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    Clinical Trial Results:
    A randomised, prospective, double-blind, comparative placebo-controlled study of intrave-nous iron isomaltoside 1000 (Monofer®) administered by infusions to non-anaemic patients undergoing elective or sub-acute CABG, valve replacement, or a combination thereof

    Summary
    EudraCT number
    		 2010-023788-16
    Trial protocol
    		 DK  
    Global end of trial date
    02 Aug 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Apr 2016
    First version publication date
    16 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Some incorrect data was discovered during the review process.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P-Monofer-CABG-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01563367
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharmacosmos A/S
    Sponsor organisation address
    Roervangsvej 30, Holbaek, Denmark, DK-4300
    Public contact
    Clinical trial disclosure desk, Pharmacosmos A/S, +45 59485935, trial@pharmacosmos.com
    Scientific contact
    Clinical trial disclosure desk, Pharmacosmos A/S, +45 59485935, trial@pharmacosmos.com
    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
    02 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective of the study was to demonstrate that IV iron isomaltoside 1000 is superior compared to placebo in leading to a less decrease in the Hb level in non-anaemic patients undergoing cardiac surgery.
    Protection of trial subjects
    The protocol and amendments were approved by local ethics committees/Institutional Review Boards and competent authorities. The trial was conducted in accordance with good clinical practice and the Declaration of Helsinki. Informed consent was obtained in writing prior to any trial-related activities.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Dec 2012
    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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    21
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were screened in the period 13 December 2012 to 01 July 2013. The trial took place at one site in Denmark.

    Pre-assignment
    Screening details
    		 Subjects ≥ 18 years of age undergoing elective or sub-acute CABG, valve replacement, or a combination thereof, with a Hb ≥ 12.0 g/dL (7.45 mmol/L) for women and a Hb ≥ 13.0 g/dL (8.1 mmol/L) for men, and who were willing to provide written informed consent were considered eligible to participate in the trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study drug was administered while the patient was in anaesthesia in order to keep the patient blinded. The randomisation, preparation, connection of infusions, and removal of used infusion material was handled by personnel otherwise unrelated to the study. The infusion bags of iron isomaltoside 1000 and placebo were of similar sizes and brand.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A, iron isomaltoside 1000
    Arm description
    		 Subjects in the iron isomaltoside 1000 group received iron isomaltoside 1000 as a single dose infusion of 1000 mg over 15 min with a maximum single dose of 20 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Iron isomaltoside 1000
    Investigational medicinal product code
    ATC code: B03AC
    Other name
    Monofer, Monover, Monofar, Monoferro
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects in the iron isomaltoside 1000 group received iron isomaltoside 1000 as a single dose infusion of 1000 mg over 15 min with a maximum single dose of 20 mg/kg. Iron isomaltoside 1000 is available as a dark brown, non-transparent aqueous solution for injection/infusion containing 100 mg iron/mL with pH between 5.0 and 7.0.

    Arm title
    		 Group B, placebo
    Arm description
    		 Subjects in the placebo group received saline (Natriumklorid 9 mg/mL, Fresenius Kabi, Copenhagen, Denmark) as a single dose infusion of 100 mL over 15 min.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects in the placebo group received saline (Natriumklorid 9 mg/mL, Fresenius Kabi, Copenhagen, Denmark) as a single dose infusion of 100 mL over 15 min

    Number of subjects in period 1
    		Group A, iron isomaltoside 1000 Group B, placebo
    Started
    30
    30
    Completed
    26
    25
    Not completed
    4
    5
         Consent withdrawn by subject
    1
    -
         Non-compliance
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    		 Subjects in the iron isomaltoside 1000 group received iron isomaltoside 1000 as a single dose infusion of 1000 mg over 15 min with a maximum single dose of 20 mg/kg.

    Reporting group title
    Group B, placebo
    Reporting group description
    		 Subjects in the placebo group received saline (Natriumklorid 9 mg/mL, Fresenius Kabi, Copenhagen, Denmark) as a single dose infusion of 100 mL over 15 min.

