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    Clinical Trial Results:
    A Multi-Centre, Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Investigate Efficacy and Safety of Sevuparin Infusion for the Management of Acute Vaso-Occlusive Crisis (VOC) in Subjects with Sickle-Cell Disease (SCD)

    Summary
    EudraCT number
    		 2014-004416-11
    Trial protocol
    		 NL   BE  
    Global end of trial date
    10 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2021
    First version publication date
    10 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TVOC01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02515838
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Modus Therapeutics AB
    Sponsor organisation address
    Olof Palmes gata 29 IV, Stockholm, Sweden, SE-111 22
    Public contact
    John Ohd, Modus Therapeutics AB, +46 707668097, john.ohd@modustx.com
    Scientific contact
    John Ohd, Modus Therapeutics AB, +46 707668097, john.ohd@modustx.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 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the time to painful VOC resolution, measured from first dose given to achievement of crises resolution, as compared to placebo. This was a multicentre, randomised, double-blind, placebo-controlled study. Eligible patients (adults and adolescents), who were hospitalised with VOC for parenteral opioid analgesia, were randomised to receive sevuparin (3 mg/kg loading dose followed by 18 mg/kg/day continuous infusion) or matching placebo. Study drug was administered within 24 hours of the hospitalisation and continued for a minimum of 48 hours. The infusion was stopped when the VOC resolved, otherwise treatment continued for a maximum of 7 days. Patients also received site-specific standard of care treatment for their VOC. Key secondary endpoints were: Mean change in pain intensity from baseline, Duration of severest pain, and Accumulated dose of parenteral opiods from baseline until VOC resulotion/readiness for discharge
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in accordance with ICH GCP. An independent Data and Safety Monitoring Board (DSMB) performed interim safety data reviews that were independent of both the Sponsor and the CRO. The DSMB reviewed data of the first adult 12 patients who received the investigational product. Any dose adjustments based on this review were to occur before adolescents were randomised into the study.
    Background therapy
    		 No pre-defined background therapy was given but the subject were given site-specific standard of care treatment for their VOC.
    Evidence for comparator
    		 This was a placebo-controlled trial vs investigational drug. No other comparators were used. Abbreviations used: CPID: Cumulative pain intensity difference IP: Investigational product PK: Pharmacokinetics IV: Intravenous SCD: Sickle cell disease VOC: Vaso-occlusive crisis
    Actual start date of recruitment
    07 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bahrain: 13
    Country: Number of subjects enrolled
    Jamaica: 15
    Country: Number of subjects enrolled
    Lebanon: 28
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Oman: 26
    Country: Number of subjects enrolled
    Saudi Arabia: 2
    Country: Number of subjects enrolled
    Turkey: 43
    Worldwide total number of subjects
    144
    EEA total number of subjects
    17
    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)
    33
    Adults (18-64 years)
    111
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was performed in 16 hospitals in the Netherlands, Lebanon, Turkey, Bahrain, Oman, Saudi Arabia, and Jamaica. Patients aged 12–50 years with a diagnosis of sickle cell disease (types HbSS, HbSC, HbSβ⁰-thalassaemia, or HbSβ+-thalassaemia) were recruited between Oct 2015 and February 2019.

    Pre-assignment
    Screening details
    		 Adult and adolescent patients with SCD were screened for eligibility when presenting at the hospital for acute VOC. Patients with more than 5 hospitalisations for VOC during the last 6 months were excluded (to exclude patients with exacerbations of chronic pain rather than true VOC) as were patients with acute SCD complications other than VOC.

    Period 1
    Period 1 title
    Overall Trial Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Monitor
    Blinding implementation details
    The appearance of the test product was the same as the NaCl solution which was used as placebo. Test product and placebo were provided in identical vials with identical labelling. Central laboratories analysed biomarkers; no data from these analyses were available to investigator sites to avoid inadvertent unblinding. An Independent Statistician was unblinded and was responsible for the generation of the randomisation list and to provide support to the DSMB meetings with unblinded analyses.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Sevuparin
    Arm description
    		 Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The IP and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevuparin 150 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.

    Arm title
    		 Placebo
    Arm description
    		 Patients with SCD, hospitalised with acute VOC, received placebo as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The placebo solution and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to treatment with placebo received a short infusion of placebo at the same dose volume as patients randomised to receive sevuparin, followed by continuous infusion of placebo solution at the same infusion rate in mL/h for 2-7 days.

