamethasone; e.g. side-effects like diabetes mellitus, insulin resistance, visceral fat gain, hypertension and hypercholesterolemia.

The third aim of the study is to determine the positive predictive value positive predictive value of the salivary very low dose dexamethasone suppression test with cortisol as a novel in vivo diagnostic test, on dexamethasone side-effects.



Study design:

A prospective double blind placebo-controlled randomized cross-over design.



Study population:

50 patients, aged 3-16 years, treated according to medium risk ALL treatment schedule will be included after informed consent.



Intervention:

During 2 identical periods of 5 days of dexamethasone treatment, in addition, patients will receive either a physiological dose of cortisol (intervention) or placebo.



Main study parameters/endpoints:

1. Questionaires: The parent-reported strength and difficulty questionnaire in Dutch (SDQ-Dut) 20 after 5 days of dexamethasone treatment with or without cortisol;

2. Bloodtest results: Cortisol, lipid spectrum etc;

3. Measurement of blood pressure, BMI, weight;

4. Complaints diary;

5. Food dairy;

6. Neuropsychological test;

7. Physical activity.



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Extent and burden is low.

The risk-benefit analysis for the study shows a favorable risk profile. The investigational medicinal product (IMP) that is studied is hydrocortisone, given in a physiological dose, NOT in a pharmacological dose. No side effects are expected in this dose. In addition, we performed pre-clinical in vitro and ex vivo studies to prove that adding cortisol to treatment will not have any negative effects on the efficacy of cytotoxic effect on leukemia cells.

Participants will fill in 4 questionairres on mood, behavior and daily activity, 1 dietary diary (24 hour) at home. They will have 4 neuropsychological tests on cognition, memory and attention during hospital visits (total extra time: 2 hours/visit). In addition they are asked to wear a accelerometer (3x3 cm on their belt) for 2x 5 days (intervention and placebo period) to measure physical activity. Before start of the intervention they will perform once a salivary diurnal cortisol rhythm and a diagnostic salivary very low dose (0,25 mg) dexamethasone suppression test at home, which involves taking 4 salivary samples one day, ingestion of 0,25 mg dexamethasone (weight adjusted) in the evening and one salivary sample the next day. Blood sampling will be done 4 times 2 ml, using the existing vascular access ports, during regular hospital visits, when routine blood tests are already planned.

The intervention drug is widely used and we have ample experience with this drug. The intervention drug is a hydrocortisone, given in a physiological dose, NOT in a pharmacological dose. No side effects are expected in this dose. In addition we performed pre-clinical in vitro and ex vivo studies to prove that adding cortisol to treatment will not have any negative effects on leukemia treatment. As the administered dose of cortisol in the intervention arm of the study is a physiological dose, we do not expect major risks, and hence we will not install a data and safety monitoring board (DSMB) for this study.

During treatment with dexamethasone, the deprived mineralocorticoid receptor may cause serious cerebral side effects. Hence, it is feasible that these side effects on mood, behaviour and cognition could be prevented, by an intervention with a natural occurring hormone that stimulates the mineralocorticoid receptor in the brain in a physiological way. This can be done by adding physiological dosages of cortisol during dexamethasone treatment. To ensure the safety of this study, we performed a preclinical study, in which we found that adding cortisol to both in vitro cultured leukemic cell lines and ex vivo cultured primary patients¡¦ cells, did not influence the anti-leukemic effect of dexamethasone. Previously, we and others have shown that in vitro dexamethasone sensitivity is strongly associated with clinical steroid response and with clinical outcome.

For individual profiles of corticosteroid sensitivity the following data will be obtained: salivary diurnal cortisol rhythm (area under the curve), salivary very low dose (0,25 mg) dexamethasone suppression test one week before start of the first dexamethasone course. Neurocognitive tests, questionnaires, blood samples will be done before start and at the end of the two five-day courses. Patients receive the IMP or the placebo during 2 periods of a 5 day dexamethasone treatment. During each course patients will report in a dietary diary and will wear an accelerometer to measure physical activity.

During 2 identical periods of 5 days of dexamethasone treatment, in addition, patients will receive either a physiological dose of cortisol (intervention) or placebo.