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    Summary
    EudraCT Number:2017-002738-22
    Sponsor's Protocol Code Number:62388
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-09
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-002738-22
    A.3Full title of the trial
    Double blind placebo controlled randomized intervention study to validate the beneficial effect of hydrocortisone on dexamethasone-induced neurobehavioral side effects in pediatric acute lymphoblastic leukemia
    Een dubbelblinde placebo gecontroleerde gerandomiseerde interventie studie om het positieve effect van hydrocortison op dexamethason geïnduceerde gedragsproblemen bij kinderen met acute lymfatische leukemie te valideren.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    DexaDays-2 study
    DexaDagen-2 studie
    A.4.1Sponsor's protocol code number62388
    A.5.4Other Identifiers
    Name:Nederlands Trial Register (NTR)Number:6695
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPrincess Máxima Center of Pediatric Oncology
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKiKa
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPrincess Máxima Center of Pediatric Oncology
    B.5.2Functional name of contact pointM.M. van den Heuvel-Eibrink
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 25
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CS
    B.5.3.4CountryNetherlands
    B.5.4Telephone number3108809727007
    B.5.6E-mailm.m.vandenheuvel-eibrink@prinsesmaximacentrum.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHydrocortisone
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHydrocortisone
    D.3.9.1CAS number 50-23-7
    D.3.9.2Current sponsor codeATC H02AB09
    D.3.9.3Other descriptive nameHYDROCORTISONE
    D.3.9.4EV Substance CodeSUB08065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute lymphoblastic leukemia
    Acute lymfatische leukemie
    E.1.1.1Medical condition in easily understood language
    Blood cancer
    Bloedkanker
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024338
    E.1.2Term Leukemia lymphoblastic acute
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To validate that addition of physiological doses of hydrocortisone to standard dexamethasone treatment reduces side effects in the acute lymphoblastic leukemia patients that suffer from clinically relevant dexamethasone-induced neurobehavioral problems.

    This randomized controlled trial closed on 5-8-2020, since the endpoint of 50 patients was reached. However, to be able to answer our secondary research questions, inclusion will continue till a total of 105 patients in our prospective Identification study is reached. These patients will not be treated with hydrocortisone in the study.
    Validatie dat het toevoegen van een fysiologische dosering hydrocortison aan de standaard dexamethason behandeling bij kinderen met acute lymfatische leukemie (ALL) de klinisch relevante dexamethason geïnduceerde gedragsproblemen vermindert.

    Deze gerandomiseerde placebo-gecontroleerde trial is beëindigd op 5-8-2020, omdat we ons eindpunt van 50 patiënten hebben behaald. Echter, om onze secundaire onderzoeksvragen goed te kunnen beantwoorden, zal inclusie van patiënten voor onze prospectieve Identificatie studie continueren, tot 105 patiënten zijn geïncludeerd. Deze patiënten worden niet in studieverband met hydrocortison behandeld.
    E.2.2Secondary objectives of the trial
    Intervention part - CLOSED
    -To examine clinically relevant dexamethasone induced sleeping problems and validate that hydrocortisone reduces these problems
    -To evaluate whether hydrocortisone improves quality of life in patients with dexamethasone induced neurobehavioral problems
    -To determine the frequency of patients that may benefit from hydrocortisone for direct frailty occurrence

    Identification part - CONTINUING
    To study:
    - the role of genetic variation in the pathophysiology of dexamethasone-induced neurobehavioral problems
    - the influence of psychosocial and environmental factors on dexamethasone-induced neurobehavioral side effects
    - the role of dexamethasone kinetics in the pathophysiology of dexamethasone-induced neurobehavioral problems
    - the prevalence of frailty and to study the effect of dexamethasone on frailty
    -To study the prevalence of nutrient deficiencies, their association with frailty and the effect of dexamethasone on these deficiencies
    Interventie studie - GESLOTEN
    -Dexamethason geïnduceerde slaapproblemen na 5 dagen dexamethason, en het effect van hydrocortison toevoeging
    -De kwaliteit van leven na 5 dagen dexamethason behandeling, met of zonder hydrocortison
    -Het effect van hydrocortison op de verschillende frailty parameters

