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    Clinical Trial Results:
    Optimizing timing of glucocorticoid treatment in children with congenital adrenal hyperplasia

    Summary
    EudraCT number
    		 2018-004802-24
    Trial protocol
    		 NL  
    Global end of trial date
    14 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Aug 2022
    First version publication date
    04 Aug 2022
    Other versions
    Summary report(s)
    		 Manuscript OPTIMED JCEM

    Trial information

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    Trial identification
    Sponsor protocol code
    NL68556.091.18
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Innovatiefonds zorgverzekeraars
    Sponsor organisation address
    NA, NA, Netherlands, NA
    Public contact
    Department of Ped Endocrinology, Radboud University Nijmegen medical centre, +31 243614430, hedi.claahsen@radboudumc.nl
    Scientific contact
    Department of Ped Endocrinology, Radboud University Nijmegen medical centre, +31 243614430, hedi.claahsen@radboudumc.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
    23 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study the effects of 2 standard treatment timing strategies for glucocorticoid dosage on androgen concentration in CAH children: a. highest dosage in the morning, b. highest dosage in the evening.
    Protection of trial subjects
    NA
    Background therapy
    		 NA
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    01 Jan 2019
    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: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    16
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were actively recruited via BijnierNet and their pediatric endocrinologists in The Netherlands. By completing a contact form, patinets and parents could indicate their interest in the study and provided consent to be contacted by the study coordinator.

    Pre-assignment
    Screening details
    		 Inclusion: -Classic 21OHD -Diagnosis confirmed by hormonal and mutation analysis -4 -20 yrs. - Treatment with Hydrocortisone. - Ability to collect saliva Exclusion: Chronic medication use other than hydrocortisone or fludrocortisone 1 patient was excluded due to medication use. Two patients withdrawled informed consent.

    Period 1
    Period 1 title
    Intervention cross-over study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Highest dosage morning
    Arm description
    		 Patient received highest hydrocortisone dose in the morning
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hydrocortisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patient administered their own formulation of hydrocortisone and patients continued their regular dosage, either administering the highst dosage in the morning or in the evening.

    Arm title
    		 Highest dose evening
    Arm description
    		 Patient received the highest hydrocortisone dose in the evening.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hydrocortisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patient administered their own formulation of hydrocortisone and patients continued their regular dosage, either administering the highst dosage in the morning or in the evening.

    Number of subjects in period 1
    		Highest dosage morning Highest dose evening
    Started
    39
    40
    Completed
    39
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention cross-over study
    Reporting group description
    		 39 patients completed the six-week cross-over study comparing the administration of the highest dose of hydrocortisone in the morning (3 weeks) with the administration of hydrocortisone in the evening (3 weeks). Patients used their regular hydrocortisone medication and started the first three-week period of thestudy with their regular dosing regimen. After three weeks patients switched to the other hydrocortisone dose timing regimen.

    Reporting group values
    		 Intervention cross-over study Total
    Number of subjects
    		 41 41
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 16 16
        Adolescents (12-17 years)
    		 20 20
        Adults (18-64 years)
    		 5 5
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 12 (4 to 19) -
    Gender categorical
    Units: Subjects
        Female
    		 19 19
        Male
    		 22 22

    End points

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    End points reporting groups
    Reporting group title
    Highest dosage morning
    Reporting group description
    		 Patient received highest hydrocortisone dose in the morning

    Reporting group title
    Highest dose evening
    Reporting group description
    		 Patient received the highest hydrocortisone dose in the evening.

