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    Clinical Trial Results:
    A Multicenter Study on Regenerative Effects of Erythropoitin (LDE) in Burn and Scaled Injuries

    Summary
    EudraCT number
    		 2006-002886-38
    Trial protocol
    		 DE  
    Global end of trial date
    06 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2021
    First version publication date
    03 Apr 2021
    Other versions
    Summary report(s)
    		 EPO

    Trial information

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    Trial identification
    Sponsor protocol code
    0506
    Additional study identifiers
    ISRCTN number
    		 ISRCTN95777824
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 BMC: doi:10.1186/1745-6215-14-124
    Sponsors
    Sponsor organisation name
    Technische Universität München, Fakultät für Medizin
    Sponsor organisation address
    Ismaningerstr. 22, München, Germany, 81675
    Public contact
    Professor Dr. med. Hans-Günther Machens, Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Plastische Chirurgie, 49 4140 2171, Hans-Guenther.Machens@mri.tum.de
    Scientific contact
    Professor Dr. med. Hans-Günther Machens, Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Plastische Chirurgie, 49 4140 2171, Hans-Guenther.Machens@mri.tum.de
    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
    28 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Time until complete reepithelialization of skin graft donor sites (thickness 0.3 mm) at a definite location on the lateral upper thigh (Primary endpoint) - To prove a cytoprotective and regenerative effect of erythropoietin in thermally injured patients in terms of reduced morbidity and mortality - To better understand the cellular mechanisms of erythropoietin in Skin Graft Donor Sites (SGDS) and Second Degree Wounds (SDW)
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance the ethical principles of Good Clinical Practice (GCP). Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. The study was regularly monitored by the Sponsor and additionally a Data Safety Monitoring Board was set up. All investigators connected to the study were GCP trained.
    Background therapy
    		 Erythropoietin application will be the only change of standard therapy protocol in all patients. Every subject had received a state of the art Treatment for burn or scald injury during study. These concomitant Treatments had been doccumented appropriately in the Standard patients´chart documentation flow sheets. All Treatments had been taken by the subjects at any time during the study in addition to the investigational product were regarded as concomitant treatments.
    Evidence for comparator
    		 Comparator(s) not applicable.
    Actual start date of recruitment
    09 Jan 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 11 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    72
    From 65 to 84 years
    11
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted multicentric in Germany between 09.01.2009 (first patient recruited) and 09.07.2013 (last patient completed).

    Pre-assignment
    Screening details
    		 Each potential patient was examined before the start of the study to determine their eligibility for participation. Patients must have all screening evaluations performed prior to the first dose of study drug and must meet all inclusion and none of the exclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Erythropoietin
    Arm description
    		 Erythropoietin (EPO, Neorecormon 50.000 IE Multidose) application: The amount of EPO given to the patients was 150 IU/kg body weight/application every second day over 21 days after randomization, injected subcutaneously in the caudal third of the abdominal wall, if not injured. EPO will be applied as NeoRecormon from multidosage vials containing 50,000 IU EPO.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NeoRecormon
    Investigational medicinal product code
    ATC code B03XA
    Other name
    Epoetin Beta, Erythropoietin, Epo
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150/KG IU every second day over 21 days after randomization, injected subcutaneously

    Arm title
    		 Placebo
    Arm description
    		 Placebo Group: Each patient will receive a placebo carrier substance (without EPO) every second day over 21 days after randomization, injected subcutaneously in the caudal third of the abdominal wall, if not injured.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    In the control group placebo was given to the patients every second day over 3 weeks after randomization, injected subcutaneously in the caudal third of the abdominal wall, if not injured.

    Number of subjects in period 1
    		Erythropoietin Placebo
    Started
    45
    39
    Completed
    23
    19
    Not completed
    22
    20
         Adverse event, serious fatal
    3
    1
         Consent withdrawn by subject
    1
    4
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    14
    14
         personal reasons
    2
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 84 84
    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
    Units: years
        median (full range (min-max))
    		 47.5 (18 to 87) -
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 66 66
    Subject analysis sets

    Subject analysis set title
    PP-EPO
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This analysis set contains all patients in the pp-set, who were in the EPO arm.

    Subject analysis set title
    PP-Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This analysis set contains all patients in the pp-set, who were in the Placebo arm.

