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    Clinical Trial Results:
    A Randomized Controlled Double-Blind Phase 3 Study to Assess Characteristics of S-303 Treated RBC Components and Evaluate Safety and Efficacy in Patients Requiring Transfusion Support of Acute Anemia

    Summary
    EudraCT number
    		 2011-006253-29
    Trial protocol
    		 DE  
    Global end of trial date
    10 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2023
    First version publication date
    16 Apr 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLI 00070
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01716923
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cerus Corporation
    Sponsor organisation address
    1220 Concord Avenue, Concord/CA, United States, 94520
    Public contact
    Carol M.Moore, Cerus Corporation, 1 9258766819, cmoore@cerus.com
    Scientific contact
    Richard J. Benjamin, MS PhD FRCPath, Cerus Corporation, 1 9252886020, rbenjamin@cerus.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
    10 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the in vitro characteristics of S-303 treated RBCs suspended in SAG-Mannitol; including mean hemoglobin per RBC component and other biochemical/metabolic properties recognized to correlate with RBC viability. The secondary objective of the study was to assess the clinical safety and efficacy of S-303 treated RBC components in patients requiring transfusion support for acute anemia (during or shortly after a cardiac surgery).
    Protection of trial subjects
    This study was conducted in compliance with Good Clinical Practice (GCP) according to the International Conference on Harmonization (ICH) guidelines, and local ethical and legal requirements that are consistent with the Declaration of Helsinki. The risks and hazards of study participation were explained to the potential study subjects, under the supervision of a qualified, licensed physician. Written informed consent was obtained from all study subjects prior to any tests or evaluations. A copy of the signed informed consent was provided to each subject and was also maintained in the subject’s medical record. Patient confidential information was protected through compliance with study and/or site specific privacy protection procedures. Personal Data of the Study Subjects were handled in accordance with the data protection laws applicable and all study activities were carried out under the Agreement as required by Article 30 of the GDPR.
    Background therapy
    		 All patients were subjected to cardio surgical procedures.
    Evidence for comparator
    		 The study was a conducted as a two-group (Test and Control) study consisting of two portions: in vitro and clinical. The in vitro characteristics of the study RBCs were compared to the EDQM criteria for RBCs, leukocyte-depleted in additive solution (Council of Europe Guide for the Preparation, Use and Quality Assurance of Blood Components, 16th edn. Strasbourg, France, Council of Europe Publishing 2010). The clinical safety and efficacy of S-303 treated RBC were compared to conventional RBC when transfused in support of acute anemia during or following cardiac surgery. The study was divided into an acute surgical care period starting at the day of surgery until 7 days post-surgery during which RBC (Test or Control) were administered and a post-surgical follow-up period of a minimum of 90 days to collect additional safety data.
    Actual start date of recruitment
    26 Oct 2012
    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
    Germany: 87
    Worldwide total number of subjects
    87
    EEA total number of subjects
    87
    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)
    7
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted in Germany at 1 blood center in Frankfurt and 2 clinical centers located in Frankfurt and Bad Nauheim. Initiation (first patient enrolled): October 26, 2013 Completion (last patient completed): August 7, 2014

    Pre-assignment
    Screening details
    		 In order to minimize the number of patients who enrolled in the study but did not require RBC transfusion, only patients with a relatively high likelihood to receive a transfusion as determined by the Investigator, or patients with a Transfusion Risk Understanding Screening Tool (TRUST) Score of 3 or greater were eligible for enrollment.

