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    Clinical Trial Results:
    A multicentre, Phase II Randomized study, Open-label, with 2-arm Parallel Group, comparing the pharmacokinetics of the Liquid and the Lyophilized Formulations of pegaspargase (S95014) in Treatment of Paediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

    Summary
    EudraCT number
    		 2020-004894-29
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    20 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-95014-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04954326
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Therapeutic Area in Oncology, Institut de Recherches Internationales Servier, +33 155724366, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Area in Oncology, Institut de Recherches Internationales Servier, +33 155724366, clinicaltrials@servier.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the pharmacokinetics (PK) of both lyophilized and liquid S95014 formulations during the induction phase after a single intravenous (IV) dose in newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL).
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 Patients received backbone chemotherapy agents as per ALL-MB 2015 protocol and according to local practice
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 May 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 89
    Worldwide total number of subjects
    89
    EEA total number of subjects
    0
    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)
    2
    Children (2-11 years)
    76
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were male or female patients aged ≥ 1 to < 18 years, with cytologically confirmed and documented newly diagnosed ALL according to NCCN guidelines 2020, excluding B-cell Burkitt ALL, and with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. They were recruited in 7 sites, all located in Russia.

    Pre-assignment
    Screening details
    		 93 patients were screened, 89 patients included and assigned to one of the treatment groups: 44 patients in the lyophilized group and 45 in the liquid group. One patient was wrongly included and withdrawn w/o IMP; one patient was assigned to lyo but received liquid formulation. Only the 88 treated patients are described here (as IMP received )

    Pre-assignment period milestones
    Number of subjects started
    		 89
    Number of subjects completed
    		 88

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 1
    Period 1
    Period 1 title
    Induction Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Subjects were randomized to the liquid and lyophilized formulations according to a 1:1 ratio. The randomization was not adaptive. No stratification factor were used during randomization.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 S95014 Lyophilizate
    Arm description
    		 The included patients were randomized to one of the two treatment groups : the lyophilized S95014 (test drug) or the liquid S95014 (reference drug). The treatment period started on Day 3 of the induction phase until the withdrawal/end-of-study visit and was by IV infusion at the dose of 2500 U/m² over 1-hour. The patients in this arm received the lyophilized S95014 formulation. Patient demographics were analysed in the Safety Analysis Set (ie subjects having an administration of S95014).
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95014
    Investigational medicinal product code
    Other name
    pegaspargase
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    S95014 lyophilized powder was reconstituted with 5.2 mL of sterile water for injection. S95014 was administered IV at the dose of 2500 U/m² on Day 3 of the induction phase, over 1-hour infusion. S95014 dosage was calculated according to body surface area (BSA). The BSA was calculated by the IRS based on the height and weight measured on the day of randomization (D000) and had to be recalculated by the investigator manually on the day of S95014 infusion (D003) (all BSA calculations were rounded to 2 decimal places). BSA (m²) = √ (Height [cm] x Weight [kg]/3600).

    Arm title
    		 S95014 Liquid
    Arm description
    		 The included patients were randomized to one of the two treatment groups : the lyophilized S95014 (test drug) or the liquid S95014 (reference drug). The treatment period started on Day 3 of the induction phase until the withdrawal/end-of-study visit and was by IV infusion at the dose of 2500 U/m² over 1-hour. The patients in this arm received the liquid S95014 formulation. Patient demographics were analysed in the Safety Analysis Set (ie subjects having an administration of S95014).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    S95014
    Investigational medicinal product code
    Other name
    pegaspargase
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each vial contained 750 U S95014 active ingredient per mL. S95014 was administered IV at the dose of 2500 U/m² on Day 3 of the induction phase, over 1-hour infusion. S95014 dosage was calculated according to body surface area (BSA). The BSA was calculated by the IRS based on the height and weight measured on the day of randomization (D000) and had to be recalculated by the investigator manually on the day of S95014 infusion (D003) (all BSA calculations were rounded to 2 decimal places). BSA (m²) = √ (Height [cm] x Weight [kg]/3600).