    Reporting group values
    		 Group A, iron isomaltoside 1000 Group B, placebo Total
    Number of subjects
    		 30 30 60
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age is calculated by subtracting the screening visit date with the birth date.
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ( 7.9 ) 65 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4 8
        Male
    		 26 26 52
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set consisted of all subjects who were randomized and received at least one dose of the trial drug. The subjects were included as treated.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all subjects who were randomized into the trial, received at least one dose of the trial drug, and had a Hb assessment at visit 4. Subjects were included as randomized, regardless of which treatment they actually received.

    Subject analysis set title
    Per protocol (PP) analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set consisted of all subjects in the FAS who did not have any major protocol deviation and had not received blood transfusion during the trial.

    Subject analysis sets values
    		 Safety analysis set Full analysis set (FAS) Per protocol (PP) analysis set
    Number of subjects
    60
    51
    43
    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
    Age is calculated by subtracting the screening visit date with the birth date.
    Units: years
        arithmetic mean (standard deviation)
    65.2 ( 9.4 )
    66 ( 8.7 )
    66.5 ( 8 )
    Gender categorical
    Units: Subjects
        Female
    8
    6
    6
        Male
    52
    45
    37

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    		 Subjects in the iron isomaltoside 1000 group received iron isomaltoside 1000 as a single dose infusion of 1000 mg over 15 min with a maximum single dose of 20 mg/kg.

    Reporting group title
    Group B, placebo
    Reporting group description
    		 Subjects in the placebo group received saline (Natriumklorid 9 mg/mL, Fresenius Kabi, Copenhagen, Denmark) as a single dose infusion of 100 mL over 15 min.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set consisted of all subjects who were randomized and received at least one dose of the trial drug. The subjects were included as treated.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all subjects who were randomized into the trial, received at least one dose of the trial drug, and had a Hb assessment at visit 4. Subjects were included as randomized, regardless of which treatment they actually received.

    Subject analysis set title
    Per protocol (PP) analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set consisted of all subjects in the FAS who did not have any major protocol deviation and had not received blood transfusion during the trial.

    Primary: Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively, FAS

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    End point title
    		 Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively, FAS
    End point description
    Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively. The analysis is performed on the FAS.
    End point type
    Primary
    End point timeframe
    Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    25
    Units: g/dL
        arithmetic mean (standard deviation)
    -1.61 ( 1.15 )
    -2.13 ( 1.09 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in Hb concentration from baseline to week 4. The number of subjects may differ from the analysis population if data is missing. The sample size calculation was based on superiority analysis, normally distributed data, Type I error = 5 %, 2-sided test, and a power of 80 %. With a sample size of 30 patients/treatment group and an assumed standard deviation of 1.50, the trial was able to detect a difference of 1.1 g/dL in change in Hb.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0124
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7728
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2968
    Notes
    [1] - The ANCOVA model was used to compare the average change in Hb concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline Hb values as covariates.

    Primary: Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively, PP

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    End point title
    		 Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively, PP
    End point description
    Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively. The analysis is performed on the PP analysis set.
    End point type
    Primary
    End point timeframe
    Change in Hb concentrations from baseline (preoperatively – the day before surgery or the same day) to 4 weeks postoperatively.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    22
    21
    Units: g/dL
        arithmetic mean (standard deviation)
    -1.45 ( 1.08 )
    -2.16 ( 1.14 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in Hb concentration from baseline to week 4. The number of subjects may differ from the analysis population if data is missing. The sample size calculation was based on superiority analysis, normally distributed data, Type I error = 5 %, 2-sided test, and a power of 80 %. With a sample size of 30 patients/treatment group and an assumed standard deviation of 1.50, the trial was able to detect a difference of 1.1 g/dL in change in Hb.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0006
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0825
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2896
    Notes
    [2] - The ANCOVA model was used to compare the average change in Hb concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline Hb values as covariates.

