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    Clinical Trial Results:
    Double blind placebo controlled randomized intervention study aiming at reducing dexamethasone related side effects in children with acute lymphoblastic leukemia (ALL).

    Summary
    EudraCT number
    		 2011-003815-46
    Trial protocol
    		 NL  
    Global end of trial date
    17 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2021
    First version publication date
    21 Aug 2021
    Other versions
    Summary report(s)
    		 HC as intervention for dexamethason induced adverse effects

    Trial information

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    Trial identification
    Sponsor protocol code
    37826
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Dutch trialregistry: NL3129
    Sponsors
    Sponsor organisation name
    Erasmus MC
    Sponsor organisation address
    Dr. Molewaterplein 60, Rotterdam, Netherlands, 3015 GJ
    Public contact
    ELT van den Akker, Erasmus MC, +31 107030703, e.l.t.vandenakker@erasmusmc.nl
    Scientific contact
    ELT van den Akker, Erasmus MC, +31 107030703, e.l.t.vandenakker@erasmusmc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To reduce dexamethasone induced cerebral side-effects on mood, behaviour, and cognition by intervention treatment with physiological doses of cortisol compared to placebo.
    Protection of trial subjects
    The risk-benefit analysis for the study showed a favorable risk profile. The IMP that was studied is hydrocortisone, given in a physiological dose, NOT in a pharmacological dose. No side effects were expected in this dose. In addition, we performed preclinical 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. Since we did not expect major risks, we did not install a data and safety monitoring board (DSMB) for this study Safety assessments consisted of collecting all adverse events (AEs), serious adverse events (SAEs), with their severity and relationship to study drug. They included the regular assessment of the patient's physical condition, and performance status
    Background therapy
    		 This study is a double blind placebo-controlled randomized crossover study. Patients received the IMP or the placebo during 2 periods of a 5-day dexamethasone treatment. All children were randomized into two groups: either dexa + IMP or dexa + placebo first. After a washout period of 2 weeks and 2 days, a new medication period was started where the group that had a placebo in the first period received the study drug and the other group got the placebo. The intervention product was hydrocortisone suspension, given orally. This drug was given in a physiological dose of 10 mg/m2/day. Patients used the hydrocortisone solution (1mg/ml) or placebo 3 times daily orally (5:3:2 ratio / circadian rhythm). Timing of intake: first dose after awakening. Second dose between 12am and 1pm, the third dose between 6pm and 8 pm.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    31 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    50
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place between 31-may-2012 and 30-mar-2015 The study has a cross-over design. Participants were randomised to: A: hydrocortisone for 5 days; after a wash-out period of 2 weeks and 2 days placebo for 5 days B: placebo for 5 days; after a wash-out period of 2 weeks and 2 days hydrocortisone for 5 days

    Pre-assignment
    Screening details
    		 101 eligible patients were screened; 51 refused for following reasons: - burden too high (37) - no side effects of dexamethasone (8) - no participation in studies (30 - refuse to drink oral solution (2)

    Pre-assignment period milestones
    Number of subjects started
    		 50
    Number of subjects completed
    		 50

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Patients were randomized electronically via the website ALEA The Erasmus MC pharmacy prepared the IMP as well as the placebo suspension

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Hydrocortisone
    Arm description
    		 treatment with Hydrocortisone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hydrocortisone
    Investigational medicinal product code
    H02AB09 (CAS 50-23-7)
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg/m2/day. Patients used the hydrocortisone solution (1mg/ml) 3 times daily in a circadian rhythm (5:3:2 ratio)

    Arm title
    		 Placebo
    Arm description
    		 Treatment with Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    not applicable
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg/m2/day. Patients used the placebo solution 3 times daily in a circadian rhythm (5:3:2 ratio)

    Number of subjects in period 1
    		Hydrocortisone Placebo
    Started
    50
    50
    completed all SDQ testmoments
    46
    48
    Completed
    46
    48
    Not completed
    4
    2
         dexamethasone was stopped
    2
    -
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 7.0 (5.5 to 12.0) -
    Gender categorical
    Units: Subjects
        Female
    		 27 27
        Male
    		 23 23
    ALL subtype
    Units: Subjects
        B-ALL
    		 46 46
        T-ALL
    		 4 4
    CNS status
    Involvement of CNS in the disease
    Units: Subjects
        CNS 1
    		 22 22
        CNS 2
    		 28 28
        CNS 3
    		 0 0
    Week of maintenance phase
    At what week during the ALL11 maintenance treatment did the intervention take place
    Units: number
        arithmetic mean (full range (min-max))
    		 37.0 (31.0 to 49.5) -

