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    Clinical Trial Results:
    A Phase 2, Multicenter, Randomized, Placebo-controlled, Double Blind Study in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) to Evaluate the Pharmacokinetics, Safety, and Efficacy of rADAMTS-13 (SHP655) Administered in Addition to Standard of Care (SoC) Treatment

    Summary
    EudraCT number
    		 2018-003775-35
    Trial protocol
    		 GB   DE   ES   IT  
    Global end of trial date
    05 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2022
    First version publication date
    20 Aug 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SHP655-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03922308
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, ClinicalTransparency@shire.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
    05 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to assess the pharmacokinetics (PK) of ADAMTS-13 in aTTP participant treated for an acute episode by daily plasma exchange (PEX), immunosuppressant therapy, with or without SHP655 supplementation and to study the PK/ pharmacodynamic (PD) relationship between ADAMTS-13 activity levels on pathophysiological biomarkers as well as clinical efficacy parameters.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Oct 2019
    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
    France: 2
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 11
    Worldwide total number of subjects
    28
    EEA total number of subjects
    8
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 12 investigative sites in Canada, France, Great Britain, Spain and United States from 09 October 2019 to 05 August 2021.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of acquired thrombotic thrombocytopenic purpura (aTTP) were enrolled to receive placebo, SHP655 once daily (QD) and twice daily (BID) in a ratio of 1:1:1 in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard of Care (SoC) + Placebo
    Arm description
    		 Participants received SoC daily plasma exchange (PEX) followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SHP655 Matching Placebo intravenous (IV) infusion

    Investigational medicinal product name
    Standard of Care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    PEX as SoC

    Arm title
    		 SoC + SHP655 + Placebo
    Arm description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Standard of Care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    PEX as SoC

    Investigational medicinal product name
    SHP655
    Investigational medicinal product code
    Other name
    rADAMTS-13
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SHP655 IV

    Arm title
    		 SoC + SHP655
    Arm description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Standard of Care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    PEX as SoC

    Investigational medicinal product name
    SHP655
    Investigational medicinal product code
    Other name
    rADAMTS-13
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SHP655 IV

    Number of subjects in period 1
    		Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Started
    10
    9
    9
    Pharmacokinetic Population
    10
    8
    9
    Completed
    9
    6
    8
    Not completed
    1
    3
    1
         Not Meeting Confirmatory Inclusion Criteria
    -
    1
    -
         Lost to follow-up
    1
    -
    -
         Reason not Specified
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard of Care (SoC) + Placebo
    Reporting group description
    		 Participants received SoC daily plasma exchange (PEX) followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group title
    SoC + SHP655 + Placebo
    Reporting group description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group title
    SoC + SHP655
    Reporting group description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655 Total
    Number of subjects
    		 10 9 9
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.2 ( 10.80 ) 51.9 ( 14.81 ) 48.4 ( 14.93 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 6 5 19
        Male
    		 2 3 4 9
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 1
        Not Hispanic or Latino
    		 10 8 9 27
        Unknown or Not Reported
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Race American Indian or Alaska Native
    		 0 0 0 0
        Race Asian
    		 0 1 0 1
        Race Black or African American
    		 4 1 2 7
        Race White
    		 6 5 6 17
        Race Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Race Other
    		 0 2 0 2
        Race Missing
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Standard of Care (SoC) + Placebo
    Reporting group description
    		 Participants received SoC daily plasma exchange (PEX) followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group title
    SoC + SHP655 + Placebo
    Reporting group description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group title
    SoC + SHP655
    Reporting group description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Primary: ADAMTS-13 Activity Levels