    Secondary: Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at day 5

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    End point title
    		 Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at day 5
    End point description
    Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at day 5. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at day 5.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    25
    Units: Proportion of subjects
        Anaemic
    24
    25
        Non-anaemic
    2
    0
    Statistical analysis title
    		 Superiority tested by Fisher Exact
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4902
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at week 4

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    End point title
    		 Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at week 4
    End point description
    Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Proportion of subjects that were anaemic (women < 12 g/dL and men < 13 g/dL) at week 4.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    25
    Units: Proportion of subjects
        Anaemic
    16
    23
        Non-anaemic
    10
    2
    Statistical analysis title
    		 Superiority tested by Fisher Exact
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0188
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at day 5

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    End point title
    		 Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at day 5
    End point description
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at day 5. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at day 5.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    25
    Units: Proportion of subjects
        Hb < 9.5 g/dL
    7
    3
        Maintain Hb (9.5 g/dL <= Hb <= 12.5 g/dL)
    17
    22
        Hb > 12.5 g/dL
    2
    0
    Statistical analysis title
    		 Superiority tested by Fisher Exact
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1181
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 4

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    End point title
    		 Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 4
    End point description
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Proportion of subjects who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at week 4.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    25
    Units: Proportion of subjects
        Hb < 9.5 g/dL
    0
    0
        Maintain Hb (9.5 g/dL <= Hb<= 12.5 g/dL)
    12
    19
        Hb > 12.5 g/dL
    14
    6
    Statistical analysis title
    		 Superiority tested by Fisher Exact
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0291
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Number of subjects in each treatment group who needed blood transfusion

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    End point title
    		 Number of subjects in each treatment group who needed blood transfusion
    End point description
    Number of subjects in each treatment group who needed blood transfusion. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    The endpoint covers the complete trial period.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    25
    Units: Number of subjects
        Needed blood transfusion
    4
    3
        Did not need blood transfusion
    22
    22
    Statistical analysis title
    		 Superiority tested by Fisher Exact
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Number of transfusions administered

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    End point title
    		 Number of transfusions administered
    End point description
    Number of transfusions administered. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    The endpoint covers the complete trial period.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    4
    2
    Units: number of blood transfusion
        arithmetic mean (standard deviation)
    1.25 ( 0.5 )
    3 ( 2.83 )
    No statistical analyses for this end point

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at day 5

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at day 5
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at day 5. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at day 5.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    24
    Units: microg/L
        arithmetic mean (standard deviation)
    905.88 ( 427.57 )
    161.62 ( 190.49 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in serum-ferritin concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group B, placebo v Group A, iron isomaltoside 1000
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    757.5476
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 556.474
         upper limit
    		 958.621
    Variability estimate
    Standard error of the mean
    Dispersion value
    99.7701

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at week 4

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at week 4
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-ferritin at week 4.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    24
    23
    Units: microg/L
        arithmetic mean (standard deviation)
    398.48 ( 306.26 )
    -18.83 ( 124.75 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in serum-ferritin concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    396.9232
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 260.449
         upper limit
    		 533.397
    Variability estimate
    Standard error of the mean
    Dispersion value
    67.5767

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at day 5

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at day 5
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at day 5. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at day 5.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    24
    Units: micromol/L
        arithmetic mean (standard deviation)
    -1.38 ( 4.62 )
    -6.75 ( 4.19 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in serum-iron concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.5395
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.119
         upper limit
    		 6.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7047

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at week 4

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at week 4
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of serum-iron at week 4.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    24
    23
    Units: micromol/L
        arithmetic mean (standard deviation)
    -0.92 ( 5.08 )
    -2.7 ( 4.27 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in serum-iron concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0299
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.6376
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.269
         upper limit
    		 5.006
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1727