    End points

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    End points reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 treatment with Hydrocortisone

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with Placebo

    Primary: SDQ

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    End point title
    		 SDQ
    End point description
    SDQ is a questionnaire to measure emotional complaints/stress. The score is given in subcategories
    End point type
    Primary
    End point timeframe
    SDQ is measured at 4 timepoints: at day 1 and 5 of hydrocortisone treatment and at day 1 and 5 of placebo treatment Number given are man delta for each arm
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    46
    46
    Units: amount
    arithmetic mean (standard error)
        SDQ overall stress
    2.6 ± 0.61
    3.4 ± 0.80
        SDQ EmoDis
    0.9 ± 0.28
    1.5 ± 0.34
        SDQ BehavDiff
    0.5 ± 0.19
    0.5 ± 0.20
        SDQ HypAttent
    0.6 ± 0.24
    0.6 ± 0.30
        SDQ GetAlong
    0.6 ± 0.16
    0.8 ± 0.25
        SDQ Helpful
    -1.6 ± 0.33
    -1.5 ± 0.37
        SDQ Impact
    0.8 ± 0.32
    1.3 ± 0.35
    Statistical analysis title
    		 SDQ
    Statistical analysis description
    Paired T-test to compare delta of SDQ-scores between two arms
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 ≤ 0.01 [2]
    Method
    		 paired T-test
    Parameter type
    		 paired T-test
    Confidence interval
    Notes
    [1] - DO SDQ differ significantly between the arms?
    [2] - Not one p-vallue proved to be significant: P value SDQ_overallstress 0.33 SDQ_EmoDis 0.08 SDQ_BehavDiff 1.00 SDQ_HypAttent 1.00 SDQ_GetAlong 0.61 SDQ_Helpful 0.71 SDQ_Impact 0.08

    Primary: SDSC

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    End point title
    		 SDSC
    End point description
    DA, disorders of arousal; DES, disorders of excessive somnolence; DIMS, disorders of initiating and maintaining sleep; SBD, sleep breathing disorders; SHY, sleep hyperhidrosis; SWTD, sleep-wake transition disorders.
    End point type
    Primary
    End point timeframe
    Questionnaire taken at day 1 and day 5 of hydrocortisone as well as placebo treatment
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    47
    47
    Units: amount
    arithmetic mean (standard error)
        SDSC total
    1.2 ± 1.2
    1.5 ± 1.1
        DIMS
    0.7 ± 0.5
    0.4 ± 0.7
        DA
    -0.1 ± 0.1
    -0.3 ± 0.1
        SBD
    -0.1 ± 0.1
    0.0 ± 0.1
        DES
    1.1 ± 0.4
    1.8 ± 0.5
        SHY
    0.0 ± 0.2
    0.3 ± 0.2
        SWTD
    -0.3 ± 0.3
    -0.7 ± 0.2
    Statistical analysis title
    		 SDSC
    Statistical analysis description
    Does hydrocortisone decrease sleeping problems caused by dexamethasone
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.01 [3]
    Method
    		 paired T-test
    Confidence interval
    Notes
    [3] - P value (Paired T-test) Total 0.84 DIMS 0.74 SWTD 0.29 DES 0.19 SBD 0.79 DA 0.45 SHY 0.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events according to the NCI CTCAE version 4.0 after 4 full days of hydrocortisone or placebo administration
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 All subjects receiving a course of hydrocortisone

    Reporting group title
    Placebo
    Reporting group description
    		 All subjects receiving a course of placebo

    Serious adverse events
    		 Hydrocortisone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 48 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Hydrocortisone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 48 (4.17%)
    General disorders and administration site conditions
    Tiredness
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Oct 2012
    Addition of questionnaire for non-participants
    19 Jun 2013
    Addition of two participating sites in the Netherlands No hydrocortisone continuation after study completion
    09 Jul 2013
    Addition of another site in the Netherlands Changing SAE reporting to 16 days after last administration of study medication
    16 Oct 2014
    Addition of another site in the Netherlands

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27161966
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