    Arm title
    		 PK - Sevuparin, Adult Male
    Arm description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevuparin 150 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.

    Arm title
    		 PK - Sevuparin, Adult Female
    Arm description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevuparin 150 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.

    Arm title
    		 PK - Sevuparin, Adolescent Male
    Arm description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevuparin 150 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.

    Arm title
    		 PK - Sevuparin, Adolescent Female
    Arm description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevuparin 150 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.

    Number of subjects in period 1
    		Sevuparin Placebo PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Started
    69
    75
    8
    2
    2
    2
    Completed
    58
    69
    8
    2
    2
    2
    Not completed
    11
    6
    0
    0
    0
    0
         Consent withdrawn by subject
    3
    -
    -
    -
    -
    -
         Physician decision
    1
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    1
    2
    -
    -
    -
    -
         Lost to follow-up
    6
    4
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sevuparin
    Reporting group description
    		 Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The IP and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients with SCD, hospitalised with acute VOC, received placebo as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The placebo solution and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line.

    Reporting group title
    PK - Sevuparin, Adult Male
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group title
    PK - Sevuparin, Adult Female
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group title
    PK - Sevuparin, Adolescent Male
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group title
    PK - Sevuparin, Adolescent Female
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group values
    		 Sevuparin Placebo PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female Total
    Number of subjects
    		 69 75 8 2 2 2 144
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 15 18 0 0 2 2 33
        Adults (18-64 years)
    		 54 57 8 2 0 0 111
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 27 27 0 2 0 2 54
        Male
    		 42 48 8 0 2 0 90
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients in the ITT population consisted of all patients who met all inclusion and exclusion criteria.

    Subject analysis sets values
    		 ITT
    Number of subjects
    144
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    33
        Adults (18-64 years)
    111
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    23.5 ( 8.33 )
    Gender categorical
    Units: Subjects
        Female
    54
        Male
    90

    End points

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    End points reporting groups
    Reporting group title
    Sevuparin
    Reporting group description
    		 Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The IP and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients with SCD, hospitalised with acute VOC, received placebo as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The placebo solution and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line.

    Reporting group title
    PK - Sevuparin, Adult Male
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group title
    PK - Sevuparin, Adult Female
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group title
    PK - Sevuparin, Adolescent Male
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Reporting group title
    PK - Sevuparin, Adolescent Female
    Reporting group description
    		 Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients in the ITT population consisted of all patients who met all inclusion and exclusion criteria.

    Primary: Time from IP administration start until VOC resolution

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    End point title
    		 Time from IP administration start until VOC resolution [1]
    End point description
    Time to vaso-occlusive crisis resolution defined as the time from the start of IP infusion until resolution of the crisis/episode which required freedom from parenteral opioid use in the preceding 8 ± 2 hours and the readiness for discharge as judged by the patient or physician, whichever occurred first.
    End point type
    Primary
    End point timeframe
    The primary endpoint was assessed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69 [2]
    75 [3]
    Units: hours
        median (confidence interval 95%)
    100.4 (85.50 to 116.82)
    86.4 (70.62 to 95.05)
    Notes
    [2] - 69 subjects were randomised to sevuparin but only 68 subjects actually received sevuparin.
    [3] - 75 subjects were randomised to placebo but 76 subjects received placebo.
    Statistical analysis title
    		 Cox proportional hazards model
    Statistical analysis description
    The treatment difference was estimated with hazard ratios and associated confidence intervals.
    Comparison groups
    Sevuparin v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5536
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.3

    Secondary: Mean change in pain intensity from baseline

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    End point title
    		 Mean change in pain intensity from baseline [4]
    End point description
    Pain intensity assessed using a VAS (0–100 mm, with 0 mm equalling no pain and 100 mm equalling the worst possible pain). Pain was assessed 30 minutes prior to start of infusion and then every 4 hours (while awake) until VOC resolution.
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69
    75
    Units: mm VAS
        arithmetic mean (standard deviation)
    -35.3 ( 19.76 )
    -34.1 ( 18.80 )
    No statistical analyses for this end point