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at day 5

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at day 5
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at day 5. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at day 5.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    24
    Units: percentage
        arithmetic mean (standard deviation)
    4.38 ( 8.12 )
    -8.96 ( 6.97 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in transferrin saturation concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    12.5977
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.697
         upper limit
    		 15.498
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4393

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at week 4

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at week 4
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of transferrin saturation (TSAT) at week 4.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    23
    23
    Units: percentage
        arithmetic mean (standard deviation)
    0.74 ( 7.65 )
    -5.78 ( 7.57 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in transferrin saturation concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.5229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.649
         upper limit
    		 10.396
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9165

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at day 5

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at day 5
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at day 5. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at day 5.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    24
    Units: 10E9/L
        arithmetic mean (standard deviation)
    40.77 ( 28.89 )
    24.08 ( 15.1 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in reticulocytes concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0157
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    16.1961
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.212
         upper limit
    		 29.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.4426

    Secondary: Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at week 4

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    End point title
    		 Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at week 4
    End point description
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at week 4. The analysis was performed on the FAS.
    End point type
    Secondary
    End point timeframe
    Change from baseline (preoperatively – the day before surgery or the same day) in concentrations of reticulocytes at week 4.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    26
    24
    Units: 10E9/L
        arithmetic mean (standard deviation)
    16.69 ( 32.91 )
    20.75 ( 13.42 )
    Statistical analysis title
    		 Superiority tested by ANCOVA
    Statistical analysis description
    An ANCOVA model was used to compare the average change in reticulocytes concentration with the use of treatment, diagnostic group (a: elective CABG, b: sub-acute CABG c: valve replacement d: combination thereof) as factors and baseline values as covariates.
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3829
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.8496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.939
         upper limit
    		 6.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.5026

    Secondary: Number of postoperative days to discharge

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    End point title
    		 Number of postoperative days to discharge
    End point description
    Number of postoperative days to discharge.
    End point type
    Secondary
    End point timeframe
    This endpoint covers the complete trial period.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    25
    24
    Units: days
        arithmetic mean (standard deviation)
    7.56 ( 3.38 )
    7.96 ( 4.81 )
    Statistical analysis title
    		 Superiority tested by Wilcoxon rank sum test
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9267
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Changes in New York Heart Association (NYHA) classification from baseline to 4 weeks postoperatively

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    End point title
    		 Changes in New York Heart Association (NYHA) classification from baseline to 4 weeks postoperatively
    End point description
    Changes in New York Heart Association (NYHA) classification from baseline to 4 weeks postoperatively.
    End point type
    Secondary
    End point timeframe
    Changes in New York Heart Association (NYHA) classification from baseline to 4 weeks postoperatively.
    End point values
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Number of subjects analysed
    13
    12
    Units: NYHA class
        Increase in NYHA class
    0
    0
        Unchanged NYHA class
    6
    6
        Decrease in NYHA class
    7
    6
    Statistical analysis title
    		 Unchanged NYHA class
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8475
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Decrease in NYHA class
    Comparison groups
    Group A, iron isomaltoside 1000 v Group B, placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8475
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time a subject had signed the ICF and until he/she has completed the study, all AEs/SAEs were collected in the CRF. SAEs occurring after study completion were reported, if considered related to the trial treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Group A, iron isomaltoside 1000
    Reporting group description
    		 Subjects in the iron isomaltoside 1000 group received iron isomaltoside 1000 as a single dose infusion of 1000 mg over 15 min with a maximum single dose of 20 mg/kg.

    Reporting group title
    Group B, placebo
    Reporting group description
    		 Subjects in the placebo group received saline (Natriumklorid 9 mg/mL, Fresenius Kabi, Copenhagen, Denmark) as a single dose infusion of 100 mL over 15 min.

