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    Clinical Trial Results:
    An open label trial evaluating the pharmacokinetics and safety of an intravenously administered single dose of Feramyl® 200 mg, 500 mg or 1500 mg vs. Ferinject® 500 mg in patients suffering from anaemia following cardiac surgery.

    Summary
    EudraCT number
    		 2015-003069-28
    Trial protocol
    		 DK  
    Global end of trial date
    14 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2017
    First version publication date
    28 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SWB0115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Serumwerk Bernburg AG
    Sponsor organisation address
    Hallesche Landstrasse 105 b, Bernburg, Germany, 06406
    Public contact
    Susanne Manhart, Serumwerk Bernburg AG, +49 3471860180, smanhart@serumwerk.de
    Scientific contact
    Christoffer von Sehested, KLIFO A/S, +45 44222916, christoffer.von.sehested@klifo.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
    20 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective is to evaluate dose proportionality of single dose Feramyl® given as 200 mg, 500 mg and 1500 mg i.v. infusion in terms of total iron in plasma. Secondary objectives are: - To evaluate general safety and tolerability of Feramyl® given as 200 mg, 500 mg and 1500 mg i.v. infusion to that of 500 mg Ferinject® i.v. infusion. - To evaluate the early phase iron parameters of Feramyl® given as 200 mg, 500 mg and 1500 mg i.v. infusion and compare Feramyl® 500 mg i.v. infusion to that of 500 mg Ferinject® i.v. infusion. - To evaluate urine iron parameters of Feramyl® given as 200 mg, 500 mg and 1500 mg i.v. infusion and compare Feramyl® 500 mg i.v. infusion to that of 500 mg Ferinject® i.v. infusion. - To characterize the pharmacokinetic parameters of Feramyl® given as 200 mg, 500 mg and 1500 mg i.v. infusion and compare Feramyl® 500 mg i.v. infusion to that of 500 mg Ferinject® i.v. infusion in terms of total iron in plasma.
    Protection of trial subjects
    The DSMB had their first meeting before trial start to decide on meeting frequency and format, the degree, form and frequency of the information neede din oter to monitor trial safety. In addition, the DSMB met prior to start of the 500 mg and 1500 mg dosing groups to evaluate whether or not it was safe to proceed to the next dose level. The DSMB's tasks were to: - Monitor safety data - Assess any critical adverse event (CAE) occuring during the trial - Assess safety profile after each dose level - Evaluate PK and urine data - Evaluate specific rat study before start of the 1500 mg feramyl(R) treatment group
    Background therapy
    		 -
    Evidence for comparator
    		 Ferinject (comparator) is an iron-containing nanoparticle, where the shielding sugar is carboxymaltose, which is less antigenic than the sugars in other iron containing drugs based on dextran as the sugar moity.
    Actual start date of recruitment
    06 Nov 2015
    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: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    11
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 8 subjects were enrolled in cohort 1 from 06-Nov-2015 to 11-Dec-2015, 18 were enrolled in cohort 2 from 23-Feb-2016 to 04-Jun-2016 (one was not treated due to withdrawal of consent) and 8 subjects were enrolled into cohort 3 from 21-Jun-2016 to 14-Oct-2016.

    Pre-assignment
    Screening details
    		 79 subjects were screened before cardiac surgery and reevaluated for particiation after surgery depedning on 1) low mortality risk, 2) severity of anaemia and 3) blood pressure.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding was used as endpoints are based on lab values.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 Subjects in cohort 1 received 200 mg Feramyl.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Feramyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg Feramyl was administered as single i.v. infusion over a period of 15 minutes by use of an infusion pump.

    Arm title
    		 Cohort 2 - experimental
    Arm description
    		 Subjects in cohort 2 were randomized to either receive 500 mg Feramyl or 500 mg Ferinject.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Feramyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg Feramyl was administered as single i.v. infusion over a period of 15 minutes by use of an infusion pump.

    Arm title
    		 Cohort 2 - comparator
    Arm description
    		 Subjects in cohort 2 were randomized to either receive 500 mg Feramyl or 500 mg Ferinject.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ferinject
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg Ferinject was administered as single i.v. infusion over a period of 15 minutes by use of an infusion pump.