    Number of subjects in period 1 [1]
    		S95014 Lyophilizate S95014 Liquid
    Started
    43
    45
    Completed
    43
    42
    Not completed
    0
    3
         Adverse event, serious fatal
    -
    2
         Physician decision
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One patient was wrongly included and withdrawn without IMP administration.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S95014 Lyophilizate
    Reporting group description
    		 The included patients were randomized to one of the two treatment groups : the lyophilized S95014 (test drug) or the liquid S95014 (reference drug). The treatment period started on Day 3 of the induction phase until the withdrawal/end-of-study visit and was by IV infusion at the dose of 2500 U/m² over 1-hour. The patients in this arm received the lyophilized S95014 formulation. Patient demographics were analysed in the Safety Analysis Set (ie subjects having an administration of S95014).

    Reporting group title
    S95014 Liquid
    Reporting group description
    		 The included patients were randomized to one of the two treatment groups : the lyophilized S95014 (test drug) or the liquid S95014 (reference drug). The treatment period started on Day 3 of the induction phase until the withdrawal/end-of-study visit and was by IV infusion at the dose of 2500 U/m² over 1-hour. The patients in this arm received the liquid S95014 formulation. Patient demographics were analysed in the Safety Analysis Set (ie subjects having an administration of S95014).

    Reporting group values
    		 S95014 Lyophilizate S95014 Liquid Total
    Number of subjects
    		 43 45 88
    Age categorical
    Units: Subjects
        <10 years
    		 30 38 68
        [10,15] years
    		 11 7 18
        ≥ 16 years
    		 2 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.9 ( 4.28 ) 5.4 ( 3.52 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 25 42
        Male
    		 26 20 46

    End points

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    End points reporting groups
    Reporting group title
    S95014 Lyophilizate
    Reporting group description
    		 The included patients were randomized to one of the two treatment groups : the lyophilized S95014 (test drug) or the liquid S95014 (reference drug). The treatment period started on Day 3 of the induction phase until the withdrawal/end-of-study visit and was by IV infusion at the dose of 2500 U/m² over 1-hour. The patients in this arm received the lyophilized S95014 formulation. Patient demographics were analysed in the Safety Analysis Set (ie subjects having an administration of S95014).

    Reporting group title
    S95014 Liquid
    Reporting group description
    		 The included patients were randomized to one of the two treatment groups : the lyophilized S95014 (test drug) or the liquid S95014 (reference drug). The treatment period started on Day 3 of the induction phase until the withdrawal/end-of-study visit and was by IV infusion at the dose of 2500 U/m² over 1-hour. The patients in this arm received the liquid S95014 formulation. Patient demographics were analysed in the Safety Analysis Set (ie subjects having an administration of S95014).

    Subject analysis set title
    Pharmacokinetic Analysis Set (PKAS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PKAS included the patients who have received at least one dose of IMP and are evaluable for PK analysis : the patients who had enough samples collected to provide interpretable PK results with no deviations that might have affected the PK interpretation (e.g. infusion interrupted for any reason, deviation in the theoretical administered dose > 10%, at least one missing PK sample during the 48 first hours, ≥ 2 missing PK samples after the 48-hour time point). Certain parameters could not be calculated if PAA went below the Lower Limit of Quantitation (LLOQ) during the 600 hr observation period.

    Subject analysis set title
    Immunogenicity Analysis Set (IAS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Immunogenicity Analysis Set (IAS) will include all subjects who have received at least one dose of IMP and have at least one post-dose sample evaluable for immunogenicity testing.

