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    Clinical Trial Results:
    Efficacy of zinc on human hepatic copper uptake: A randomized intervention study

    Summary
    EudraCT number
    		 2019-000905-57
    Trial protocol
    		 DK  
    Global end of trial date
    01 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2021
    First version publication date
    07 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N/A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Hepatology & Gastroenterology
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Thomas Sandahl, Aarhus University Hospital , thomsand@rm.dk
    Scientific contact
    Thomas Sandahl, Aarhus University Hospital , thomsand@rm.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
    19 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of zinc on blocking human gut copper uptake in relation to the type of zinc (zinc acetate/zinc gluconate) and the dose regimen (once a day/ thrice a day). This is quantified by 64CuCl2 PET/CT scans.
    Protection of trial subjects
    Blood samples to exclude unknown liver/kidney disease at inclusion Medical observation for at least 30 minutes after tracer intake Medical observation during scans including stethoscopy and blood pressure before and after the scan
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 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
    Denmark: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    27
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were included from the 30th of May 2019 to the 28th of January 2020 by advertisements at the hospital, on a trial participant recruitment website and in a local newspaper.

    Pre-assignment
    Screening details
    		 Interested volunteers would send an e-mail and have the participant information forwarded. If still interested after reading this, they would receive a phone call to set a date for the inclusion conversation.

    Pre-assignment period milestones
    Number of subjects started
    		 40
    Number of subjects completed
    		 40

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zinc acetate 50 mg x 3
    Arm description
    		 Control treatment
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Wilzin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg thrice daily, one hour fast before and after oral intake

    Arm title
    		 Zinc acetate 150 mg x 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Wilzin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg once daily, one hour fast before and after oral intake

    Arm title
    		 Zinc gluconate 50 mg x 3
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zink "Natur-Drogeriet"
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg thrice daily, one hour fast before and after oral intake

    Arm title
    		 Zinc gluconate 150 mg x 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zink "Natur-Drogeriet"
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg once daily, one hour fast before and after oral intake

    Number of subjects in period 1
    		Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Started
    10
    10
    10
    10
    Completed
    10
    9
    9
    10
    Not completed
    0
    1
    1
    0
         Technical error before end-of-treatment scan
    -
    1
    -
    -
         Other illness before baseline scan
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zinc acetate 50 mg x 3
    Reporting group description
    		 Control treatment

    Reporting group title
    Zinc acetate 150 mg x 1
    Reporting group description
    		 -

    Reporting group title
    Zinc gluconate 50 mg x 3
    Reporting group description
    		 -

    Reporting group title
    Zinc gluconate 150 mg x 1
    Reporting group description
    		 -

    Reporting group values
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1 Total
    Number of subjects
    		 10 10 10 10 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 9 6 5 7 27
        From 65-84 years
    		 1 4 5 3 13
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 6 6 9 27
        Male
    		 4 4 4 1 13
    Body mass index
    Units: N/A
        arithmetic mean (standard deviation)
    		 23.2 ( 3.3 ) 23.4 ( 2.5 ) 24.3 ( 2.3 ) 23.6 ( 3.1 ) -
    Plasma zinc
    Units: Micromole/L
        arithmetic mean (standard deviation)
    		 11.3 ( 1.7 ) 12.3 ( 2.5 ) 11.0 ( 1.0 ) 11.4 ( 1.6 ) -
    Alanine aminotransferase
    Units: U/L
        arithmetic mean (standard deviation)
    		 25.2 ( 13.2 ) 27.8 ( 10.1 ) 20.7 ( 7.5 ) 24.7 ( 8.8 ) -
    Bilirubin
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    		 10.4 ( 2.8 ) 12.2 ( 6.0 ) 14.4 ( 4.7 ) 11.3 ( 5.7 ) -
    Creatinine
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    		 69.6 ( 13.1 ) 61.9 ( 11.6 ) 65.9 ( 10.9 ) 61.1 ( 7.0 ) -
    Subject analysis sets

    Subject analysis set title
    All completed participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with baseline and end-of-treatment scan

    Subject analysis sets values
    		 All completed participants
    Number of subjects
    37
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Female
    24
        Male
    13
    Body mass index
    Units: N/A
        arithmetic mean (standard deviation)
    ( )
    Plasma zinc
    Units: Micromole/L
        arithmetic mean (standard deviation)
    ( )
    Alanine aminotransferase
    Units: U/L
        arithmetic mean (standard deviation)
    ( )
    Bilirubin
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    ( )
    Creatinine
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Zinc acetate 50 mg x 3
    Reporting group description
    		 Control treatment

    Reporting group title
    Zinc acetate 150 mg x 1
    Reporting group description
    		 -

    Reporting group title
    Zinc gluconate 50 mg x 3
    Reporting group description
    		 -

    Reporting group title
    Zinc gluconate 150 mg x 1
    Reporting group description
    		 -

    Subject analysis set title
    All completed participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with baseline and end-of-treatment scan

    Primary: Ratio (mean hepatic SUV)