    Arm title
    		 Cohort 3
    Arm description
    		 Subjects in cohort 3 received 1500 mg Feramyl.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Feramyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1500 mg Feramyl was administered as single i.v. infusion over a period of 15 minutes by use of an infusion pump.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Started
    8
    9
    8
    8
    per cohort
    8
    9
    8
    8
    Completed
    7
    9
    8
    8
    Not completed
    1
    0
    0
    0
         Consent withdrawn by subject
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 33 33
    Age categorical
    One subject withdrew consent before randomisation. This subject is not included in the age listing.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 11 11
        From 65-84 years
    		 22 22
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 33 33

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Subjects in cohort 1 received 200 mg Feramyl.

    Reporting group title
    Cohort 2 - experimental
    Reporting group description
    		 Subjects in cohort 2 were randomized to either receive 500 mg Feramyl or 500 mg Ferinject.

    Reporting group title
    Cohort 2 - comparator
    Reporting group description
    		 Subjects in cohort 2 were randomized to either receive 500 mg Feramyl or 500 mg Ferinject.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Subjects in cohort 3 received 1500 mg Feramyl.

    Primary: Total Iron in Plasma AUC(0-infinity)

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    End point title
    		 Total Iron in Plasma AUC(0-infinity) [1]
    End point description
    The primary objective of the trial was examined by the co-primary endpoints: AUC(0-infinity) and Cmax of total iron in plasma following infusion calculated for subjects exposed to Feramyl® treatment. AUC(0-infinity) is the area under the concentration time curve for plasma total iron from time 0 (start of infusion) to infinity and Cmax the maximum concentration of the same profile. Dose proportionality could not be claimed for Feramyl, as the 90% CI for both co-primary endpoints was not entirely contained within the limits 0.80 – 1.25. The 90% CI for AUC(0-infinity) ranged between 1.05 – 1.39. Scatterplot of AUC(0-infinity) did however show dose dependency.
    End point type
    Primary
    End point timeframe
    72 hours
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary objective of the trial is examined by the co-primary endpoints: AUC(0-infinity) and Cmax of total iron in plasma following infusion calculated for subjects exposed to treatment with Feramyl. AUC(0-infinity) is the area under the concentration time curve for plasma total iron from time 0 (start of infusion) to infinity and Cmax the maximum concentration of the same profile. The resuluts will be used for comparison between the 4 groups. No statistical analysis is performed.
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: microgram(s)*hour/millilitre
        geometric mean (full range (min-max))
    123.19 (94.6 to 147.1)
    426.7 (246.7 to 625.5)
    1873.46 (1194.8 to 2567.0)
    1204.70 (441.5 to 3423.1)
    No statistical analyses for this end point

    Primary: Total Iron in Plasma C(max)

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    End point title
    		 Total Iron in Plasma C(max) [2]
    End point description
    The primary objective of the trial was examined by the co-primary endpoints: AUC(0-infinity) and Cmax of total iron in plasma following infusion calculated for subjects exposed to Feramyl® treatment. AUC(0-infinity)) is the area under the concentration time curve for plasma total iron from time 0 (start of infusion) to infinity and Cmax the maximum concentration of the same profile. Dose proportionality could not be claimed for Feramyl, as the 90% CI for both co-primary endpoints was not entirely contained within the limits 0.80 – 1.25. The 90% CI for Cmax ranged between 0.78 – 1.01. Scatterplot Cmax did however show dose dependency.
    End point type
    Primary
    End point timeframe
    72 hours
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary objective of the trial is examined by the co-primary endpoints: AUC(0-infinity) and Cmax of total iron in plasma following infusion calculated for subjects exposed to treatment with Feramyl. AUC(0-infinity) is the area under the concentration time curve for plasma total iron from time 0 (start of infusion) to infinity and Cmax the maximum concentration of the same profile. The resuluts will be used for comparison between the 4 groups. No statistical analysis is performed.
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: microgram(s)/millilitre
        geometric mean (full range (min-max))
    61.20 (40.25 to 73.73)
    147.60 (101.66 to 199.50)
    128.08 (107.75 to 155.75)
    333.94 (189.07 to 598.60)
    No statistical analyses for this end point