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    End point title
    		 ADAMTS-13 Activity Levels [1]
    End point description
    ADAMTS-13 Activity Levels was assessed by fluorescence resonance energy transfer (FRETS) ADAMTS13 activity, with or without SHP655 Supplementation. Schedule A (Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter) or Schedule B (Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter). Data is reported for multiple timepoints: within(≤)15 minutes pre-PEX & post-PEX;≤15 minutes 0.5-3 hours,4-6 hours post end of investigational product(IP) infusion 1;≤15 minutes,0.5-3 hours post end IP infusion 2;30 minutes pre-IP infusion 2 of Schedule A & Schedule B (up to Day 11 or 12).Pharmacokinetic (PK) Set:all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity).Overall number:participants available for analyses. 'n':participants with data available.9999: Data not estimable for 1 participant.99999:Data not estimable due to less participants.
    End point type
    Primary
    End point timeframe
    Up to Days 11 or 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical data was collected for this outcome measure.
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: international units(IU)/ml
    arithmetic mean (standard deviation)
        Day 1: ≤15min Pre-PEX(n=8,7,8)
    0.1439 ( 0.19247 )
    99999 ( 99999 )
    99999 ( 99999 )
        Day 1: ≤15 min Post-PEX(n=9,8,9)
    0.5418 ( 0.18345 )
    0.5011 ( 0.19236 )
    0.3029 ( 0.29020 )
        Day 1: ≤15 min Post End of IP1(n=10,7,9)
    0.4571 ( 0.19125 )
    2.012 ( 0.82832 )
    1.352 ( 0.93502 )
        Day 1: 0.5-3 hr Post End of IP 1(n=10,7,9)
    0.4420 ( 0.20895 )
    1.905 ( 0.83349 )
    1.266 ( 0.98904 )
        Day 1: 4-6 hr Post End of IP 1(n=10,5,9)
    0.3197 ( 0.20545 )
    1.163 ( 0.61343 )
    0.7912 ( 0.69403 )
        Day 1: ≤30 min Pre-IP 2(n=10,6,9)
    0.2108 ( 0.19731 )
    1.027 ( 0.55951 )
    0.4949 ( 0.54891 )
        Day 1: ≤15 min Post End of IP 2(n=9,8,9)
    0.2267 ( 0.18660 )
    1.022 ( 0.52060 )
    1.545 ( 1.0854 )
        Day 1: 0.5-3 hr Post End of IP 2(n=8,7,9)
    0.2007 ( 0.20012 )
    1.015 ( 0.56462 )
    1.300 ( 1.1114 )
        Day 2: ≤15 min Pre-PEX(n=10,7,8)
    0.1691 ( 0.15909 )
    0.7650 ( 0.61929 )
    0.9482 ( 0.99771 )
        Day 2: ≤15 min Post-PEX(n=10,7,9)
    0.5801 ( 0.16107 )
    0.7808 ( 0.36544 )
    0.8426 ( 0.54317 )
        Day 2: ≤15 min Post End of IP 1(n=10,6,9)
    0.5433 ( 0.20267 )
    1.965 ( 0.72122 )
    1.977 ( 0.98427 )
        Day 2: 0.5-3 hr Post End of IP 1(n=10,8,9)
    0.5281 ( 0.24842 )
    2.105 ( 1.0656 )
    2.153 ( 1.3856 )
        Day 2: 4-6 hr Post End of IP 1(n=9,8,9)
    0.4170 ( 0.25202 )
    1.622 ( 0.78046 )
    1.411 ( 0.75100 )
        Day 2: ≤30 min Pre-IP 2(n=10,8,9)
    0.3117 ( 0.24934 )
    1.309 ( 0.48787 )
    1.044 ( 0.55923 )
        Day 2: ≤15 min Post End of IP 2(n=10,8,9)
    0.2998 ( 0.24960 )
    1.283 ( 0.52550 )
    1.960 ( 0.99952 )
        Day 2: 0.5-3 hr Post End of IP 2(n=10,8,9)
    0.2833 ( 0.23999 )
    1.398 ( 0.47591 )
    2.129 ( 1.4547 )
        Day 3: ≤15 min Pre-PEX(n=9,6,5)
    0.2468 ( 0.23669 )
    1.044 ( 0.54178 )
    1.129 ( 1.0570 )
        Day 3: ≤15 min Post-PEX(n=10,8,6)
    0.5342 ( 0.22251 )
    0.7786 ( 0.16455 )
    0.7020 ( 0.40432 )
        Day 3: ≤15 min Post End of IP 1(n=10,8,6)
    0.5215 ( 0.23522 )
    2.210 ( 0.96057 )
    1.911 ( 1.6633 )
        Day 3: 0.5-3 hr Post End of IP 1(n=10,8,6)
    0.4970 ( 0.23979 )
    2.086 ( 0.85567 )
    1.785 ( 1.1566 )
        Day 3: 4-6 hr Post End of IP 1(n=10,8,7)
    0.4670 ( 0.30646 )