    Subject analysis sets values
    		 PP-EPO PP-Placebo
    Number of subjects
    29
    24
    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
        median (full range (min-max))
    51 (19 to 87)
    43 (18 to 74)
    Gender categorical
    Units: Subjects
        Female
    8
    2
        Male
    21
    22

    End points

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    End points reporting groups
    Reporting group title
    Erythropoietin
    Reporting group description
    		 Erythropoietin (EPO, Neorecormon 50.000 IE Multidose) application: The amount of EPO given to the patients was 150 IU/kg body weight/application every second day over 21 days after randomization, injected subcutaneously in the caudal third of the abdominal wall, if not injured. EPO will be applied as NeoRecormon from multidosage vials containing 50,000 IU EPO.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo Group: Each patient will receive a placebo carrier substance (without EPO) every second day over 21 days after randomization, injected subcutaneously in the caudal third of the abdominal wall, if not injured.

    Subject analysis set title
    PP-EPO
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This analysis set contains all patients in the pp-set, who were in the EPO arm.

    Subject analysis set title
    PP-Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This analysis set contains all patients in the pp-set, who were in the Placebo arm.

    Primary: Time to complete reepithelialization

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    End point title
    		 Time to complete reepithelialization
    End point description
    The primary endpoint analysis was performed by a two-sided van Elteren’s test with ABSI score (<7 versus ≥7) as strata on a confirmatory 5% significance level using the ITT population. Missing values were imputed according to the „worst-case scenario”.
    End point type
    Primary
    End point timeframe
    Time from study begin to complete reepithelialization
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    45
    39
    Units: day
    arithmetic mean (standard deviation)
        ABSI <7
    24.1 ( 10.1 )
    12.6 ( 4.0 )
        ABSI >=7
    28.7 ( 6.2 )
    14.6 ( 3.4 )
    Statistical analysis title
    		 Difference between groups
    Statistical analysis description
    Using the Van Elteren Test there was a statistically significant difference between the two groups (ITT) in favor of the placebo group, which was mainly due to the imputation of missing values because of the conservative substitution.
    Comparison groups
    Placebo v Erythropoietin
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Van Elteren Test
    Confidence interval
    Notes
    [1] - The Van Elteren test stratified by ABSI score (<7 or >=7) was used.

    Primary: Grade of re-epithelialization

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    End point title
    		 Grade of re-epithelialization
    End point description
    Sensitivity analysis of the primary endpoint. Since wound healing was recorded as ordinal data in the CRF (values: 0%; 1-25%, 26-50%, 51-75%, 76-99%, 100%), the last recorded value for re-epithelialization was compared between treatment groups using number and percent for each re-epithelialization value and an exploratory Mann-Whitney-U test as sensitivity analysis.
    End point type
    Primary
    End point timeframe
    End of study
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    40 [2]
    37 [3]
    Units: Patients
        26-50%
    1
    2
        51-75%
    8
    4
        76-99%
    22
    20
        100%
    9
    11
    Notes
    [2] - 5 patients with missing values
    [3] - 2 patients with missing values
    Statistical analysis title
    		 Comparison of grade of re-epithelialization
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to complete wound healing of type 2a SDW

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    End point title
    		 Time to complete wound healing of type 2a SDW
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment until study end
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    45
    39
    29
    24
    Units: day
        arithmetic mean (standard deviation)
    27.3 ( 7.7 )
    25.9 ( 8.5 )
    27.1 ( 7.8 )
    24.6 ( 9.5 )
    Statistical analysis title
    		 Comparison complete wound healing type 2a SDW ITT
    Statistical analysis description
    Comparison of time to complete wound healing type 2a SDW on the ITT set.
    Comparison groups
    Placebo v Erythropoietin
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.401
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison complete wound healing type 2a SDW PP
    Statistical analysis description
    Comparison of time to complete wound healing type 2a SDW on the PP set.
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.278
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to complete wound healing of TDW

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    End point title
    		 Time to complete wound healing of TDW
    End point description
    Time until complete wound healing of skin graft
    End point type
    Secondary
    End point timeframe
    From study begin to end of study
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    45
    39
    29
    24
    Units: day
        arithmetic mean (standard deviation)
    26.4 ( 8.2 )
    23.1 ( 9.9 )
    27.2 ( 7.6 )
    23.1 ( 10.6 )
    Statistical analysis title
    		 Difference in TDW on ITT
    Statistical analysis description
    Difference in time to complete wound healing of skin graft on the ITT set.
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Difference in TDW on PP
    Statistical analysis description
    Difference in time to complete wound healing of skin graft on the PP set.
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.134
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of scar formation on type 2a SDW

