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    Clinical Trial Results:
    PlenadrEMA study - Effect of modified-release compared to conventional hydrocortisone on fatigue, measured by Ecological Momentary Assessments; a pilot study to assess feasibility, responsiveness of outcomes and to inform power calculations for future large-scale RCTs

    Summary
    EudraCT number
    		 2014-002039-32
    Trial protocol
    		 DK  
    Global end of trial date
    03 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2021
    First version publication date
    21 Mar 2021
    Other versions
    Summary report(s)
    		 Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    PlenadrEMA/1.1/2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Copenhagen University Hospital, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    PlenadrEMA Study Information, Copenhagen University Hospital, Rigshospitalet, +45 35452535, thea.christoffersen@regionh.dk
    Scientific contact
    PlenadrEMA Study Information, Copenhagen University Hospital, Rigshospitalet, +45 35452535, thea.christoffersen@regionh.dk
    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
    24 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate feasibility of EMA assessments as outcome in future large-scale randomized clinical trials (RCT) of modified release hydrocortisone. To quantify the variability of such measurements in patients with adrenal insufficiency due to hypopituitarism and to acquire an estimate of the size of the expected difference in scores; both of which are required for sample size calculations. To identify the best suited outcome for an RCT, i.e. the most informative with the least participant burden; i.e. the most responsive, brief summary measure.
    Protection of trial subjects
    Patients kept a diary to register disease, stress or other events. They were instructed to administer supplementary hydrocortisone in these instances. Blood samples were drawn at screening, baseline and follow-up to make sure trial subjects' biochemistry were in order.
    Background therapy
    		 Patients continued their standard care as per clinical guidelines in the first phase of the trial which was the comparator For the second part of the trial, all participant switched to the imp
    Evidence for comparator
    		 The comparator in this study was hydrocortisone. In this patient population, hydrocortisone is vital and standard treatment.
    Actual start date of recruitment
    01 Apr 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    17
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the outpatient clinic at the department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital. Recruitment took place from March 2018 to January 2019

    Pre-assignment
    Screening details
    		 From March 2018 to January 2019, patients receiving hydrocortisone tablets from the outpatient clinic at the Department of Endocrinology and Metabolism, Rigshospitalet, were screened for eligibility.

    Period 1
    Period 1 title
    baseline period - comparator
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    		 Comparator
    Arm description
    		 Standard hydrocortisone replacement therapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    hydrocortisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As per routine clinical care

    Number of subjects in period 1
    		Comparator
    Started
    31
    Completed
    31
    Period 2
    Period 2 title
    follow up - imp
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    		 follow up - imp
    Arm description
    		 All participants were switched to imp
    Arm type
    		 Experimental

    Investigational medicinal product name
    plenadren
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received the same total daily dose as on conventional hydrocortisone and were instructed to take the dose in fasting state upon waking. Plenadren is only available in 20 and 5 mg tablets; consequently, intermediate doses were rounded up to the nearest 5 mg (e.g., three-times daily hydrocortisone: 10 + 5 + 2.5 mg was transformed to 20 mg of Plenadren).

    Number of subjects in period 2
    		follow up - imp
    Started
    31
    Completed
    27
    Not completed
    4
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    baseline period - comparator
    Reporting group description
    		 Patients with secondary adrenal insuficiency due to hypopituitarism

    Reporting group values
    		 baseline period - comparator Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 17
        From 65-84 years
    		 14 14
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (38 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 27 27
    MFI20 - general fatigue
    MFI20 - general fatigue
    Units: score
        arithmetic mean (standard deviation)
    		 10.3 ( 4.5 ) -
    MFI20 - reduced motivation
    MFI20 - reduced motivation
    Units: score
        arithmetic mean (standard deviation)
    		 8.8 ( 4.0 ) -
    MFI20 - physical fatigue
    MFI20 - physical fatigue
    Units: score
        arithmetic mean (standard deviation)
    		 9.5 ( 4.3 ) -
    MFI20 - reduced activity
    MFI20 - reduced activity
    Units: score
        arithmetic mean (standard deviation)
    		 9.1 ( 4.25 ) -
    MFI20 - mental fatigue
    MFI20 - mental fatigue
    Units: score
        arithmetic mean (standard deviation)
    		 8.9 ( 14.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Comparator
    Reporting group description
    		 Standard hydrocortisone replacement therapy
    Reporting group title
    follow up - imp
    Reporting group description
    		 All participants were switched to imp