    1.680 ( 0.46457 )
    1.271 ( 0.71567 )
        Day 3: ≤30 min Pre-IP 2(n=10,7,7)
    0.3424 ( 0.29275 )
    1.196 ( 0.44550 )
    1.041 ( 0.84152 )
        Day 3: ≤15 min Post End of IP 2(n=10,7,6)
    0.3514 ( 0.31264 )
    1.263 ( 0.38468 )
    1.478 ( 1.0343 )
        Day 3: 0.5-3 hr Post End of IP 2(n=10,7,7)
    0.3227 ( 0.28191 )
    1.267 ( 0.43580 )
    1.902 ( 1.4522 )
        Day4 or 5:≤15min Pre-PEX(n=7,6,5)
    0.2378 ( 0.30513 )
    1.094 ( 0.67793 )
    1.378 ( 1.1964 )
        Day4 or 5:≤15min Post-PEX(n=7,8,5)
    0.4554 ( 0.26405 )
    0.8222 ( 0.21072 )
    0.8725 ( 0.57834 )
        Day4 or 5:≤15min Post End of IP1(n=7,8,5)
    0.7599 ( 1.0062 )
    2.257 ( 0.95791 )
    1.679 ( 1.3803 )
        Day4 or 5:0.5-3hr Post End of IP1(n=7,8,5)
    0.6699 ( 0.76875 )
    2.425 ( 1.4869 )
    1.405 ( 1.0118 )
        Day4 or 5:4-6hr Post End of IP1(n=7,7,5)
    0.5663 ( 0.69581 )
    1.741 ( 0.84171 )
    1.214 ( 1.0280 )
        Day4 or 5:≤30min Pre-IP2(n=6,6,5)
    0.5045 ( 0.60730 )
    1.290 ( 0.64745 )
    1.255 ( 0.98796 )
        Day4 or 5:≤15min Post End of IP2(n=6,6,5)
    0.4596 ( 0.58498 )
    1.288 ( 0.63801 )
    2.306 ( 1.6006 )
        Day4 or 5:0.5-3hr Post End of IP2(n=6,6,5)
    0.4129 ( 0.49574 )
    1.106 ( 0.59034 )
    2.009 ( 1.4354 )
        Day6 or 7:≤15 min Pre-PEX(n=4,2,2)
    0.1246 ( 0.24910 )
    99999 ( 99999 )
    99999 ( 99999 )
        FRETS:Day6 or 7:≤15min Post-PEX(n=4,3,2)
    0.2587 ( 0.30131 )
    0.7311 ( 0.48855 )
    99999 ( 99999 )
        Day6 or 7:≤15min Post End of IP1(n=4,3,2)
    0.2150 ( 0.26924 )
    1.481 ( 0.89773 )
    99999 ( 99999 )
        Day 6 or 7:0.5-3hr Post End of IP1(n=4,3,2)
    0.2194 ( 0.24929 )
    1.673 ( 1.0721 )
    99999 ( 99999 )
        Day6 or 7:4-6hr Post End of IP1(n=4,3,2)
    0.1443 ( 0.24485 )
    1.467 ( 1.1232 )
    99999 ( 99999 )
        Day6 or 7:≤30min Pre-IP2(n=4,2,2)
    0.1272 ( 0.25440 )
    99999 ( 99999 )
    99999 ( 99999 )
        Day6 or 7:≤15min Post End of IP2(n=4,2,2)
    0.1422 ( 0.28435 )
    99999 ( 99999 )
    99999 ( 99999 )
        Day6 or 7:0.5-3hr Post End of IP2(n=4,2,1)
    0.1336 ( 0.26710 )
    99999 ( 99999 )
    9999 ( 9999 )
        Day8 or 9:≤15min Pre-PEX(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day8 or 9:≤15min Post-PEX(n=0,2,0)
    0 ( 0 )
    99999 ( 99999 )
    0 ( 0 )
        Day8 or 9:≤15min Post End of IP1(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day8 or 9:0.5-3hr Post End of IP1(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day8 or 9:4-6hr Post End of IP Infusion1(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day8 or 9:≤30min Pre-IP2(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day8 or 9:≤15min Post End of IP2(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day8 or 9:0.5-3hr Post End of IP2(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day 11 or 12:≤15 min Pre-PEX(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day11 or 12: ≤15min Post-PEX(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day11 or 12: ≤15min Post End of IP1(n=0,1,0)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Day11 or 12:0.5-3hr Post End of IP1(n=0,1,0)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Day11 or 12:4-6hr Post End of IP1(n=0,1,0)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Day11 or 12:≤30min Pre-IP2(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day11 or 12: ≤15min Post End of IP2(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day11 or 12:0.5-3hr Post End of IP2(n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
    No statistical analyses for this end point