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Blinding was achieved by transferring the Control RBC components to a Storage Container identical to the Storage Container used for the Test RBC components processed with the S-303 Treatment System. The labels for Test and Control RBC components were identical. Blood Center personnel involved in processing, preparation, storage, cross-matching, and distribution of study RBC components were not blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test
    Arm description
    		 S-303 RBC components (Test) were prepared at a licensed Blood Center following training and completion of the S-303 Treatment System for RBC process validation studies. The S-303 treatment process was performed on RBC components prepared from leukocyte reduced whole blood collections. Prior to treatment, a sample of the input RBCs was retained for assessment of RBC in vitro characteristics on Day 0. The S-303 RBC Treatment System consists of 4 components: Processing set, Filter set, Amustaline dihydrochloride (S-303), Glutathione sodium Salt (GSH). For the in vitro portion of the study, RBC components were processed using the Test or Control procedure based on simple randomization. For the clinical portion of the study, anticipated prognostic factors including the clinical site and elective cardiac procedure were balanced using a stratified randomization scheme. Randomized patients who did not require any RBC transfusions during the 7-day transfusion period were replaced.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INTERCEPT Blood System for Red Blood Cells
    Investigational medicinal product code
    Other name
    INTERCEPT treated Red Blood Cells
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage (transfusion) depended on Investigators decision and patients actual need (actual Hb/Hematocrit requirement)

    Arm title
    		 Control
    Arm description
    		 The Control RBC components were prepared by conventional methods approved for use in the blood centers participating in the clinical study but were stored in the same type of storage bag as that of the Test RBCs to facilitate blinding of hospital personnel and clinicians administering the Test and Control RBC units to patients in the clinical study. For the in vitro portion of the study, RBC components were processed using the Test or Control procedure based on simple randomization. For the clinical portion of the study, anticipated prognostic factors including the clinical site and elective cardiac procedure were balanced using a stratified randomization scheme. Randomized patients who did not require any RBC transfusions during the 7-day transfusion period were replaced.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Conventional Red Blood Cells
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Physician decision and patient need (actual Hb/Hematocrit requirement)

    Number of subjects in period 1
    		Test Control
    Started
    45
    42
    Completed
    36
    37
    Not completed
    9
    5
         Adverse event, serious fatal
    3
    2
         Adverse event, non-fatal
    1
    -
         Other
    -
    3
         Patient decision to withdraw
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Test
    Reporting group description
    		 S-303 RBC components (Test) were prepared at a licensed Blood Center following training and completion of the S-303 Treatment System for RBC process validation studies. The S-303 treatment process was performed on RBC components prepared from leukocyte reduced whole blood collections. Prior to treatment, a sample of the input RBCs was retained for assessment of RBC in vitro characteristics on Day 0. The S-303 RBC Treatment System consists of 4 components: Processing set, Filter set, Amustaline dihydrochloride (S-303), Glutathione sodium Salt (GSH). For the in vitro portion of the study, RBC components were processed using the Test or Control procedure based on simple randomization. For the clinical portion of the study, anticipated prognostic factors including the clinical site and elective cardiac procedure were balanced using a stratified randomization scheme. Randomized patients who did not require any RBC transfusions during the 7-day transfusion period were replaced.

    Reporting group title
    Control
    Reporting group description
    		 The Control RBC components were prepared by conventional methods approved for use in the blood centers participating in the clinical study but were stored in the same type of storage bag as that of the Test RBCs to facilitate blinding of hospital personnel and clinicians administering the Test and Control RBC units to patients in the clinical study. For the in vitro portion of the study, RBC components were processed using the Test or Control procedure based on simple randomization. For the clinical portion of the study, anticipated prognostic factors including the clinical site and elective cardiac procedure were balanced using a stratified randomization scheme. Randomized patients who did not require any RBC transfusions during the 7-day transfusion period were replaced.

    Reporting group values
    		 Test Control Total
    Number of subjects
    		 45 42 87
    Age categorical
    Adults: 18-84 years
    Units: Subjects
        Adults (18-64 years)
    		 6 1 7
        From 65-84 years
    		 39 41 80
    Gender categorical
    Age ≥18 years, of either gender Total number of patients Test: Female (11) Male (14) Control: Female (16) Male (10)
    Units: Subjects
        Female
    		 24 22 46
        Male
    		 21 20 41
    Surgical Procedure
    Subjects must be scheduled to receive one of the following operative procedures: o Coronary artery bypass graft (CABG) only, first procedure o Valve repair or replacement only, first procedure o A combination of first time CABG and valve repair or replacement o Surgery scheduled, but postponed
    Units: Subjects
        CABG surgery
    		 20 20 40
        Valve repair or replacement
    		 18 13 31
        Combination of CABG and Valve repair
    		 4 5 9
        Surgery postponed
    		 3 2 5
        Surgery scheduled, patient decided not to proceed
    		 0 2 2
    Subject analysis sets

    Subject analysis set title
    Intent to Treat (ITT) Group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included all randomized patients regardless of surgical or transfusion status.