    Identificatie studie
    De invloed van
    - dragerschap van verschillende polymorfismen, onder andere het BclI polymorfisme (glucocorticoïd receptor gen) en rs4918 polymorfismen (Alpha2-HS glycoprotein (AHSG) gen) op het ontstaan van klinisch relevante gedragsproblemen
    - dexamethason kinetiek op het ontstaan van dexamethason geïnduceerde gedragsproblemen
    - verschillende (psycho)sociale en omgevingsfactoren op het ontstaan van gedragsproblemen
    - De prevalentie van frailty in kinderen met ALL en het effect van dexamethason op alle frailty parameters
    -De prevalentie van nutriënt deficiënties, de associatie tussen frailty en deze deficiënties en het effect van dexamethason
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent
    - Age 3-18
    - Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL)
    - Inclusion in DCOG ALL medium risk group protocol
    - Able to comply with scheduled follow-up
    - Informed consent
    - Leeftijd 3-18 jaar
    - Histologisch of cytologisch bevestigde acute lymfatische leukemie (ALL)
    - Behandeling volgens DCOG ALL medium risk protocol
    - In de mogelijkheid om aan geplande follow-up te voldoen
    E.4Principal exclusion criteria
    - Patient or parent refusal
    - Anticipated compliance problems
    - Underlying conditions which affect the absorption of oral medication
    - Pregnant or lactating patients
    - Current uncontrolled infection or any other complication which may interfere with
    dexamethasone treatment
    - Language barrier
    - Pre-existing mental retardation
    - Current oral hydrocortisone use
    - Risperidone use
    - Weigering van patiënt of ouder(s)
    - Verwachte compliantie problemen
    - Onderliggende aandoening die de opname van medicatie kan beïnvloeden
    - Zwangere of borstvoeding gevende patiënten
    - Een bestaande ongecontroleerde infectie of andere complicatie die kan interfereren met de dexamethason behandeling
    - Taalbarrière
    - Pre-existente mentale retardatie
    - Huidige orale hydrocortison behandeling
    - Huidige risperidon behandeling
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome parameter of the Intervention study (RCT) is
    - The occurrence of neurobehavioral problems after 5 days of dexamethasone treatment with or without hydrocortisone addition. These neurobehavioral problems will be measured with the parent-reported strength and difficulty questionnaire (SDQ).

    The amount of patients (n=50) to answer this primary outcome, was reached on 5-8-2020, therefore the RCT was closed.
    Primaire uitkomstvariabele in de Interventie studie (RCT):
    - Het optreden van dexamethason geïnduceerde gedragsproblemen na 5 dagen dexamethason behandeling, met of zonder hydrocortison toevoeging. De gedragsproblemen zullen worden gemeten met behulp van de Strengths and Difficulties Questionnaire (SDQ)

    Het aantal patiënten (n=50) om onze primaire onderzoeksvraag te kunnen beantwoorden was bereikt op 5-8-2020, de RCT is derhalve gesloten.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 5 days of dexamethasone treatment with or without hydrocortisone.
    Na 5 dagen dexamethason behandeling met of zonder hydrocortison toevoeging.
    E.5.2Secondary end point(s)
    The secondary outcome parameters of the RCT - CLOSED
    - The occurrence of dexamethasone related sleeping difficulties after 5 days of dexamethasone treatment with or without hydrocortisone, measured by the Sleep Disturbance Scale for Children (SDSC) and actigraphy.
    - Quality of life after 5 days of dexamethasone treatment with or without hydrocortisone, measured with the Pediatric Quality of Life questionnaire (PedsQL).
    - Frailty with or without hydrocortisone addition, measured through bio-impedance, ultrasonography and upper leg circumference, activiy questionnaire, timed Up and Go test, fatigue (PedsQL), hand grip and musculus rectus femoris strength (dynamometer) and the 'Time to rise from floor' test.