    Primary: Platelet Count

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    End point title
    		 Platelet Count [2]
    End point description
    The platelet counts are reported in units of 10^9 per liter blood. SAS included all participants randomized, who received any dose of investigational product. Overall number analyzed are the number of participants with data evaluable for analyses. Number analyzed is the number of participants available for analysis.
    End point type
    Primary
    End point timeframe
    Baseline and end of study (EOS) (up to approximately 15 months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical data was collected for this outcome measure.
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: 10^9 platelets/L
    arithmetic mean (standard deviation)
        Baseline (n=10,9,8)
    35.80 ( 32.076 )
    27.67 ( 17.571 )
    15.38 ( 7.463 )
        EOS (n=9,7,9)
    278.89 ( 79.592 )
    267.00 ( 86.906 )
    286.22 ( 109.264 )
    No statistical analyses for this end point

    Primary: Lactate Dehydrogenase (LDH) Levels

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    End point title
    		 Lactate Dehydrogenase (LDH) Levels [3]
    End point description
    The lactate dehydrogenase levels are reported. The lactate dehydrogenase levels are reported.
    End point type
    Primary
    End point timeframe
    Baseline and EOS (up to approximately 15 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical data was collected for this outcome measure.
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    8
    Units: international units (IU)/L
    arithmetic mean (standard deviation)
        Baseline (n=10,9,8)
    634.6 ( 378.37 )
    616.3 ( 478.14 )
    787.8 ( 188.39 )
        EOS (n=8,6,8)
    197.3 ( 42.00 )
    208.8 ( 75.20 )
    220.4 ( 69.93 )
    No statistical analyses for this end point

    Secondary: Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13

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    End point title
    		 Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13
    End point description
    Dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of rADAMTS-13 in order to support induction of remission and to reduce the number of PEX procedures needed for the treatment of acute aTTP episodes was assessed.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 13 weeks (following remission up to 6 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    Units: participants
    Notes
    [4] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [5] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [6] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    No statistical analyses for this end point

    Secondary: PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity

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    End point title
    		 PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity
    End point description
    Parameters included platelet and LDH counts.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: participants
    Notes
    [7] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [8] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [9] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    No statistical analyses for this end point

    Secondary: Number of Participants With ADAMTS-13 Binding Antibodies Per Titer

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    End point title
    		 Number of Participants With ADAMTS-13 Binding Antibodies Per Titer
    End point description
    Antibody titer indicates the level of the antibodies in a blood sample, defined as the greatest dilution (or lowest concentration) of the blood sample at which an antibody assay (such as ELISA for e.g.), still produces a detectable positive result. Data is presented per titer. SAS included all participants randomized, who received any dose of investigational product. Overall number analyzed are the number of ADA positive participants. 'n' indicates number analyzed is the number of participants available for analysis. Data is presented per titer for ADA positive participants only.
    End point type
    Secondary
    End point timeframe
    Baseline and EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    7
    8
    8
    Units: participants
        Baseline- 1:20 (n=7,8,8)
    2
    3
    1
        Baseline- 1:40 (n=7,8,8)
    3
    2
    2
        Baseline- 1:80 (n=7,8,8)
    2
    0
    1
        Baseline- 1:160 (n=7,8,8)
    0
    1
    2
        Baseline- 1:320 (n=7,8,8)
    0
    2
    0
        Baseline- 1:640 (n=7,8,8)
    0
    0
    1
        Baseline- 1:1280 (n=7,8,8)
    0
    0
    1
        EOS- 1:20 (n=3,2,5)
    0
    1
    0
        EOS- 1:40 (n=3,2,5)
    2
    0
    1
        EOS- 1:80 (n=3,2,5)
    1
    0
    2
        EOS- 1:2560 (n=3,2,5)
    0
    1
    0
        EOS- 1:5120 (n=3,2,5)
    0
    0
    1
        EOS- 1:81920 (n=3,2,5)
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Inhibitory Autoantibody (Nab) Levels by Time

