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    Clinical Trial Results:
    Proton pump inhibition for secondary hemochromatosis in hereditary anemia, a phase III placebo controlled randomized cross-over clinical trial.

    Summary
    EudraCT number
    		 2017-003777-34
    Trial protocol
    		 NL  
    Global end of trial date
    12 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2022
    First version publication date
    21 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NL63198.041.17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UMC Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands,
    Public contact
    Van Creveldkliniek, UMC Utrecht, 0031 088-7558450, vck-research@umcutrecht.nl
    Scientific contact
    Van Creveldkliniek, UMC Utrecht, 0031 088-7558450, vck-research@umcutrecht.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
    12 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show that PPIs compared to placebo are an effective treatment of secondary hemochromatosis in a relative large number of patients with hereditary anemia and mild to modereate iron overload.
    Protection of trial subjects
    Strict monitoring scheme according to trial protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2018
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    26
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Not applicable.

    Period 1
    Period 1 title
    First trial year (12 months)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Esomeprazole
    Arm description
    		 Esomeprazole 40mg BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esomeprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    40 milligram twice daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Esomeprazole Placebo
    Started
    16
    14
    Completed
    14
    14
    Not completed
    2
    0
         Consent withdrawn by subject
    2
    -
    Period 2
    Period 2 title
    Second trial year (12 months)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily 1 capsule

    Arm title
    		 Esomeprazole
    Arm description
    		 Esomeprazole 40mg BID
    Arm type
    		 experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Placebo Esomeprazole
    Started
    14
    14
    Completed
    12
    12
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Esomeprazole
    Reporting group description
    		 Esomeprazole 40mg BID

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Esomeprazole Placebo Total
    Number of subjects
    		 16 14 30
    Age categorical
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 14 14 28
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Age continuous
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 47 (19 to 66) 35 (23 to 59) -
    Gender categorical
    Units: Subjects
        Female
    		 9 6 15
        Male
    		 7 8 15
    Deferasirox (DFX) use
    Units: Subjects
        No DFX
    		 10 9 19
        DFX
    		 6 5 11

    End points

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    End points reporting groups
    Reporting group title
    Esomeprazole
    Reporting group description
    		 Esomeprazole 40mg BID

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Esomeprazole
    Reporting group description
    		 Esomeprazole 40mg BID

    Primary: Change in delta liver iron content (delta LIC)

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    End point title
    		 Change in delta liver iron content (delta LIC)
    End point description
    Cross-over design. Difference in change when comparing both treatments.
    End point type
    Primary
    End point timeframe
    Comparison of two treatments of both 12 months.
    End point values
    		 Esomeprazole Placebo
    Number of subjects analysed
    16 [1]
    14 [2]
    Units: mg Fe/g dw
        arithmetic mean (standard deviation)
    -0.11 ( 0.75 )
    -0.57 ( 1.20 )
    Notes
    [1] - All esomeprazole periods.
    [2] - All placebo periods.
    Statistical analysis title
    		 Primary efficacy analysis
    Statistical analysis description
    Linear mixed model with delta LIC as dependent variable, a random intercept at patient level and treatment as independent variable. Sex, iron chelator use, (period) baseline LIC and randomized order of treatment were included as covariates.
    Comparison groups
    Placebo v Esomeprazole
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 -0.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Length of trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Esomeprazole
    Reporting group description
    		 All patients that received esomeprazole.

    Reporting group title
    Placebo
    Reporting group description
    		 All patients that received placebo.

    Serious adverse events
    		 Esomeprazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 26 (11.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Abdominal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Vaso-occlusive crisis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectus hematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endocarditis bacterial
    Additional description: Mechanic valve.
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 26 (3.85%)
         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: 5%
    Non-serious adverse events
    		 Esomeprazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 30 (50.00%)
    17 / 26 (65.38%)
    Social circumstances
    Malaise
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Fatigue
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Epigastric discomfort
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Diarrhoea
         subjects affected / exposed
    6 / 30 (20.00%)
    2 / 26 (7.69%)
         occurrences all number
    6
    2
    Abdominal pain
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 26 (15.38%)
         occurrences all number
    3
    4
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 30 (33.33%)
    10 / 26 (38.46%)
         occurrences all number
    17
    23
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Flue
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2018
    Addition of one additional participating center. Minor adjustments inclusion criteria.
    06 Jun 2018
    Addition of one additional participating center.
    26 Sep 2018
    Adjustment inclusion criteria: deletion of transferrin saturation criterion.
    08 Apr 2019
    Adjustment/correction sample size calculation.

    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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