    Subject analysis set title
    Modified Intent to Treat (MITT) Group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Included all randomized patients exposed to any on-study RBC components during the study transfusion period (includes patients who were only exposed due to the priming of a cardiopulmonary bypass circuit).

    Subject analysis set title
    Randomized Non Treated Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Included all randomized patients who were not exposed to any on-study RBC components (regardless of surgical status).

    Subject analysis sets values
    		 Intent to Treat (ITT) Group Modified Intent to Treat (MITT) Group Randomized Non Treated Group
    Number of subjects
    87
    51
    36
    Age categorical
    Adults: 18-84 years
    Units: Subjects
        Adults (18-64 years)
    7
    4
    3
        From 65-84 years
    80
    47
    33
    Age continuous
    Randomized
    Units: years
        median (standard deviation)
    ( )
    ( )
    ( )
    Gender categorical
    Age ≥18 years, of either gender Total number of patients Test: Female (11) Male (14) Control: Female (16) Male (10)
    Units: Subjects
        Female
    46
    27
    19
        Male
    41
    24
    17
    Surgical Procedure
    Subjects must be scheduled to receive one of the following operative procedures: o Coronary artery bypass graft (CABG) only, first procedure o Valve repair or replacement only, first procedure o A combination of first time CABG and valve repair or replacement o Surgery scheduled, but postponed
    Units: Subjects
        CABG surgery
    40
    25
    15
        Valve repair or replacement
    31
    18
    13
        Combination of CABG and Valve repair
    9
    8
    1
        Surgery postponed
    5
    0
    5
        Surgery scheduled, patient decided not to proceed
    2
    0
    2

    End points

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    End points reporting groups
    Reporting group title
    Test
    Reporting group description
    		 S-303 RBC components (Test) were prepared at a licensed Blood Center following training and completion of the S-303 Treatment System for RBC process validation studies. The S-303 treatment process was performed on RBC components prepared from leukocyte reduced whole blood collections. Prior to treatment, a sample of the input RBCs was retained for assessment of RBC in vitro characteristics on Day 0. The S-303 RBC Treatment System consists of 4 components: Processing set, Filter set, Amustaline dihydrochloride (S-303), Glutathione sodium Salt (GSH). For the in vitro portion of the study, RBC components were processed using the Test or Control procedure based on simple randomization. For the clinical portion of the study, anticipated prognostic factors including the clinical site and elective cardiac procedure were balanced using a stratified randomization scheme. Randomized patients who did not require any RBC transfusions during the 7-day transfusion period were replaced.

    Reporting group title
    Control
    Reporting group description
    		 The Control RBC components were prepared by conventional methods approved for use in the blood centers participating in the clinical study but were stored in the same type of storage bag as that of the Test RBCs to facilitate blinding of hospital personnel and clinicians administering the Test and Control RBC units to patients in the clinical study. For the in vitro portion of the study, RBC components were processed using the Test or Control procedure based on simple randomization. For the clinical portion of the study, anticipated prognostic factors including the clinical site and elective cardiac procedure were balanced using a stratified randomization scheme. Randomized patients who did not require any RBC transfusions during the 7-day transfusion period were replaced.

    Subject analysis set title
    Intent to Treat (ITT) Group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included all randomized patients regardless of surgical or transfusion status.

    Subject analysis set title
    Modified Intent to Treat (MITT) Group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Included all randomized patients exposed to any on-study RBC components during the study transfusion period (includes patients who were only exposed due to the priming of a cardiopulmonary bypass circuit).

    Subject analysis set title
    Randomized Non Treated Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Included all randomized patients who were not exposed to any on-study RBC components (regardless of surgical status).