    Primary: 17-hydroxyprogesterone

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    End point title
    		 17-hydroxyprogesterone [1]
    End point description
    End point type
    Primary
    End point timeframe
    17-hydroxyprogesterone levels were reported at 5.00AM, 7.00AM, 3.00PM, 11.00PM at day 20 and 21 of 41 and 42 of the intervention period.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A detailed description of the statistical analyses can be found in the manuscript: DOI: 10.1210/clinem/dgab826
    End point values
    		 Highest dosage morning Highest dose evening
    Number of subjects analysed
    39
    39
    Units: nmol/L
    median (inter-quartile range (Q1-Q3))
        5.00AM
    0.566 (0.204 to 1.252)
    0.250 (0.045 to 0.745)
        7.00AM
    1.357 (0.537 to 3.814)
    1.909 (0.738 to 2.753)
        3.00PM
    0.518 (0.084 to 1.748)
    0.786 (0.424 to 2.045)
        11.00PM
    0.078 (0.024 to 0.167)
    0.100 (0.040 to 0.164)
    No statistical analyses for this end point

    Primary: androstenedione

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    End point title
    		 androstenedione [2]
    End point description
    End point type
    Primary
    End point timeframe
    Androstenedione was quantified in saliva collected at 5.00AM, 7.00AM, 3.00PM, and 11.00PM.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A detailed description of the statistical analyses can be found in the manuscript: DOI: 10.1210/clinem/dgab826
    End point values
    		 Highest dosage morning Highest dose evening
    Number of subjects analysed
    39
    39
    Units: nmol/L
    median (inter-quartile range (Q1-Q3))
        5.00AM
    0.162 (0.062 to 0.418)
    0.188 (0.058 to 0.341)
        7.00AM
    0.232 (0.100 to 0.689)
    0.381 (0.165 to 0.701)
        3.00PM
    0.121 (0.055 to 0.352)
    0.281 (0.088 to 0.469)
        11.00PM
    0.065 (0.022 to 0.198)
    0.096 (0.031 to 0.252)
    No statistical analyses for this end point

    Secondary: Subjective sleepscores

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    End point title
    		 Subjective sleepscores
    End point description
    End point type
    Secondary
    End point timeframe
    Patients (or their caretakers) gave daily sleepscores during the entire study period.
    End point values
    		 Highest dosage morning Highest dose evening
    Number of subjects analysed
    39
    39
    Units: 1-5
    5
    5
    No statistical analyses for this end point

    Secondary: Subjective activity scores

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    End point title
    		 Subjective activity scores
    End point description
    Mean of mean sleepscores per subject are provided.
    End point type
    Secondary
    End point timeframe
    Patients (or their caretakers) gave daily activity scores during the entire study period.
    End point values
    		 Highest dosage morning Highest dose evening
    Number of subjects analysed
    39
    39
    Units: 1-10
        Morning
    6
    6
        Afternoon
    7
    7
        Evening
    6
    6
    No statistical analyses for this end point

    Secondary: Blood pressure

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    End point title
    		 Blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Overnight blood pressure was determined for 1 night during week 3 and week 6 of the intervention period.
    End point values
    		 Highest dosage morning Highest dose evening
    Number of subjects analysed
    32
    30
    Units: mmHg
    arithmetic mean (full range (min-max))
        Systolic
    108.8 (94.6 to 125.6)
    106.5 (84.4 to 127.9)
        Diastolic
    61.8 (45.7 to 73.0)
    60.5 (49.7 to 71.75)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start study intervention until the end of intervention.
    Adverse event reporting additional description
    Patients were asked to write down adverse events in a diary or by contacting the study team.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Subjects participating intervention period
    Reporting group description
    		 -

    Serious adverse events
    		 Subjects participating intervention period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 39 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Subjects participating intervention period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 39 (28.21%)
    General disorders and administration site conditions
    General malaise
    Additional description: Not related to hydrocortisone.
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Stomach ache
    Additional description: One time not related to hydrocortisone and one time not known if related to hydrocortisone.
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Inflammation perineum
    Additional description: Not related to hydrocortisone.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Stomach ache/vomitting
    Additional description: Not related to hydrocortisone.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Headache
    Additional description: Not known if related to hydrocortisone.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Illness
    Additional description: Not related to hydrocortisone.
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Cold sore
    Additional description: Not related to hydrocortisone.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Falling off the stairs
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Common cold
    Additional description: Not related to hydrocortisone.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2019
    The inclusion criteria on age was adapted from 4-18 years to children from 4 years of age and adolescents.

    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.
    NA
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