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    End point title
    		 Inhibitory Autoantibody (Nab) Levels by Time
    End point description
    SAS included all participants randomized, who received any dose of investigational product. Overall number analyzed are the number of participants with data evaluable for analyses. 'n' indicates number analyzed is the number of participants available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: days
    median (full range (min-max))
        Baseline (n=10,9,9)
    1.25 (0.6 to 3.4)
    1.25 (1.0 to 1.8)
    1.80 (0.6 to 4.0)
        EOS (n=9,7,8)
    0.60 (0.6 to 0.6)
    0.70 (0.7 to 1.7)
    4.00 (4.0 to 4.0)
    No statistical analyses for this end point

    Secondary: ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS

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    End point title
    		 ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS
    End point description
    ADAMTS-13 activity levels in participants receiving additional SHP655 for up to 30 days after the resolution of the thrombotic thrombocytopenic purpura (TTP) episode were assessed. Resolution was defined as a normal platelet count and LDH <2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period). PK Set included all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). Overall number analyzed are the number of participants available for analyses. 'n' indicates number analyzed is the number of participants with data available for analyses at given time point. 9999: Mean and SD was not estimable due to low number of evaluable participants.
    End point type
    Secondary
    End point timeframe
    At Days 3, 7, 10, 21, 28, 42, 56 and 84
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    7
    7
    6
    Units: IU/mL
    arithmetic mean (standard deviation)
        Day 3 (n=6,2,6)
    0.4602 ( 0.14328 )
    -99999 ( 99999 )
    0.1171 ( 0.28688 )
        Day 7 (n=4,2,7)
    0.3037 ( 0.26921 )
    0.3180 ( 0.34714 )
    -99999 ( 99999 )
        Day 10 (n=3,4,5)
    0.9021 ( 0.20520 )
    0.5518 ( 0.33962 )
    0.4904 ( 0.46441 )
        Day 21 (n=4,5,5)
    0.8102 ( 0.52773 )
    0.6264 ( 0.60971 )
    0.5320 ( 0.51432 )
        Day 28 (n=4,5,4)
    0.8830 ( 0.51516 )
    0.8931 ( 0.41323 )
    0.8632 ( 0.62848 )
        Day 42 (n=4,4,4)
    0.9968 ( 0.36745 )
    0.8842 ( 0.39784 )
    1.055 ( 0.36080 )
        Day 56 (n=3,4,3)
    1.088 ( 0.25524 )
    0.9923 ( 0.33663 )
    1.092 ( 0.19961 )
        Day 84 (n=7,6,6)
    0.9708 ( 0.43831 )
    1.021 ( 0.65715 )
    0.6051 ( 0.48113 )
    No statistical analyses for this end point

    Secondary: Relationship Between ADAMTS-13 Activity and End-organ Disease Status

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    End point title
    		 Relationship Between ADAMTS-13 Activity and End-organ Disease Status
    End point description
    Data could not be analyzed due to sparse sample collections and confounding dosing inputs with daily sequential PEX + SHP655 dosing.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    Units: participants
    Notes
    [10] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [11] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [12] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    No statistical analyses for this end point

    Secondary: Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio

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    End point title
    		 Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio
    End point description
    PK Set included all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). Overall number analyzed are the number of participants available for analyses. 'n' indicates number analyzed is the number of participants with data available for analyses at given time point. 9999: Mean and SD was not estimable due to low number of evaluable participants. 99999: Mean and SD was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-PEX and post-PEX at multiple timepoints at Days 1, 2, 3, 4 or 5, 6 or 7, 8 or 9, and 11 or 12
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    7
    7
    9
    Units: ratio
    arithmetic mean (standard deviation)
        FRETS: Day 1 (n=5,2,1)
    2.744 ( 3.3837 )
    99999 ( 99999 )
    9999 ( 9999 )
        FRETS: Day 2 (n=4,7,7)
    2.587 ( 0.92176 )
    3.534 ( 2.4373 )
    3.675 ( 2.3380 )
        FRETS: Day 3 (n=4,7,6)
    1.669 ( 0.34045 )
    2.134 ( 0.45392 )
    2.268 ( 1.0679 )
        FRETS: Day 4 or 5 (n=2,5,5)
    99999 ( 99999 )
    2.543 ( 0.59576 )
    1.972 ( 0.91248 )
        FRETS: Day 6 or 7 (n=1,2,1)
    9999 ( 9999 )
    99999 ( 99999 )
    9999 ( 9999 )
        FRETS: Day 8 or 9 (n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        FRETS: Day 11 or 12 (n=0,0,0)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS

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    End point title
    		 AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS
    End point description
    Pharmacokinetic (PK) Set included all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). 'n' indicates number analyzed are the number of participants available for analysis at the specific time point. 9999: Mean and SD was not estimable due to low number of evaluable participants.
    End point type
    Secondary
    End point timeframe
    Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 1, 2, 3, 4 or 5 and 6 or 7
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: h*IU/mL
    arithmetic mean (standard deviation)
        Day 1(n=9,7,8)
    3.563 ( 2.5551 )
    19.87 ( 9.1150 )
    12.80 ( 8.4633 )
        Day 2(n=10,8,9)
    4.461 ( 3.9480 )
    24.16 ( 9.0323 )
    21.97 ( 11.135 )
        Day 3(n=9,7,6)
    5.590 ( 4.7232 )
    22.75 ( 5.6549 )
    23.49 ( 9.2589 )
        Day 4 or 5(n=5,6,5)
    9.507 ( 11.592 )
    24.10 ( 11.357 )
    22.05 ( 14.192 )
        Day 6 or 7(n=2,2,2)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Systemic and Antibody Induced Clearance

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    End point title
    		 Systemic and Antibody Induced Clearance
    End point description
    Data could not be analyzed due to sparse sample collections and confounding dosing inputs with daily sequential PEX + SHP655 dosing.
    End point type
    Secondary
    End point timeframe
    15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion 1,30 minutes pre-IP infusion 2,15 minutes, 0.5-3 hours post-IP infusion 2 of Schedule A or Schedule B (up to 6 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    Units: participants
    Notes
    [13] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [14] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    [15] - Data not analyzed due to sparse sample collections and confounding dosing inputs.
    No statistical analyses for this end point

    Secondary: Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS

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    End point title
    		 Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS
    End point description
    PK Set included all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). 'n' indicates number analyzed is the number of participants available for analyses at given time point. 9999: Mean and SD was not estimable for 1 participant. 99999: Mean and SD was not estimable due to low number of evaluable participants.
    End point type
    Secondary
    End point timeframe
    Pre-PEX and post-PEX at multiple timepoints at Days 1, 2, 3, 4 or 5, 6 or 7, 8 or 9, and 11 or 12
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: IU/mL
    arithmetic mean (standard deviation)
        Day 1 (n=10,7,9)
    0.4157 ( 0.17075 )
    2.011 ( 0.79036 )
    1.653 ( 1.0655 )
        Day 2 (n=10,7,9)
    0.4951 ( 0.27178 )
    2.153 ( 1.1404 )
    2.458 ( 1.4369 )
        Day 3 (n=10,8,7)
    0.4307 ( 0.28420 )
    2.228 ( 0.93968 )
    2.222 ( 1.5080 )
        Day 4 or 5 (n=7,7,5)
    0.6438 ( 0.97767 )
    2.633 ( 1.4955 )
    2.377 ( 1.5934 )
        Day 6 or 7 (n=4,3,2)
    0.1362 ( 0.095283 )
    1.625 ( 1.0126 )
    9999 ( 9999 )
        Day 8 or 9 (n=0,1,0)
    0 ( 0 )
    9999 ( 9999 )
    0 ( 0 )
        Day 11 or 12 (n=0,0,0)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS

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    End point title
    		 Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS
    End point description
    PK Set included all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). Overall number analyzed are the number of participants available for analyses. 'n' number analyzed are the number of participants with data available for analysis at the specific time point. 9999: Mean and SD was not estimable due to low number of evaluable participants.
    End point type
    Secondary
    End point timeframe
    Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 2, 3, 4 or 5 and 6 or 7
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    7
    8
    9
    Units: IU/mL
    arithmetic mean (standard deviation)
        Day 2(n=7,8,9)
    0.1667 ( 0.17308 )
    0.8493 ( 0.62139 )
    0.9274 ( 0.93426 )
        Day 3(n=7,7,7)
    0.2579 ( 0.26836 )
    1.110 ( 0.52612 )
    1.174 ( 0.93910 )
        Day 4 or 5(n=4,7,5)
    0.3138 ( 0.38416 )
    1.180 ( 0.65905 )
    1.378 ( 1.1976 )
        Day 5 or 6(n=3,3,2)
    0.1660 ( 0.28752 )
    1.070 ( 0.98879 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%