    Primary: MFI20 - general fatigue

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    End point title
    		 MFI20 - general fatigue
    End point description
    End point type
    Primary
    End point timeframe
    After 16 weeks of imp
    End point values
    		 Comparator follow up - imp
    Number of subjects analysed
    27
    27
    Units: score
        arithmetic mean (standard deviation)
    10.3 ( 4.5 )
    9.3 ( 4.6 )
    Statistical analysis title
    		 mixed models for repeated measurements
    Comparison groups
    Comparator v follow up - imp
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16

    Primary: MFI20 - reduced motivation

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    End point title
    		 MFI20 - reduced motivation
    End point description
    End point type
    Primary
    End point timeframe
    after 16 weeks of imp
    End point values
    		 Comparator follow up - imp
    Number of subjects analysed
    27
    27
    Units: score
        arithmetic mean (standard deviation)
    8.8 ( 4.0 )
    9.3 ( 4.6 )
    Statistical analysis title
    		 mixed models for repeated measurements
    Comparison groups
    Comparator v follow up - imp
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Primary: MFI20 - physical fatigue

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    End point title
    		 MFI20 - physical fatigue
    End point description
    End point type
    Primary
    End point timeframe
    after 16 weeks of imp
    End point values
    		 Comparator follow up - imp
    Number of subjects analysed
    27
    27
    Units: score
        arithmetic mean (standard deviation)
    9.5 ( 4.3 )
    8.6 ( 4.4 )
    Statistical analysis title
    		 mixed models for repeated measurements
    Comparison groups
    follow up - imp v Comparator
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26

    Primary: MFI20 - reduced activity

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    End point title
    		 MFI20 - reduced activity
    End point description
    End point type
    Primary
    End point timeframe
    after 16 weeks on IMP
    End point values
    		 Comparator follow up - imp
    Number of subjects analysed
    27
    27
    Units: score
        arithmetic mean (standard deviation)
    9.1 ( 4.3 )
    13.2 ( 4.5 )
    Statistical analysis title
    		 mixed models for repeated measurements
    Comparison groups
    Comparator v follow up - imp
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29

    Primary: MFI20 - mental fatigue

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    End point title
    		 MFI20 - mental fatigue
    End point description
    End point type
    Primary
    End point timeframe
    after 16 weeks on IMP
    End point values
    		 Comparator follow up - imp
    Number of subjects analysed
    27
    27
    Units: score
        arithmetic mean (standard deviation)
    8.9 ( 3.8 )
    8.2 ( 3.7 )
    Statistical analysis title
    		 mixed models for repeated measurements
    Comparison groups
    Comparator v follow up - imp
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    21 weeks: 5 weeks on comparator and 16 weeks for imp.
    Adverse event reporting additional description
    through diary. And at all visits, patients were asked about AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    comparator
    Reporting group description
    		 -

    Reporting group title
    follow-up - imp
    Reporting group description
    		 -

    Serious adverse events
    		 comparator follow-up - imp
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 31 (9.68%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary adenoma enlargement
    Additional description: Pituitary adenoma enlargement
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrilation
    Additional description: Patient with paroxysmal atrial fibrilation had an electrical cardioversion performed twice due to exacerbations
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilated cardiomyopathy
    Additional description: Hospitalization where patient was diagnosed with dilated cardiomyopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         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: 0.05%
    Non-serious adverse events
    		 comparator follow-up - imp
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 31 (16.13%)
    18 / 31 (58.06%)
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 31 (0.00%)
    6 / 31 (19.35%)
         occurrences all number
    0
    6
    Skin and subcutaneous tissue disorders
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Photosensitivity reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 31 (9.68%)
    4 / 31 (12.90%)
         occurrences all number
    3
    4
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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