    Serious adverse events
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 30 (26.67%)
    9 / 30 (30.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (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
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A, iron isomaltoside 1000 Group B, placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 30 (63.33%)
    24 / 30 (80.00%)
    Investigations
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 30 (13.33%)
         occurrences all number
    4
    4
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    11 / 30 (36.67%)
    10 / 30 (33.33%)
         occurrences all number
    11
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Pleural effusion
         subjects affected / exposed
    2 / 30 (6.67%)
    6 / 30 (20.00%)
         occurrences all number
    2
    6
    Respiratory failure
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Infection
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    Oral candidiasis
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    Pneumonia
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Aug 2011
    • In the inclusion criterion no. 3, the Hb level for women was changed from “< 12.0 g/dL (7.3 mmol/L)” to “< 11.5 g/dL (7.1 mmol/L)” • Impaired renal function was added as exclusion criteria no. 15 • Stratification by diagnostic group and baseline Hb level was added to the randomisation procedure • Blood transfusion was added to the list of protocol deviations, however patients requiring blood transfusion would not be withdrawn from the study • Dosing was to be done at the time of surgery when the patient was under anaesthesia to ensure blinding • Mean corpuscular Hb, globulin, and albumin:globulin ratio were deleted from the list of laboratory assessments • “Natriumklorid” was specifically mentioned as the placebo used for reference therapy • List of concomitant medications administered as part of the standard procedure in patients undergoing elective or sub-acute CABG, valve replacement, or a combination were added as Appendix 2 • List of AEs known to occur during surgery or postoperatively after the cardiac surgery were added as Appendix 3
    20 Dec 2011
    • Secondary objectives were added in accordance to the secondary endpoints • Secondary endpoint no. 6 was modified from number of patients in each randomisa-tion group who experience any “Suspected Unexpected Serious Adverse Event (SU-SAR)” to “study drug related adverse events (AEs/SAEs/SUSARs)” • Description of body measurements and six minute walking distance test was added to the study assessments • Analysis of laboratory parameters was to be conducted at the “local laboratory” in-stead of the “central laboratory” • Unblinding was to performed by the study nurse at the Department of Cardiothoracic Surgery • The safety reporting and study management sections were modified to reflect that Pharmacosmos A/S was the sponsor of the study and MNI was the sponsor designee for pharmacovigilance • Safety review by safety review committee was added • Time points for efficacy assessments were mentioned as: at baseline, 4 weeks, and 3 months postoperatively • Statistical methods for analyses of the number of patients who need blood transfusion, number of postoperative days to discharge, and change in six-minute walking distance from baseline to 4 weeks postoperatively were added • Role and responsibility of the investigator during an audit was added
    15 Nov 2012
    • The study population was changed from anaemic to non-anaemic • Dose of iron isomaltoside 1000 was changed from “20 mg/kg” to “1000 mg” • Addition and deletion of secondary endpoints. Two secondary endpoints “proportion of patients that are anaemic (women < 12 g/dL and men < 13 g/dL) at day 5 and week 4” and “proportion of patients able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at day 5 and week 4” were added, and the endpoint “change in Hb concentrations from baseline (preoperatively – the day before surgery or same day) to 3 months postoperatively” was deleted • The secondary endpoint “change of reticulocytes from baseline” was changed from 4 weeks and 3 months to day 5 and week 4 • Duration of the study for each individual patient was changed from “3 months” to “4 weeks” • Inclusion criterion 3 was revised where Hb level for women was changed from “< 11.5 g/dL (7.1 mmol/L)” to “≥ 12.0 g/dL (7.45 mmol/L)” and from “< 13.0 g/dL (8.1 mmol/L)” to “≥ 13.0 g/dL (8.1 mmol/L)” for men • Additional exclusion criterion “patients receiving blood transfusion < 30 days before screening and/or during the elective or sub-acute CABG, valve replacement, or a com-bination thereof” was added • Minor revisions in statistical analyses section were done, including revision of the def-inition of PP population and the number of randomised patients were changed from “80” to “60”
    21 Mar 2013
    • Six minute walking distance was replaced by NYHA classification • Instead of analysis of co-variance model, chi-square test was used to compare the average change in NYHA classification

    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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