    Primary: Post-Production Hemoglobin Content

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    End point title
    		 Post-Production Hemoglobin Content
    End point description
    The primary efficacy endpoint was the hemoglobin content per RBC component derived from the in-vitro portion of the study (grams of hemoglobin per processed component). This endpoint was captured after the INTERCEPT process and after the bag transfer for Test and Control components, respectively. The study employed an equivalence design to test the hypothesis that S-303 treated RBC components (Test) were equivalent to conventional RBC components (Control) with respect to mean grams of hemoglobin per component processed.
    End point type
    Primary
    End point timeframe
    Post-production
    End point values
    		 Test Control
    Number of subjects analysed
    25 [1]
    26 [2]
    Units: g/component
        arithmetic mean (standard deviation)
    53.6 ( 5.6 )
    56.3 ( 6.0 )
    Notes
    [1] - Number of test components produced: 389
    [2] - Number of control components produced: 365
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.61
         upper limit
    		 -1.92
    Notes
    [3] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component

    Secondary: End of Storage Hemoglobin Content

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    End point title
    		 End of Storage Hemoglobin Content
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    End of Storage (Day 35-38)
    End point values
    		 Test Control
    Number of subjects analysed
    25 [4]
    26 [5]
    Units: g/component
        arithmetic mean (standard deviation)
    53.1 ( 5.7 )
    55.8 ( 5.9 )
    Notes
    [4] - Number of test components produced: 301
    [5] - Number of control components produced: 261
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.76
         upper limit
    		 -1.92
    Notes
    [6] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component

    Secondary: Post-production Hematocrit

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    End point title
    		 Post-production Hematocrit
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    Post-production
    End point values
    		 Test Control
    Number of subjects analysed
    25 [7]
    26 [8]
    Units: percentage
        arithmetic mean (standard deviation)
    57.4 ( 2.0 )
    57.3 ( 2.9 )
    Notes
    [7] - Number of test components produced: 389
    [8] - Number of control components produced: 367
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    P-value
    		 = 0.209
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.45
    Notes
    [9] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component

    Secondary: End of Storage Hematocrit

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    End point title
    		 End of Storage Hematocrit
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    End of Storage (Day 35-38)
    End point values
    		 Test Control
    Number of subjects analysed
    25 [10]
    26 [11]
    Units: percentage
        arithmetic mean (standard deviation)
    60.4 ( 3.2 )
    60.9 ( 3.5 )
    Notes
    [10] - Number of test components produced: 301
    [11] - Number of control components produced: 261
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    P-value
    		 = 0.149
    Method
    		 ANCOVA
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 0.12
    Notes
    [12] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component

    Secondary: End of Storage Hemolysis

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    End point title
    		 End of Storage Hemolysis
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    End of Storage (Day 35-38)
    End point values
    		 Test Control
    Number of subjects analysed
    25 [13]
    26 [14]
    Units: percentage
        arithmetic mean (standard deviation)
    0.28 ( 0.12 )
    0.35 ( 0.16 )
    Notes
    [13] - Number of test components produced: 301
    [14] - Number of control components produced: 261
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001 [15]
    Method
    		 ANCOVA
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 -0.04
    Notes
    [15] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component.

    Secondary: End of Storage Normalized ATP (BCW)

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    End point title
    		 End of Storage Normalized ATP (BCW)
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    End of Storage (Day 35-38)
    End point values
    		 Test Control
    Number of subjects analysed
    25 [16]
    26 [17]
    Units: μmol/g
        arithmetic mean (standard deviation)
    1.66 ( 0.44 )
    1.29 ( 0.29 )
    Notes
    [16] - Number of test components produced: 257
    [17] - Number of control components produced: 222
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.44
    Notes
    [18] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component.

    Secondary: End of Storage Normalized ATP (DRK)

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    End point title
    		 End of Storage Normalized ATP (DRK)
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    End of Storage (Day 35-38)
    End point values
    		 Test Control
    Number of subjects analysed
    25 [19]
    26 [20]
    Units: μmol/g
        arithmetic mean (standard deviation)
    2.8 ( 0.9 )
    2.4 ( 0.7 )
    Notes
    [19] - Number of test components produced: 294
    [20] - Number of control components produced: 262
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001 [21]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.59
    Notes
    [21] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component.