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    End point title
    		 Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%
    End point description
    PK Set included all enrolled participants with confirmed aTTP diagnosis who received at least 1 dose of investigational product and who had at least 1 evaluable post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). Overall number analyzed are the particiapnts from PK set, which included number of participants available for analysis. 'n' indicates number analyzed are the number of participants available with ADAMTS activity absolute Ctrough values at given time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Days 2, 3 4 or 5, 6 or 7, 8 or 9, and 11 or 12
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    7
    8
    9
    Units: percentage of participants
    number (not applicable)
        Day 2 (n=7,8,9)
    57.1
    100.0
    77.8
        Day 3 (n=7,7,7)
    57.1
    100.0
    85.7
        Day 4 or 5 (n=4,6,5)
    50.0
    100.0
    100.0
        Day 6 or 7 (n=3,3,2)
    33.3
    66.7
    50.0
        Day 8 or 9 (n=0,1,0)
    0
    100.0
    0
        Day 11 or 12 (n=0,1,0)
    0
    100.0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants who Achieved Remission Following Normalization of Platelet Count

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    End point title
    		 Number of Participants who Achieved Remission Following Normalization of Platelet Count
    End point description
    Remission was defined as the time taken to achieve platelet count ≥150,000/μL, which was confirmed by a second normal platelet count ≥150,000/μL and LDH <2 ULN 48 hours following initial normalization. FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 13 weeks (following remission up to 6 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: participants
    9
    8
    8
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Remission

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    End point title
    		 Percentage of Participants Achieving Remission
    End point description
    Remission was defined as a normal platelet count and LDH <2 upper limit of normal (ULN) for at least 48 hours following initial normalization of platelet count (acute episode period). Normalization of platelet count was defined ≥150,000/μL, which was confirmed by a second normal platelet count ≥150,000/μL and LDH <2 ULN. Overall number analyzed are the number of participants with data available for analysis. FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 13 weeks (following remission up to 6 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    8
    Units: percentage of participants
        number (confidence interval 95%)
    100.0 (69.15 to 100.00)
    100.0 (63.06 to 100.00)
    88.9 (51.75 to 99.72)
    No statistical analyses for this end point

    Secondary: Time to First Exacerbation

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    End point title
    		 Time to First Exacerbation
    End point description
    Exacerbation was defined as recurrent thrombocytopenia following a response and requiring a reinitiation of daily plasma exchange treatment after ≥1 day but ≤30 days of no plasma exchange treatment. Data is reported based on Kaplan-Meier estimates. Data was reported for time to first exacerbation in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS). FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample. 99999: The median and upper limit of confidence interval (CI) was not evaluable due to no events in participants.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: days
    median (confidence interval 50%)
        From Study Start up to 11 Months
    99999 (2.00 to 99999)
    99999 (99999 to 99999)
    8.0 (5.00 to 99999)
        From 11 Months up to EOS(up to approx. 15 months)
    99999 (4.00 to 99999)
    99999 (99999 to 99999)
    99999 (6.00 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Relapse

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    End point title
    		 Time to Relapse
    End point description
    Relapse was determined by platelet count or the occurrence after remission of a major clinical event (e.g., Myocardial Infraction (MI), stroke, death) deemed by the investigator to be related to aTTP. Data was reported for time to relapse in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS). FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample. 99999: The median, lower and upper limit of CI was not evaluable due to no events in participants.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: days
    median (confidence interval 50%)
        From Study Start up to 11 Months(n=10,8,9)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        'From 11 Months up to EOS(up to approx. 15 months)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Exacerbation

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    End point title
    		 Percentage of Participants With Exacerbation
    End point description
    Exacerbation was determined by platelet count or the occurrence after remission of a major clinical event (e.g., myocardial infarction (MI), stroke, death) deemed by the investigator to be related to aTTP. Data was reported for percentage of participants with exacerbation in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS). FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: percentage of participants
    number (confidence interval 95%)
        From Study Start up to 11 Months
    50.0 (6.76 to 93.24)
    0.0 (0.00 to 60.24)
    60.0 (14.66 to 94.73)
        'From 11 Months up to EOS(up to approx. 15 months)
    33.3 (4.33 to 77.72)
    0.0 (0.00 to 60.24)
    33.3 (0.84 to 90.57)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Relapse