    Secondary: Median duration of severest pain

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    End point title
    		 Median duration of severest pain [5]
    End point description
    The median duration of severest pain was defined as time to a 30% reduction in pain intensity (VAS) compared to baseline and maintained during at least 8 hours.
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69
    75
    Units: hours
        median (confidence interval 95%)
    24.10 (16.00 to 39.92)
    20.08 (16.00 to 24.02)
    No statistical analyses for this end point

    Secondary: Mean cumulative dose of parenteral opioids

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    End point title
    		 Mean cumulative dose of parenteral opioids [6]
    End point description
    The use of parenteral opioids (accumulated parenteral opioid consumption until readiness for discharge).
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    67
    73
    Units: mg
        arithmetic mean (standard deviation)
    150.2 ( 138.37 )
    137.0 ( 124.67 )
    No statistical analyses for this end point

    Secondary: Median time to discharge

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    End point title
    		 Median time to discharge [7]
    End point description
    Number of hours between the first study drug dose given and discharge.
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69
    75
    Units: hours
        median (confidence interval 95%)
    121.5 (99.00 to 141.00)
    94.5 (79.42 to 118.50)
    No statistical analyses for this end point

    Secondary: Median time to readiness for discharge

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    End point title
    		 Median time to readiness for discharge [8]
    End point description
    Time to readyness for discharge, as judged by the the subject or investigator (number of hours between the first study drug dose given and timepoint at which the subject feels readiness or the investigator judges readiness for discharge from the hospital) which ever comes first. The assessment was done every 4 hours during awake time, starting from the time when the subject had been without parenteral opioids for 8 hours.
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69
    75
    Units: hours
        median (confidence interval 95%)
    99.0 (74.33 to 114.50)
    85.3 (70.50 to 94.43)
    No statistical analyses for this end point

    Secondary: Median time to IV opioid discontinuation

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    End point title
    		 Median time to IV opioid discontinuation [9]
    End point description
    Time to discontinuation of IV opioids, defines as number of hours between the first study drug dose given and discontinuation of parenteral opioids.
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69
    75
    Units: hours
        median (confidence interval 95%)
    84.0 (63.33 to 93.17)
    67.8 (60.43 to 78.18)
    No statistical analyses for this end point

    Secondary: Cumulative frequency of VOC resolution

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    End point title
    		 Cumulative frequency of VOC resolution [10]
    End point description
    Time from start of infusion to 25%, 50% and 75% of subjects achieving VOC resolution.
    End point type
    Secondary
    End point timeframe
    Assessments were performed from start of IP infusion and up to a maximum of 7 days.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69
    75
    Units: Cumulative frequency (%)
        Within 24 hours
    1
    0
        Within 48 hours
    12
    16
        Within 72 hours
    29
    44
        Within 96 hours
    46
    63
        Within 120 hours
    65
    71
        Within 144 hours
    74
    80
    No statistical analyses for this end point

    Secondary: Mean Clinical Global Impression of Change

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    End point title
    		 Mean Clinical Global Impression of Change [11]
    End point description
    The CGIC is an instrument that measures change in a patient overall status on a 7-point scale ranging from 1 (Very much improved) to 7 (Very much worse), rated by the physician. N differed for the different time points. Clarification for Notes below: First digit = Visit No. DI = During infusion EoI = End of infusion Value = N
    End point type
    Secondary
    End point timeframe
    The Clinician Global Impression of Change (CGIC) was measured once daily, starting on Day 3 until end of treatment.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69 [12]
    75 [13]
    Units: Score
    arithmetic mean (standard deviation)
        Visit 3, During infusion
    4.3 ( 1.57 )
    4.6 ( 1.64 )
        Visit 3, End of infusion
    6.3 ( 0.98 )
    5.8 ( 1.53 )
        Visit 4, During infusion
    5.1 ( 1.43 )
    4.8 ( 1.78 )
        Visit 4, End of infusion
    6.2 ( 1.70 )
    6.1 ( 1.24 )
        Visit 5, During infusion
    5.3 ( 1.65 )
    5.0 ( 1.86 )
        Visit 5, End of infusion
    6.3 ( 0.65 )
    6.3 ( 1.29 )
        Visit 6, During infusion
    5.1 ( 1.39 )
    5.2 ( 1.76 )
        Visit 6, End of infusion
    6.3 ( 0.82 )
    5.6 ( 2.00 )
        Visit 7, During infusion
    5.4 ( 1.68 )
    5.2 ( 1.64 )
        Visit 7, End of infusion
    6.4 ( 1.01 )
    5.0 ( 2.83 )
        Visit 8, End of infusion
    4.0 ( 1.83 )
    4.8 ( 1.47 )
    Notes
    [12] - 3 DI:60 3 EoI:12 4 DI:47 4 EoI:12 5 DI:32 5 EoI:11 6 DI:18 6 EoI:6 7 DI:12 7 EoI:9 8 EoI:4
    [13] - 3 DI:70 3 EoI:12 4 DI:51 4 EoI:19 5 DI:31 5 EoI:16 6 DI:18 6 EoI:8 7 DI:9 7 EoI:4 8 EoI:6
    No statistical analyses for this end point