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    End point title
    		 Ratio (mean hepatic SUV)
    End point description
    Mean hepatic SUV on follow-up scan divided by mean hepatic SUV on baseline scan yielding a ratio between the two
    End point type
    Primary
    End point timeframe
    Continuous assessment of PET data during the study
    End point values
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Number of subjects analysed
    10
    9
    9
    9
    Units: N/A
        arithmetic mean (standard deviation)
    0.57 ( 0.34 )
    0.63 ( 0.33 )
    0.50 ( 0.22 )
    0.85 ( 0.41 )
    Statistical analysis title
    		 Difference in ratio among the groups
    Statistical analysis description
    Oneway ANOVA
    Comparison groups
    Zinc acetate 50 mg x 3 v Zinc acetate 150 mg x 1 v Zinc gluconate 50 mg x 3 v Zinc gluconate 150 mg x 1
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 ANOVA
    Confidence interval

    Primary: Noninferiority test

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    End point title
    		 Noninferiority test [1]
    End point description
    Difference between means (standard treatment vs. test treatment) Non-inferiority margin of 25% (based on the lower 95% confidence interval around the estimated difference between standard treatment and no treatment and a clinical judgement about how much of the margin should be preserved).
    End point type
    Primary
    End point timeframe
    PET data was analysed through out the study. The analysis was performed after all data was collected.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The noninferiority test compares test treatments against standard treatment, thus no values are appropriate for standard treatment baseline arm
    End point values
    		 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Number of subjects analysed
    9
    9
    9
    Units: percent
        arithmetic mean (confidence interval 95%)
    5.7 (-26.6 to 38.1)
    -7.3 (-35.0 to 20.4)
    28.5 (-7.4 to 64.4)
    Statistical analysis title
    		 Noninferiority
    Statistical analysis description
    Non-inferiority analysis with a non-inferiority margin of 25% (based on the lower 95% confidence interval around the estimated difference between standard treatment and no treatment and a clinical judgement about how much of the margin should be preserved (75%)).
    Comparison groups
    Zinc gluconate 50 mg x 3 v Zinc acetate 150 mg x 1 v Zinc gluconate 150 mg x 1
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.01 [2]
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35
         upper limit
    		 20.4
    Notes
    [2] - For only non inferior treatment zinc gluconate 50 mg x 3

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    Collected through out the study
    End point values
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Number of subjects analysed
    10
    9
    9
    9
    Units: Numbers
        Gastric discomfort
    2
    4
    0
    1
        Nausea
    5
    5
    1
    2
        Headache
    0
    2
    0
    0
        Palpitation
    0
    1
    0
    0
        Obstipation
    0
    2
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Compliance

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    End point title
    		 Compliance
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Assessment after study termination
    End point values
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Number of subjects analysed
    10
    9
    9
    9
    Units: percent
        median (full range (min-max))
    97.5 (96 to 100)
    87.6 (46 to 100)
    96 (90 to 100)
    99.2 (96 to 100)
    Statistical analysis title
    		 Difference between groups
    Comparison groups
    Zinc acetate 50 mg x 3 v Zinc acetate 150 mg x 1 v Zinc gluconate 50 mg x 3 v Zinc gluconate 150 mg x 1
    Number of subjects included in analysis
    37
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Post-hoc: Plasma zinc after treatment

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    End point title
    		 Plasma zinc after treatment
    End point description
    End point type
    Post-hoc
    End point timeframe
    Continuous assessment during the study
    End point values
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Number of subjects analysed
    5
    5
    9
    5
    Units: Micromole/L
        arithmetic mean (standard deviation)
    25.2 ( 5.0 )
    20.4 ( 4.0 )
    18.9 ( 4.3 )
    17.3 ( 1.5 )
    Statistical analysis title
    		 Difference among groups
    Comparison groups
    Zinc acetate 50 mg x 3 v Zinc acetate 150 mg x 1 v Zinc gluconate 50 mg x 3 v Zinc gluconate 150 mg x 1
    Number of subjects included in analysis
    24
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.04
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 days after last scan
    Adverse event reporting additional description
    By the participant calling an investigator - registered in REDCap directly By the participant noting it on sheet handed out for drug and adverse event registration - registered in REDCap after trial completion
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Zinc acetate 50 mg x 3
    Reporting group description
    		 -

    Reporting group title
    Zinc acetate 150 mg x 1
    Reporting group description
    		 -

    Reporting group title
    Zinc gluconate 50 mg x 3
    Reporting group description
    		 -

    Reporting group title
    Zinc gluconate 150 mg x 1
    Reporting group description
    		 -

    Serious adverse events
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zinc acetate 50 mg x 3 Zinc acetate 150 mg x 1 Zinc gluconate 50 mg x 3 Zinc gluconate 150 mg x 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    8 / 9 (88.89%)
    1 / 9 (11.11%)
    3 / 9 (33.33%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Discomfort
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 9 (44.44%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    4
    0
    1
    Nausea
         subjects affected / exposed
    5 / 10 (50.00%)
    5 / 9 (55.56%)
    1 / 9 (11.11%)
    2 / 9 (22.22%)
         occurrences all number
    5
    5
    1
    2
    Obstipation
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Nov 2019
    We added an additional treatment arm with zinc gluconate 50 mg x 3 daily (10 participants). This to be able to compare the zinc formula if taken thrice daily similar to the control treatment. Furthermore, a plasma zinc sample on all remaining participants was added. This to investigate if the variance in effect of zinc on hepatic copper uptake could by explained by zinc levels. The amendment was not considered to modify any ethical considerations.

    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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