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    End point title
    		 Quality of scar formation on type 2a SDW
    End point description
    Quality of scar formation on type 2a SDW at day 42 - Vancouver Scar Scale
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    18 [4]
    13 [5]
    13 [6]
    10 [7]
    Units: points
        arithmetic mean (standard deviation)
    2.7 ( 1.4 )
    2.9 ( 1.6 )
    2.9 ( 1.4 )
    2.7 ( 1.5 )
    Notes
    [4] - Available for 18 patients at day 42
    [5] - Available for 13 patients at day 42
    [6] - Available for 13 patients at day 42.
    [7] - Available for 10 patients at day 42.
    Statistical analysis title
    		 Comparison SDW quality of scar score ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.838
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison SDW quality of scar score PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.678
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of scar formation on TDW

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    End point title
    		 Quality of scar formation on TDW
    End point description
    Quality of scar formation on TDW - Vancouver Scar Scale
    End point type
    Secondary
    End point timeframe
    day 42
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    26 [8]
    18 [9]
    19 [10]
    14 [11]
    Units: points
        arithmetic mean (standard deviation)
    5.0 ( 2.0 )
    3.7 ( 1.7 )
    5.1 ( 2.1 )
    3.4 ( 1.5 )
    Notes
    [8] - Values available for 26 patients.
    [9] - Values available for 18 patients.
    [10] - Values available for 19 patients.
    [11] - Values available for 14 patients.
    Statistical analysis title
    		 Comparison TDW quality of scar score ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison TDW quality of scar score PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Quality of scar formation on SGDS

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    End point title
    		 Quality of scar formation on SGDS
    End point description
    Quality of scar formation on skin graft donor site (SGDS) at day 42 – Vancouver Scar Scale
    End point type
    Secondary
    End point timeframe
    day 42
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    27 [12]
    18 [13]
    20 [14]
    14 [15]
    Units: points
        arithmetic mean (standard deviation)
    3.1 ( 1.3 )
    3.6 ( 1.6 )
    3.2 ( 1.2 )
    3.1 ( 1.6 )
    Notes
    [12] - Values available for 27 patients only.
    [13] - Values available for 18 patients only.
    [14] - Values available for 20 patients only.
    [15] - Values available for 14 patients only.
    Statistical analysis title
    		 Comparison SGDS quality of scar score ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.394
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison SGDS quality of scar score PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.719
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Red cells

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    End point title
    		 Red cells
    End point description
    Number of packed red cell units, which are transfused during the treatment.
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    43 [16]
    38 [17]
    27 [18]
    23 [19]
    Units: Packs
        arithmetic mean (standard deviation)
    6.9 ( 11.9 )
    7.1 ( 9.0 )
    6.7 ( 7.8 )
    9.3 ( 10.1 )
    Notes
    [16] - Values available for 43 patients only.
    [17] - Values available for 38 patients only.
    [18] - Values available for 27 patients only.
    [19] - Values available for 23 patients only.
    Statistical analysis title
    		 Comparison of red cell units on ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison of red cell units on PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.283
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Respiratory SOFA score Day 7

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    End point title
    		 Respiratory SOFA score Day 7
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 7.
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    40 [20]
    37 [21]
    Units: points
        arithmetic mean (standard deviation)
    0.6 ( 1.0 )
    1.1 ( 1.3 )
    Notes
    [20] - Values available for 40 patients only.
    [21] - Values available for 37 patients only.
    Statistical analysis title
    		 Comparison Resp. SOFA Day 7
    Comparison groups
    Placebo v Erythropoietin
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Respiratory SOFA score Day 14

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    End point title
    		 Respiratory SOFA score Day 14
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 14.
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    39 [22]
    35 [23]
    Units: points
        arithmetic mean (standard deviation)
    0.5 ( 0.8 )
    0.7 ( 0.9 )
    Notes
    [22] - Values available for 39 patients only.
    [23] - Values available for 35 patients only.
    Statistical analysis title
    		 Comparison Resp. SOFA Day 14
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.145
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cardiovascular SOFA day 7

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    End point title
    		 Cardiovascular SOFA day 7
    End point description
    Cardiovascular SOFA score on day 7
    End point type
    Secondary
    End point timeframe
    Measured on day 7.
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    40 [24]
    37 [25]
    Units: points
        arithmetic mean (standard deviation)
    0.5 ( 1.1 )
    0.6 ( 1.2 )
    Notes
    [24] - Values available for 40 patients only.
    [25] - Values available for 37 patients only.
    Statistical analysis title
    		 Comparison Cardio SOFA Day 7
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.678
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Cardiovascular SOFA day 14