    Secondary: Safety

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    End point title
    		 Safety
    End point description
    Infusion site reactions, hypersensitivity reactions, all-cause mortality. For hypersensitivity reactions blood preasure and heart rate will be evaluated at t=15 minutes (end of infusion), 30 minutes and 60 minutes following infusion.
    End point type
    Secondary
    End point timeframe
    60 minutes following infusion
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: Hypersensitivy reactions
        15 min
    0
    0
    0
    0
        30 min
    0
    0
    0
    0
        60 min
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Transferrin Saturation (TSAT)

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    End point title
    		 Transferrin Saturation (TSAT)
    End point description
    Transferrin saturation (TSAT) is a measurement of how much iron is bound and will be shown as a ratio.
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    7 [3]
    9 [4]
    8 [5]
    8 [6]
    Units: ratio
    geometric mean (standard deviation)
        Screening
    0.206 ± 0.083
    0.272 ± 0.05
    0.293 ± 0.074
    0.174 ± 0.066
        Post-operation and pre-infusion
    0.083 ± 0.036
    0.091 ± 0.033
    0.099 ± 0.039
    0.079 ± 0.019
        8 hours
    0.083 ± 0.016
    0.124 ± 0.043
    0.649 ± 0.223
    0.367 ± 0.191
        24 hours
    0.101 ± 0.020
    0.177 ± 0.084
    0.354 ± 0.193
    0.246 ± 0.104
        48 hours
    0.123 ± 0.043
    0.183 ± 0.071
    0.184 ± 0.024
    0.205 ± 0.057
        72 hours
    0.124 ± 0.033
    0.209 ± 0.096
    0.154 ± 0.033
    0.231 ± 0.084
    Notes
    [3] - For timeponint "post-operation and pre-infusion" N=8
    [4] - At screening N=5
    [5] - At screening N=6
    [6] - At screening and 24 hours N=7
    No statistical analyses for this end point

    Secondary: Haemoglobin

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    End point title
    		 Haemoglobin
    End point description
    haemoglobin (mmol/L)
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    7 [7]
    9
    8
    8 [8]
    Units: millimole(s)/litre
    geometric mean (standard deviation)
        Screening
    8.30 ± 1.05
    8.77 ± 0.94
    9.35 ± 0.62
    7.89 ± 0.75
        Post-operation and pre-infusion
    6.19 ± 0.62
    6.86 ± 0.82
    7.09 ± 0.73
    5.78 ± 0.38
        8 hours
    5.78 ± 0.71
    6.50 ± 0.71
    6.86 ± 0.80
    5.71 ± 0.54
        24 hours
    5.77 ± 0.57
    6.33 ± 0.89
    6.69 ± 0.64
    5.51 ± 0.34
        48 hours
    5.71 ± 0.79
    6.13 ± 0.92
    6.68 ± 0.47
    5.36 ± 0.40
        72 hours
    5.80 ± 0.78
    6.47 ± 0.73
    6.70 ± 0.65
    5.30 ± 0.55
    Notes
    [7] - At screening and post-operation and pre-infusion N=8 At 8 hours N=6
    [8] - At 24 hours N=7
    No statistical analyses for this end point

    Secondary: Ferritin

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    End point title
    		 Ferritin
    End point description
    ferritin (µg/L)
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    7 [9]
    9
    8
    8 [10]
    Units: microgram(s)/litre
    geometric mean (standard deviation)
        Screening
    162.9 ± 100.2
    281.3 ± 353.8
    271.4 ± 107.3
    187.6 ± 127.1
        Post-operation and pre-infusion
    259.5 ± 98.3
    333.4 ± 334.7
    334.4 ± 99.6
    294.9 ± 191.5
        8 hours
    259.6 ± 91.8
    360.3 ± 320.1
    342.8 ± 83.4
    311.1 ± 180.2
        24 hours
    298.7 ± 104.8
    458.6 ± 272.8
    493.5 ± 84.0
    549.4 ± 240.7
        48 hours
    386.7 ± 167.4
    659.0 ± 334.5
    809.0 ± 104.3
    876.3 ± 411.5
        72 hours
    480.6 ± 227.0
    1418.9 ± 2027.3
    1003.9 ± 174.0
    1103.9 ± 515.5
    Notes
    [9] - At post-operation and pre-infusion N=8
    [10] - At 24 hours N=7
    No statistical analyses for this end point