    Secondary: Mean Patient Global Impression of Change

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    End point title
    		 Mean Patient Global Impression of Change [14]
    End point description
    The PGIC is an instrument that measures change in a patient overall status on a 7-point scale ranging from 1 (Very much improved) to 7 (Very much worse), rated by the patient. N differed for the different time points. Clarification for Notes below: First digit = Visit No. DI = During infusion EoI = End of infusion Value = N
    End point type
    Secondary
    End point timeframe
    The Patient Global Impression of Change (PGIC) was measured once daily, starting on Day 3 until end of treatment.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    69 [15]
    75 [16]
    Units: Score
    arithmetic mean (standard deviation)
        Visit 3, During infusion
    4.4 ( 1.48 )
    4.4 ( 1.79 )
        Visit 3, End of infusion
    6.2 ( 0.75 )
    6.3 ( 1.28 )
        Visit 4, During infusion
    5.0 ( 1.60 )
    4.7 ( 1.89 )
        Visit 4, End of infusion
    6.3 ( 1.72 )
    5.9 ( 1.39 )
        Visit 5, During infusion
    5.2 ( 1.50 )
    4.9 ( 1.81 )
        Visit 5, End of infusion
    6.1 ( 0.70 )
    6.1 ( 1.31 )
        Visit 6, During infusion
    5.0 ( 1.64 )
    5.1 ( 1.55 )
        Visit 6, End of infusion
    6.0 ( 1.10 )
    5.6 ( 2.00 )
        Visit 7, During infusion
    4.9 ( 2.02 )
    4.6 ( 1.81 )
        Visit 7, End of infusion
    6.0 ( 1.50 )
    5.0 ( 2.71 )
        Visit 8, End of infusion
    4.5 ( 1.91 )
    4.0 ( 1.55 )
    Notes
    [15] - 3 DI:60 3 EoI:11 4 DI:46 4 EoI:12 5 DI:32 5 EoI:11 6 DI:18 6 EoI:6 7 DI:12 7 EoI:9 8 EoI:4
    [16] - 3 DI:69 3 EoI:15 4 DI:51 4 EoI:19 5 DI:31 5 EoI:16 6 DI:18 6 EoI:8 7 DI:9 7 EoI:4 8 EoI:6
    No statistical analyses for this end point

    Secondary: Mean cumulative pain intensity

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    End point title
    		 Mean cumulative pain intensity [17]
    End point description
    Pain intensity was assessed on VAS every 4 hours during awake time, until VOC resolution. The mean accumulated change in pain intensity (CPID), defined as the difference between VAS at each of the time points assessed compared to baseline, for each visit and timepoint was evaluated.
    End point type
    Secondary
    End point timeframe
    From 30 min before infusion treatment and up to a maximum of 7 days.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    67
    74
    Units: CPID
        arithmetic mean (standard deviation)
    -2985.746 ( 2218.7055 )
    -2827.853 ( 2152.4352 )
    No statistical analyses for this end point

    Secondary: Mean daily dose of opioid consumption

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    End point title
    		 Mean daily dose of opioid consumption [18]
    End point description
    Amount of parenteral opioids (accumulated opioid consumption as average per 24 hours after start of IP administration and until VOC resolution.
    End point type
    Secondary
    End point timeframe
    From start of IP administration and up to a maximum of 7 days.
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    66
    73
    Units: mg
        arithmetic mean (standard deviation)
    45.227 ( 40.4522 )
    37.779 ( 20.6040 )
    No statistical analyses for this end point