    Secondary: End of Storage Plasma Free Hemoglobin

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    End point title
    		 End of Storage Plasma Free Hemoglobin
    End point description
    Secondary efficacy endpoints included the post-storage measurements of Hct, hemolysis, normalized ATP, plasma-free hemoglobin, and hemoglobin content. These endpoints were only collected from the non-transfused RBC components held until the end of storage (Day 35 to 38). Note that the hgb content at the end of storage was calculated by multiplying the hgb concentration (g/dL, measured at the end of storage) by the volume (mL, measured at post-production). The analysis was conducted using all RBC components available at the end of storage where: - Proportion of T and C RBC components satisfying the EU guidelines for Hct, hemolysis, and hgb content were computed. The guidelines are: Between 50-70% for Hct; < 0.8% for hemolysis; and, ≥ 40 g/component for hgb content. - Proportion of T and C RBC components that had normalized ATP levels >2 μmol/g (of Hgb) were computed. - Proportion of T and C RBC components that had plasma-free hgb levels < 6 g/L (< 0.8% hemolysis) were computed.
    End point type
    Secondary
    End point timeframe
    End of Storage (Day 35-38)
    End point values
    		 Test Control
    Number of subjects analysed
    25 [22]
    26 [23]
    Units: g/L
        arithmetic mean (standard deviation)
    1.42 ( 0.64 )
    1.79 ( 0.88 )
    Notes
    [22] - Number of test components produced: 263
    [23] - Number of control components produced: 225
    Statistical analysis title
    		 ANCOVA model
    Statistical analysis description
    p-values were obtained from the full model where each covariate was included regardless of statistical significance; 95% CIs for the LS mean treatment difference (Test – Control) are based on a mixed effects ANCOVA model controlling for the treatment, gender, blood type, input hematocrit, and input volume.
    Comparison groups
    Test v Control
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.001 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 -0.23
    Notes
    [24] - Equivalence between the Test and Control RBC components post production, prior to storage, was declared since the 95% CI for the mean treatment difference was well within the a-priori defined margins of -5 to 5 g/component.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from informed consent signature until study completion.
    Adverse event reporting additional description
    Time of consent to the day of surgery (Day 0) - All AEs & SAEs (spontaneously reported to the attending physician) Day 0 to Day 13 or discharge (whichever occurs first) - All AEs & SAEs (active surveillance by study staff) Day 14 or day of discharge (whichever occurs first) to Day 90 - All SAEs (spontaneously reported to the attending physician)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Test RBC
    Reporting group description
    		 Treatment assessments were divided into an acute surgical care period starting at the day of surgery until 7 days post-surgery during which RBC (Test or Control) were administered and a post-surgical follow-up period of a minimum of 90 days to collect additional safety data.

    Reporting group title
    Control RBC
    Reporting group description
    		 Treatment assessments were divided into an acute surgical care period starting at the day of surgery until 7 days post-surgery during which RBC (Test or Control) were administered and a post-surgical follow-up period of a minimum of 90 days to collect additional safety data. The control article was conventional RBC components stored at 2°C to 6°C for up to 35 days post-donation and administered intravenously. Dose and schedule of RBC transfusions were determined by the treating physician.