    Secondary: Urine Iron Excretion

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    End point title
    		 Urine Iron Excretion
    End point description
    Summary of urine iron excretion (mg) by time period reported as number of patients with urinary iron above lower limit of quantification (LLQ) per patients observed.
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9 [11]
    8
    8
    Units: Patients
        0-8 hours
    0
    0
    8
    1
        8-24 hours
    0
    0
    5
    1
        24-48 hours
    0
    1
    0
    1
        48-72 hours
    0
    0
    0
    1
    Notes
    [11] - At t=48-72 N=8
    No statistical analyses for this end point

    Secondary: Tmax

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    End point title
    		 Tmax
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: minute
        geometric mean (full range (min-max))
    17.1 (15 to 30)
    24.0 (15 to 63)
    47.6 (15 to 120)
    15.0 (15 to 15)
    No statistical analyses for this end point

    Secondary: T(half)

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    End point title
    		 T(half)
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: hour
        geometric mean (full range (min-max))
    1.58 (1.16 to 2.29)
    1.25 (0.79 to 2.01)
    8.96 (7.48 to 10.70)
    1.08 (0.42 to 1.92)
    No statistical analyses for this end point

    Secondary: Clearence

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    End point title
    		 Clearence
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: Litre(s)/hour
        geometric mean (full range (min-max))
    1.623 (1.36 to 2.11)
    1.179 (0.80 to 2.03)
    0.267 (0.19 to 0.42)
    1.245 (0.44 to 3.40)
    No statistical analyses for this end point

    Secondary: Total Iron in Plasma AUC(0-72)

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    End point title
    		 Total Iron in Plasma AUC(0-72)
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: hour/litre
        geometric mean (full range (min-max))
    120.69 (93.8 to 144.6)
    418.02 (246.6 to 613.9)
    1782.42 (1161.3 to 2237.1)
    1174.21 (435.8 to 3180.8)
    No statistical analyses for this end point

    Secondary: Lambda(z)

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    End point title
    		 Lambda(z)
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: 1/hour
        geometric mean (full range (min-max))
    0.44 (0.30 to 0.60)
    0.56 (0.35 to 0.88)
    0.08 (0.07 to 0.09)
    0.64 (0.36 to 1.67)
    No statistical analyses for this end point

    Secondary: Volume of Distribution(z)

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    End point title
    		 Volume of Distribution(z)
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Number of subjects analysed
    8
    9
    8
    8
    Units: litre(s)
        geometric mean (full range (min-max))
    3.70 (2.80 to 5.36)
    2.12 (1.40 to 3.19)
    3.45 (2.49 to 6.18)
    1.94 (0.97 to 6.35)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE reporting period begins from screening until the subject terminates the trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 - experimental
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 - comparator
    Reporting group description
    		 One subject randomized withdrew his consent before dosing. This subjects did not experience any adverse events and is not included in the summary below (as he withdrew right after screening).

    Reporting group title
    Cohort 3
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Haemorrhage
    Additional description: Surgical bleeding
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 - experimental Cohort 2 - comparator Cohort 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    5 / 9 (55.56%)
    3 / 8 (37.50%)
    3 / 8 (37.50%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    3
    1
    0
    2
    Atrioventricular block
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    1
    Respiratory failure
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Hypovolaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2016
    Substantial amendment specifying that anesthesia was not required to be transcribed from source data to the eCRF, as the operation was not considered trial related. In addition, the amendment covered a specification of inclusion criteria no 4 (level of anaemia) for the 1500 mg treatment group.
    28 Jun 2016
    Opening of an extra site in Århus as recruitment for the 1500 mg treatment group was significantly delayed at Rigshospitalet. The delay was due to the severe anaemia required for subjects to qualify for the 1500 mg treatment group. This amendment never came into force as the subjects became available at Rigshospitalet.

    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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