    Secondary: Proportion of patients re-hospitalised for VOC

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    End point title
    		 Proportion of patients re-hospitalised for VOC [19]
    End point description
    Re-occurrence of VOC within 3 or 28 days from last dose of study medication.
    End point type
    Secondary
    End point timeframe
    From resolution of VOC and up to 28 days thereafter.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 Sevuparin Placebo
    Number of subjects analysed
    58
    62
    Units: percent (%)
        Re-occurrence of VOC within 3 days: Yes
    2
    5
        Re-occurrence of VOC within 3 days: No
    98
    95
        Re-occurrence of VOC within 28 days: Yes
    14
    13
        Re-occurrence of VOC within 28 days: No
    86
    87
    No statistical analyses for this end point

    Secondary: PK: Cmax

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    End point title
    		 PK: Cmax [20]
    End point description
    In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion. In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
    End point type
    Secondary
    End point timeframe
    Predose and until end of infusion.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Number of subjects analysed
    8
    2
    2
    2
    Units: µg/mL
        arithmetic mean (standard deviation)
    15.0 ( 5.41 )
    16.8 ( 1.48 )
    11.5 ( 1.06 )
    13.4 ( 3.04 )
    No statistical analyses for this end point

    Secondary: PK: Cmin

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    End point title
    		 PK: Cmin [21]
    End point description
    In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion. In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
    End point type
    Secondary
    End point timeframe
    Predose and until end of infusion.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Number of subjects analysed
    8
    2
    2
    2
    Units: µg/mL
        arithmetic mean (standard deviation)
    7.93 ( 2.22 )
    8.2 ( 4.50 )
    5.6 ( 3.27 )
    4.9 ( 5.02 )
    No statistical analyses for this end point

    Secondary: PK: AUClast

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    End point title
    		 PK: AUClast [22]
    End point description
    In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion. In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
    End point type
    Secondary
    End point timeframe
    Predose and until end of infusion.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Number of subjects analysed
    8
    2
    2
    2
    Units: µg*hr/mL
        arithmetic mean (standard deviation)
    684 ( 579 )
    1300 ( 75.7 )
    911 ( 616 )
    769 ( 472 )
    No statistical analyses for this end point

    Secondary: PK: Css,av

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    End point title
    		 PK: Css,av [23]
    End point description
    In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion. In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
    End point type
    Secondary
    End point timeframe
    Predose and until end of infusion.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Number of subjects analysed
    8
    2
    2
    2
    Units: µg/mL
        arithmetic mean (standard deviation)
    10.2 ( 2.55 )
    12.4 ( 1.87 )
    7.2 ( 3.13 )
    9.5 ( 0.27 )
    No statistical analyses for this end point

    Secondary: PK: CL

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    End point title
    		 PK: CL [24]
    End point description
    In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion. In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
    End point type
    Secondary
    End point timeframe
    Predose and until end of infusion.
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Number of subjects analysed
    8
    2
    2
    2
    Units: L/h
        arithmetic mean (standard deviation)
    5.5 ( 1.48 )
    3.5 ( 0.36 )
    4.6 ( 2.90 )
    4.4 ( 0.77 )
    No statistical analyses for this end point

    Secondary: PK: Total dose

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    End point title
    		 PK: Total dose [25]
    End point description
    In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion. In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
    End point type
    Secondary
    End point timeframe
    From start of IP administration and until end of infusion.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters.
    End point values
    		 PK - Sevuparin, Adult Male PK - Sevuparin, Adult Female PK - Sevuparin, Adolescent Male PK - Sevuparin, Adolescent Female
    Number of subjects analysed
    8
    2
    2
    2
    Units: mg
        arithmetic mean (standard deviation)
    4441.3 ( 2361.4 )
    4946 ( 480.1 )
    3417.4 ( 166 )
    3608.4 ( 1106.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the start of study treatment, or as required by local regions, until the last FU visit or 30 days after the last dose of study drug whichever lasted longer.
    Adverse event reporting additional description
    Clinically relevant changes in vital signs, physical examination, ECG, and laboratory safety analyses were reported as advese events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Sevuparin
    Reporting group description
    		 Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients with SCD, hospitalised with acute VOC, received placebo solution as an IV infusion for 2-7 days.