    Primary: Maximum Observed Plasma Asparaginase Activity (Cmax) of S95014 After Single Dose Administration

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    End point title
    		 Maximum Observed Plasma Asparaginase Activity (Cmax) of S95014 After Single Dose Administration
    End point description
    Maximum observed plasma asparaginase activity of S95014 (Pegaspargase) in serum after single dose administration was assessed using a validated enzymatic assay method (ELISA).
    End point type
    Primary
    End point timeframe
    Predose up to 600 hours post dose
    End point values
    		 S95014 Lyophilizate S95014 Liquid
    Number of subjects analysed
    41
    40
    Units: mU/mL
        geometric mean (geometric coefficient of variation)
    1563.115 ( 23.11 )
    1672.136 ( 41.91 )
    Statistical analysis title
    		 Statistical Evaluation of Cmax
    Statistical analysis description
    Cmax was natural log-transformed and analyzed using an analysis of variance (ANOVA) with fixed effect for formulation. The two one-sided tests procedures were performed on the geometric mean ratio (GMR) between test (S95014 lyophilizate) and reference (S95014 liquid formulation) treatments. The 90% confidence interval for the ratio was obtained within the framework of the ANOVA.
    Comparison groups
    S95014 Lyophilizate v S95014 Liquid
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 GMR (%)
    Point estimate
    93.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 82.9
         upper limit
    		 105.5
    Notes
    [1] - PK comparability between the test treatment and the reference treatment was concluded if the 90% CI for GMR is within the [80.00%; 125.00%] range.

    Primary: Area Under the Plasma Asparaginase Activity-Time Curve from Time Zero to Infinity (AUCinf) of S95014 After Single Dose Administration

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    End point title
    		 Area Under the Plasma Asparaginase Activity-Time Curve from Time Zero to Infinity (AUCinf) of S95014 After Single Dose Administration
    End point description
    The value of AUCinf was considered unreliable if the terminal area beyond the last quantified sample is greater than 20% of the total AUCinf.
    End point type
    Primary
    End point timeframe
    Predose up to 600 hours
    End point values
    		 S95014 Lyophilizate S95014 Liquid
    Number of subjects analysed
    41
    39 [2]
    Units: mU*day/mL
        geometric mean (geometric coefficient of variation)
    362028.656 ( 33.55 )
    352248.907 ( 31.08 )
    Notes
    [2] - AUCinf could not be calculated in one patient who had only 3 positive values exceeding the LLOQ
    Statistical analysis title
    		 Statistical Evaluation of AUCinf
    Statistical analysis description
    AUCinf was natural log-transformed and analyzed using an analysis of variance (ANOVA) with fixed effect for formulation. The two one-sided tests procedures were performed on the geometric mean ratio (GMR) between test (S95014 lyophilizate) and reference (S95014 liquid formulation) treatments. The 90% confidence interval for the ratio was obtained within the framework of the ANOVA.
    Comparison groups
    S95014 Lyophilizate v S95014 Liquid
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 GMR (%)
    Point estimate
    102.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 91.4
         upper limit
    		 115.6
    Notes
    [3] - PK comparability between the test treatment and the reference treatment was concluded if the 90% CI for GMR is within the [80.00%; 125.00%] range.

    Secondary: Observed Plasma Asparaginase Activity 14 days post-dose (Cday 14) of S95014 After Single Dose Administration

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    End point title
    		 Observed Plasma Asparaginase Activity 14 days post-dose (Cday 14) of S95014 After Single Dose Administration
    End point description
    Observed plasma asparaginase activity of S95014 (Pegaspargase) in serum 14 days post dose was assessed using a validated enzymatic assay method (ELISA).
    End point type
    Secondary
    End point timeframe
    Predose to day 14 post dose
    End point values
    		 S95014 Lyophilizate S95014 Liquid
    Number of subjects analysed
    41
    39 [4]
    Units: mU/mL
        geometric mean (geometric coefficient of variation)
    496.599 ( 37.96 )
    408.655 ( 80.35 )
    Notes
    [4] - Cday14 could not be calculated in one patient who had only 3 positive values exceeding the LLOQ
    Statistical analysis title
    		 Statistical Evaluation of Cday14
    Statistical analysis description
    Cday14 was natural log-transformed and analyzed using an analysis of variance (ANOVA) with fixed effect for formulation. The two one-sided tests procedures were performed on the geometric mean ratio (GMR) between test (S95014 lyophilizate) and reference (S95014 liquid formulation) treatments. The 90% confidence interval for the ratio was obtained within the framework of the ANOVA.
    Comparison groups
    S95014 Lyophilizate v S95014 Liquid
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    Method
    Parameter type
    		 GMR (%)
    Point estimate
    121.5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 98.7
         upper limit
    		 149.6
    Notes
    [5] - PK comparability between the test treatment and the reference treatment was concluded if the 90% CI for GMR is within the [80.00%; 125.00%] range.