    We will contin ue to include patients in our Identification study. In this cohort (105 patients) we study possible determinants of the inter-patient variability in developing dexamethasone induced neurobehavioral and sleeping problems.
    We study:
    - The influence of carrier status of single nucleotide polymorphisms (SNPs) on the development of dexamethasone induced clinically relevant neurobehavioral problems.
    - The effect of dexamethasone kinetics on the development of dexamethasone induced clinically relevant neurobehavioral problems
    - The impact of psychosocial and environmental factors on the development of dexamethasone induced clinically relevant neurobehavioral problems.
    - The prevalence of frailty and muscle wasting after 5 days of dexamethasone treatment.
    - The prevalence of vitamin D and B as well as other nutrient deficiencies, the effect of dexamethasone on these deficiencies and the association between nutrient deficiencies and frailty occurrence
    Secundaire uitkomstvariabelen in de RCT: - GESLOTEN
    - Dexamethason geïnduceerde slaapproblemen na 5 dagen dexamethason behandeling, met of zonder hydrocortison toevoeging. Slaapproblemen worden gemeten met de Sleep Disturbance Scale for Children (SDSC) en een actigraaf.
    - De kwaliteit van leven na 5 dagen dexamethason behandeling, met of zonder hydrocortison toevoeging. De kwaliteit van leven wordt gemeten met de Pediatric Quality of Life questionnaire (PedsQL)
    - De mate van frailty met of zonder hydrocortison toevoeging. De verschillende frailty parameters zullen worden onderzocht middels bio-impedantie, echografie en omtrek van het bovenbeen, de PedsQL, een fysieke activiteiten vragenlijst, een timed Up and Go test, een handknijpkracht en musculus rectus femoris krachtmeter en de 'Opstaan van de grond' test.

    De inclusie van kinderen in het Identificatie cohort zal continueren. In dit cohort (105 patiënten) bestuderen we de mogelijke determinanten voor het ontwikkelen van dexamethason geïnduceerde gedrags- en slaapproblemen.
    We onderzoeken:
    - De invloed van dragerschap van verschillende polymorfismen (SNP array), onder andere het BclI polymorfisme (glucocorticoïd receptor gen) en rs4918 polymorfismen (Alpha2-HS glycoprotein (AHSG) gen) op het ontstaan van klinisch relevante gedragsproblemen.
    - De bijdrage van dexamethason farmacokinetiek op het ontstaan van dexamethason geïnduceerde gedragsproblemen. Hiertoe zullen zowel dal- als piekspiegels van dexamethason gemeten worden.
    - De invloed van verschillende (psycho)sociale en omgevingsfactoren op het ontstaan van gedragsproblemen, gemeten met verschillende vragenlijsten.
    - De prevalentie van frailty in kinderen met ALL, en het effect van dexamethason op de verschillende frailty parameters.
    - De prevalentie van (o.a.) vitamine D en B deficiënties, het effect van dexamethason op deze deficiënties en de associatie tussen frailty en de deficiënties
    E.5.2.1Timepoint(s) of evaluation of this end point
    Before and after 5 days of dexamethasone treatment
    Voor en na 5 dagen dexamethason behandeling
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Inter-patient variability
    Inter-patiënt variabiliteit
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Laatste bezoek laatste patiënt
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 105
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 85
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state105
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There are no strict plans for treatment after the subject has ended participation in the trial besides follow up for adverse events. However, if a patient with severe neurobehavioral side effects seems to benefit from the treatment with hydrocortisone and wants to continue treatment this could be considered. Since blinding till the last patients last visit, we will not know wether the effect was attributable to the medication or placebo and continued use will not be encouraged.
    Er zijn geen vaste plannen voor behandeling na het eindigen van de studie behoudens follow up voor adverse events. Indien patiënten met ernstige gedragsproblemen het idee hebben dat de interventie heel goed werkt, kan overwogen worden na de studie hydrocortison als "compassionate care" voor te schrijven. Vanwege blindering tot en met de last patient visit weten we echter niet of het effect van placebo of medicatie is geweest. Het doorgebruiken van hydrocortison zal niet worden aangemoedigd.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-01-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-03-27
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