    Serious adverse events
    		 Sevuparin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 68 (22.06%)
    17 / 76 (22.37%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypersplenism
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 76 (5.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    2 / 68 (2.94%)
    6 / 76 (7.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sevuparin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 68 (66.18%)
    50 / 76 (65.79%)
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    8 / 68 (11.76%)
    0 / 76 (0.00%)
         occurrences all number
    8
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 76 (2.63%)
         occurrences all number
    4
    2
    Bilirubin conjugated increased
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 76 (5.26%)
         occurrences all number
    4
    4
    Blood bilirubin increased
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 76 (5.26%)
         occurrences all number
    5
    4
    Blood calcium decreased
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 76 (3.95%)
         occurrences all number
    4
    3
    C-reactive protein increased
         subjects affected / exposed
    11 / 68 (16.18%)
    12 / 76 (15.79%)
         occurrences all number
    11
    12
    Haemoglobin decreased
         subjects affected / exposed
    18 / 68 (26.47%)
    8 / 76 (10.53%)
         occurrences all number
    20
    8
    Oxygen saturation decreased
         subjects affected / exposed
    5 / 68 (7.35%)
    1 / 76 (1.32%)
         occurrences all number
    5
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 68 (2.94%)
    5 / 76 (6.58%)
         occurrences all number
    2
    5
    Sickle cell anaemia with crisis
         subjects affected / exposed
    3 / 68 (4.41%)
    6 / 76 (7.89%)
         occurrences all number
    6
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 76 (2.63%)
         occurrences all number
    5
    2
    Chest pain
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 76 (3.95%)
         occurrences all number
    6
    6
    Pyrexia
         subjects affected / exposed
    17 / 68 (25.00%)
    17 / 76 (22.37%)
         occurrences all number
    20
    17
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 76 (1.32%)
         occurrences all number
    4
    1
    Constipation
         subjects affected / exposed
    12 / 68 (17.65%)
    17 / 76 (22.37%)
         occurrences all number
    13
    17
    Diarrhoea
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 76 (2.63%)
         occurrences all number
    5
    2
    Nausea
         subjects affected / exposed
    8 / 68 (11.76%)
    13 / 76 (17.11%)
         occurrences all number
    10
    15
    Vomiting
         subjects affected / exposed
    6 / 68 (8.82%)
    10 / 76 (13.16%)
         occurrences all number
    7
    10
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    5 / 68 (7.35%)
    0 / 76 (0.00%)
         occurrences all number
    5
    0
    Cough
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 76 (2.63%)
         occurrences all number
    4
    2
    Dyspnoea
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 76 (1.32%)
         occurrences all number
    4
    1
    Epistaxis
         subjects affected / exposed
    5 / 68 (7.35%)
    0 / 76 (0.00%)
         occurrences all number
    6
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 76 (5.26%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 76 (5.26%)
         occurrences all number
    2
    4
    Pain in extremity
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 76 (3.95%)
         occurrences all number
    5
    3
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
    4 / 76 (5.26%)
         occurrences all number
    1
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 68 (4.41%)
    3 / 76 (3.95%)
         occurrences all number
    3
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2015
    Modification of the pharmacokinetic evaluations sections in compliance with the main text (section 12.6) Definition of DSMB (section V) Description of DSMB roles, responsibilities and decision criteria (section 12.6) Clarification that, for ethical reasons, biomarkers samples were not to be taken in adolescents who provided PK samples. The reason was to reduce blood volumes to be drawn in adolescents.
    14 Dec 2015
    The number of sites was increased. The study period was extended. The timeframes for study procedures were altered. ULN for hepatic and coagulation factors were altered. Inclusion and exclusion criteria were modified. Dose adjustment was permitted earlier to increase patient safety.
    16 Jan 2017
    Inclusion and exclusion criteria were adjusted. Methodology, statistical methods, and administrative structure were clarified. The sample size was increased. Secondary objectives were added. Safety analyses and methodology for concomitant medication usage were further specified. The treatment and dose justification were clarified. The informed consent for adolescents was altered. The number of Investigator sites were increased. The study enrollment period was extended.

    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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