    Secondary: Immunogenicity by measuring anti-drug antibodies (ADA) formation against S95014 and anti-PEG with the lyophilized or liquid formulations (positive patients)

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    End point title
    		 Immunogenicity by measuring anti-drug antibodies (ADA) formation against S95014 and anti-PEG with the lyophilized or liquid formulations (positive patients)
    End point description
    The number of patients having anti-S95014 after the administration of either liquid or lyophilized S95014 was determined. Seroconversion upon treatment was considered if a patient converted from negative at baseline to positive at Day 17 and Day 28 . If a confirmed positive sample at baseline has titer increase at Day 17 or Day 28 by at least 4-fold then it was included within the seroconverters. A patient starting with pre-existing antibodies (positive baseline) was considered for positive post-baseline anti-drug antibodies. A patient with missing baseline will be considered as negative baseline to be conservative. For all positive anti-S95014 evaluations there is an associated anti-PEG results. Post-treatment results of ADA formation against S95014 and against anti-pegaspargase are reported.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 14 and 25 days post-dose
    End point values
    		 S95014 Lyophilizate S95014 Liquid
    Number of subjects analysed
    43
    43
    Units: number of patients
    number (not applicable)
        Anti-S95014 positive
    5
    4
        Anti-S95014 positive/Anti-PEG negative
    3
    1
        Anti-S95014 positive/Anti-PEG positive
    2
    3
    No statistical analyses for this end point

    Secondary: Achievement of Plasma Asparaginase Activity (PAA) of ≥100 mU/mL after the administration of either lyophilized or liquid S95014

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    End point title
    		 Achievement of Plasma Asparaginase Activity (PAA) of ≥100 mU/mL after the administration of either lyophilized or liquid S95014
    End point description
    The achievement of PAA ≥ 100 mU/mL was assessed at 7, 14, 18 and 25 days after the infusion of either liquid or lyophilized S95014. The number of patients achieving a PAA of ≥ 100 mU/mL 7, 14, 18 and 25 days after the administration of either liquid or lyophilized S95014 is reported.
    End point type
    Secondary
    End point timeframe
    Day 7, 14, 18 and 25 post-dose of either liquid or lyophilized S95014
    End point values
    		 S95014 Lyophilizate S95014 Liquid
    Number of subjects analysed
    43
    45
    Units: number of patients
    number (not applicable)
        Day 10 PAA ≥ 100 mU/mL (n=44 LIQ)
    43
    43
        Day 17 PAA ≥ 100 mU/mL (n=43 LIQ)
    43
    41
        Day 21 PAA ≥ 100 mU/mL (n=43 LIQ, n=42 LYO)
    41
    39
        Day 28 PAA ≥ 100 mU/mL (n=43 LIQ, n=42 LYO)
    18
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent AEs were recorded from IMP admininistration on Day 3, until the withdrawal/end-of-study visit, which was at least 30 days after S95014 infusion, and before starting the consolidation phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    S95014 Lyophilizate
    Reporting group description
    		 -