    Serious adverse events
    		 Test RBC Control RBC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 25 (52.00%)
    9 / 26 (34.62%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hepatic rupture
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iatrogenic injury
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasoplegia syndrome
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphatic fistula
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ disorder
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Postoperative wound infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Test RBC Control RBC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 25 (72.00%)
    20 / 26 (76.92%)
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
         subjects affected / exposed
    6 / 25 (24.00%)
    10 / 26 (38.46%)
         occurrences all number
    6
    10
    Pneumothorax
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 26 (15.38%)
         occurrences all number
    2
    4
    Psychotic disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Coombs direct test
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Enterococcus test positive
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Coombs indirect test
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Facial bones fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Weaning failure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    6 / 25 (24.00%)
    7 / 26 (26.92%)
         occurrences all number
    6
    7
    Atrial tachycardia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Atrioventricular block
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Subileus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Renal failure
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    renal failure acute
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Endocarditis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2012
    The updates to the CLI 00070 Protocol are as follows: - Provide the EUDRA CT Number for the Clinical Trial Application. - Add the competency in cardiovascular surgery at the clinical sites participating in this study. - Present the differences between the two blood centers in France and Germany in collection of whole blood and the overnight whole blood conditions prior to the production of RBC components. - Provide details on QP review and release of the RBC components prepared with the Second Generation S-303 Treatment Process. Also, provide details on the criteria for release of the RBC components into the clinical inventory. - Add clarification that Blood Center standard practices will be followed for matching the age of Test and Control RBC components. - Add details on the procedures for blinding Test and Control RBC units and differentiate between clinical site staff and Blood Center staff about blinding. - Provide details on the risks related to the user and patients and describe the procedures implemented to eliminate or reduce these potential risks. - Add two new exclusion criteria, to exclude patients with special requirements for gamma irradiated RBCs or removal of plasma and anyone with prior severe allergic transfusion reactions. - Provide description that effort will be made to match the age of Test and Control RBC components. Provide clarification that during the study, compatibility and phenotyping will be performed according to local standard practices and Good Transfusion Practices. - Include Direct and Indirect Antiglobulin Test at the end of study at Day 90 to detect any immunological changes after transfusion of study RBC units.
    12 Jun 2012
    The updates to the CLI 00070 Protocol are as follows: - Updated the protocol per PEI recommendations - Updated the protocol title match the protocol synopsis title that is more detailed in describing the protocol design and to reflect the new version. - Updated the abbreviations and definitions list to add ANCOVA – Analysis of Covariance, and ANOVA - Analysis of Variance - Updated Incubation time from 16 hours to 18 hours - Overall changes made for clarification purposes and also per the request from PEI several Quality Control measurements were added. - Investigational Plan- Inclusion Criteria: Add other criteria to be used by the Investigators along with the TRUST score to identify patients to include in the study. Add both genders to the inclusion criteria. Delete inclusion criteria “Must be willing to participate in the second 6MWT at 7 to 10 days after discharge”. - Revise Six Minute Walk Test from “2-3 days prior to discharge” to “at the time of first ambulation”. Update timing of Six Minute Walk Test and make reference to the study operations manual - Serum sample for S-303 antibody screening at pre-op (Day -7-0) removed as it is performed during screening (Day -30 – 0). - Revise the formatting to separate Exclusion criteria number 8 into 8, 9, and 10, then renumber the current numbers 9 and 10 to 11 and 12.
    07 Sep 2012
    The updates to the CLI 00070 Protocol are as follows: - Updated the incubation time for the preparation of test RBC components from 18 to 24 hours. - Updated the temperature for overnight incubation to 20-25°C. - Add the requirement to have an FDA Form 1572 included in the study files in addition to the MDA form
    30 Aug 2013
    The updates to the protocol include the following: -Updated to be more generic with regards to site and blood center, to avoid any future protocol amendments in the event additional sites or blood centers are added. For a multi-center study a Coordinating Investigator is required therefore the administrative structure was updated to reflect this. An external reviewer for telemetry will not be used for this study therefore this reference was deleted - Revised the text regarding the disposal of Test and Control components to clarify that study units must be retained until all study-specified assessments have been performed. The revised text provides clear instructions on timing of discarding of study components. To provide clarification to study sites on the timing and sequence for discarding component - Updated inclusion criteria regarding contraception and acceptable forms as well as the requirement for a negative pregnancy test for consistency. Remove the inclusion criteria for the requirement for a negative S-303 crossmatch at study entry - Added a new section titled, ‘Additional Criteria to Satisfy Prior to Transfusion’ to instruct the clinical site that patients must have a confirmed negative crossmatch for S-303 prior to receiving their first study transfusion - Added clarification that patients who receive a study transfusion but discontinue the study early must have their study assessments completed at the end of study. Clarification was made that only subjects who are exposed to study RBCs will be included in the total of 3 patients who demonstrate a confirmed positive crossmatch to S-303 RBCs. Add language around confirmed negative crossmatch requirement prior to study RBC transfusion and timing of follow-up - Changes made to reflect that quantitative safety data will be summarized descriptively, without formal statistical hypothesis testing - Updated the formula to identify site as the blood center and NOT the clinical site

    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.
    N/A

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29498049
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