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    End point title
    		 Cardiovascular SOFA day 14
    End point description
    Cardiovascular SOFA score measured on day 14.
    End point type
    Secondary
    End point timeframe
    Measured on day 14
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    39 [26]
    35 [27]
    Units: points
        arithmetic mean (standard deviation)
    0.2 ( 0.7 )
    0.8 ( 1.3 )
    Notes
    [26] - Values available for 39 patients only.
    [27] - Values available for 35 patients only.
    Statistical analysis title
    		 Comparison Cardio SOFA Day 14
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SF-36, physical functioning

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    End point title
    		 SF-36, physical functioning
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months post trauma.
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    13 [28]
    12 [29]
    10
    10
    Units: points
        arithmetic mean (standard deviation)
    83.5 ( 23.3 )
    77.5 ( 16.6 )
    79.0 ( 25.0 )
    75.0 ( 17.0 )
    Notes
    [28] - Values available for 13 patients only.
    [29] - Values available for 12 patients only.
    Statistical analysis title
    		 Comparison SF-36, physical functioning, ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.467
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison SF-36, physical functioning, PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.682
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SF-36, physical role functioning

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    End point title
    		 SF-36, physical role functioning
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months post trauma.
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    12 [30]
    12 [31]
    9
    10
    Units: points
        arithmetic mean (standard deviation)
    52.1 ( 44.5 )
    33.3 ( 45.6 )
    38.9 ( 43.5 )
    27.5 ( 44.8 )
    Notes
    [30] - Values available for 12 patients only.
    [31] - Values available for 12 patients only.
    Statistical analysis title
    		 Comparison SF-36, physical role functioning, ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison SF-36, physical role functioning, PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.582
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SF-36, emotional role functioning

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    End point title
    		 SF-36, emotional role functioning
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months post trauma.
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    12 [32]
    12 [33]
    9
    10
    Units: points
        arithmetic mean (standard deviation)
    77.8 ( 41.0 )
    79.2 ( 33.4 )
    77.8 ( 41.0 )
    79.2 ( 33.4 )
    Notes
    [32] - Values available for 12 patients only.
    [33] - Values available for 12 patients only.
    Statistical analysis title
    		 Comparison SF-36, emotional role functioning, ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.928
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison SF-36, emotional role functioning, PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.809
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SF-36, mental health

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    End point title
    		 SF-36, mental health
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months post trauma.
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    13 [34]
    12 [35]
    Units: points
        arithmetic mean (standard deviation)
    81.5 ( 17.3 )
    78.0 ( 14.2 )
    Notes
    [34] - Values available for 13 patients only.
    [35] - Values available for 12 patients only.
    Statistical analysis title
    		 Comparison SF-36, mental health
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.581
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SF-36, vitality

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    End point title
    		 SF-36, vitality
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months post trauma.
    End point values
    		 Erythropoietin Placebo PP-EPO PP-Placebo
    Number of subjects analysed
    13 [36]
    12 [37]
    10
    10
    Units: points
        arithmetic mean (standard deviation)
    71.9 ( 17.9 )
    62.9 ( 19.8 )
    69.0 ( 19.6 )
    61.5 ( 21.6 )
    Notes
    [36] - Values available for 13 patients only.
    [37] - Values available for 12 patients only.
    Statistical analysis title
    		 Comparison SF-36, vitality, ITT
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.247
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison SF-36, vitality, PP
    Comparison groups
    PP-EPO v PP-Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.426
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SF-36, general health

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    End point title
    		 SF-36, general health
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months post trauma.
    End point values
    		 Erythropoietin Placebo
    Number of subjects analysed
    13 [38]
    12 [39]
    Units: points
        arithmetic mean (standard deviation)
    79.8 ( 20.8 )
    75.5 ( 17.2 )
    Notes
    [38] - Values available for 13 patients only.
    [39] - Values available for 12 patients only.
    Statistical analysis title
    		 Comparison SF-36, general health
    Comparison groups
    Erythropoietin v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.578
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 Adverse events analysis was conducted on the ITT set.

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 84 (22.62%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood culture positive
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sudden cardiac death
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Enterococcal sepsis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 84 (45.24%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    10 / 84 (11.90%)
         occurrences all number
    12
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences all number
    11
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    12 / 84 (14.29%)
         occurrences all number
    19
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 84 (11.90%)
         occurrences all number
    16

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30429786
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