    Reporting group title
    S95014 Liquid
    Reporting group description
    		 -

    Serious adverse events
    		 S95014 Lyophilizate S95014 Liquid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 43 (44.19%)
    18 / 45 (40.00%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 45 (8.89%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antithrombin III decreased
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood fibrinogen decreased
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein S decreased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem stroke
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic convulsion
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 45 (8.89%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypofibrinogenaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Catheter site thrombosis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Neutropenic colitis
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 45 (8.89%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Appendicitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida pneumonia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 S95014 Lyophilizate S95014 Liquid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 43 (100.00%)
    44 / 45 (97.78%)
    Investigations
    Blood fibrinogen decreased
         subjects affected / exposed
    33 / 43 (76.74%)
    37 / 45 (82.22%)
         occurrences all number
    33
    39
    Antithrombin III decreased
         subjects affected / exposed
    30 / 43 (69.77%)
    31 / 45 (68.89%)
         occurrences all number
    30
    31
    Lymphocyte count decreased
         subjects affected / exposed
    29 / 43 (67.44%)
    23 / 45 (51.11%)
         occurrences all number
    31
    29
    White blood cell count decreased
         subjects affected / exposed
    15 / 43 (34.88%)
    13 / 45 (28.89%)
         occurrences all number
    15
    13
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 43 (18.60%)
    17 / 45 (37.78%)
         occurrences all number
    9
    18
    Blood bilirubin increased
         subjects affected / exposed
    13 / 43 (30.23%)
    11 / 45 (24.44%)
         occurrences all number
    14
    11
    Protein S decreased
         subjects affected / exposed
    9 / 43 (20.93%)
    9 / 45 (20.00%)
         occurrences all number
    9
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 43 (13.95%)
    10 / 45 (22.22%)
         occurrences all number
    6
    10
    Ammonia increased
         subjects affected / exposed
    5 / 43 (11.63%)
    6 / 45 (13.33%)
         occurrences all number
    5
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 43 (9.30%)
    7 / 45 (15.56%)
         occurrences all number
    4
    7
    Platelet count decreased
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 45 (8.89%)
         occurrences all number
    4
    4
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    5 / 43 (11.63%)
    1 / 45 (2.22%)
         occurrences all number
    5
    1
    Blood albumin decreased
         subjects affected / exposed
    2 / 43 (4.65%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    International normalised ratio increased
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 45 (4.44%)
         occurrences all number
    3
    2
    Neutrophil count decreased
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 45 (6.67%)
         occurrences all number
    2
    4
    Blood urea increased
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 45 (2.22%)
         occurrences all number
    4
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 45 (6.67%)
         occurrences all number
    1
    3
    Nervous system disorders
    Toxic neuropathy
         subjects affected / exposed
    11 / 43 (25.58%)
    6 / 45 (13.33%)
         occurrences all number
    11
    6
    Neuropathy peripheral
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    Headache
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 43 (23.26%)
    16 / 45 (35.56%)
         occurrences all number
    10
    17
    Thrombocytopenia
         subjects affected / exposed
    8 / 43 (18.60%)
    13 / 45 (28.89%)
         occurrences all number
    8
    13
    Leukopenia
         subjects affected / exposed
    12 / 43 (27.91%)
    8 / 45 (17.78%)
         occurrences all number
    12
    8
    Neutropenia
         subjects affected / exposed
    6 / 43 (13.95%)
    8 / 45 (17.78%)
         occurrences all number
    6
    10
    Hypofibrinogenaemia
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 45 (6.67%)
         occurrences all number
    5
    3
    Lymphopenia
         subjects affected / exposed
    2 / 43 (4.65%)
    5 / 45 (11.11%)
         occurrences all number
    2
    5
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    5 / 43 (11.63%)
    5 / 45 (11.11%)
         occurrences all number
    5
    5
    Diarrhoea
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 45 (4.44%)
         occurrences all number
    4
    2
    Abdominal pain
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    Neutropenic colitis
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 45 (2.22%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 43 (23.26%)
    8 / 45 (17.78%)
         occurrences all number
    10
    9
    Hypocalcaemia
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 45 (4.44%)
         occurrences all number
    5
    2
    Hyperglycaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2020
    It mainly concerned the study protocol following Food & Drug Administration (FDA) non-hold comments: ­ Clarification about the collection of PK and PAA samples ­ Addition of an immunogenicity timepoint 14 days post-dose (Day 17) ­ Clarification about the sample size calculation ­ Addition of 14-day post-dose time point (CDay14) as a PK secondary endpoint ­ Deletion of a specific dosing regimen of 82.5 U/kg for patients with low BSA ­ Additional minor changes

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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