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    End point title
    		 Percentage of Participants With Relapse
    End point description
    Relapse was determined by platelet count or the occurrence after remission of a major clinical event (e.g., Myocardial Infraction (MI), stroke, death) deemed by the investigator to be related to aTTP. Data was reported for percentage of participants with exacerbation in categories for participants enrolled before protocol amendment 4 (from study start up to 11 months) and after protocol amendment 4 (from 11 months up to the EOS).
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: percentage of participants
    number (confidence interval 95%)
        From Study Start up to 11 Months
    0.0 (0.0 to 60.24)
    0.0 (0.0 to 60.24)
    0.0 (0.0 to 52.18)
        'From 11 Months up to EOS(up to approx. 15 months)
    0.0 (0.0 to 45.93)
    0.0 (0.0 to 60.24)
    0.0 (0.0 to 70.76)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)

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    End point title
    		 Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)
    End point description
    Major clinical events related to TTP included Death, Stroke, MI and organ dysfunction not normalized within the 90-day observation period which consisted of chronic renal insufficiency, neurologic impairment and neurocognitive deficits. FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: percentage of participants
    number (not applicable)
        Renal Insufficiency
    90.0
    100.0
    88.9
        Neurologic Deficits
    60.0
    100.0
    77.8
        Brain Injury
    50.0
    62.5
    66.7
        Death, Stroke and MI
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Major Clinical Events Related to PEX

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    End point title
    		 Number of Participants With Major Clinical Events Related to PEX
    End point description
    Major clinical events included clinically relevant bleeding (modified ITP score) or thrombosis at the site of line insertion, adverse reactions to plasma, including citrate reactions, allergic reactions, and transfusion-related acute lung injury (TRALI). Data is reported by summarizing the data for all parameters. FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: participants
    6
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline

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    End point title
    		 Number of Participants with Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline
    End point description
    SAS included all participants randomized, who received any dose of investigational product. Overall number analyzed are the number of participants available for analyses. Number analyzed are the number of participants with data available for analysis at the specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline and EOS (at approximately Month 15)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: participants
        Baseline (n=10,9,9)
    7
    8
    8
        EOS at Month 15 (n=9,7,8)
    3
    2
    5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655

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    End point title
    		 Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655
    End point description
    Percentages are based on the total number of participants per treatment group that have at least one ADA sample analyzed. Full Analysis Set (FAS) included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: percentage of participants
    number (not applicable)
        ADA Positive: up to 3 Months
    80.0
    62.5
    88.9
        ADA Positive: up to 6 Months
    20.0
    75.0
    33.3
        Nab Positive: up to 3 Months
    40.0
    37.5
    33.3
        Nab Positive: up to 6 Months
    30.0
    37.5
    22.2
    No statistical analyses for this end point

    Secondary: Number of Participants with Inhibitory Antibodies Relative to Baseline

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    End point title
    		 Number of Participants with Inhibitory Antibodies Relative to Baseline
    End point description
    SAS included all participants randomized, who received any dose of investigational product. Overall number analyzed are the number of participants available for analyses. Number analyzed are the number of participants with data available for analysis at the specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline and EOS (at approximately Month 15)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: participants
        Baseline (n=10,9,9)
    6
    4
    7
        EOS at Month 15 (n=9,7,8)
    3
    3
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs
    End point description
    AE:any untoward medical occurrence in a participants administered IP that does not necessarily have a causal relationship with the treatment.TEAE:an adverse event with an onset that occurs after receiving study drug. SAE:an AE with any untoward clinical manifestation of signs, symptoms/outcomes which results in death, requires inpatient hospitalization/prolongation of hospitalization, results in persistent or significant disability/incapacity, congenital abnormality/birth defect, important medical event, bronchospasm associated with anaphylaxis, reviewed & confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V). Product related AE:any event emerging/manifesting at or after the initiation of treatment with an IP/medicinal product or any existing event that worsens. SAS:all participants randomized, who received any dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: participants
        Any TEAEs
    10
    9
    8
        Specifically Product-Related TEAEs
    0
    1
    0
        Serious TEAEs
    4
    1
    3
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Relevant Changes in Vital Signs

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    End point title
    		 Number of Participants with Clinically Relevant Changes in Vital Signs
    End point description
    Vital signs were assessed based on blood pressure, pulse rate, respiratory rate and body temperature. SAS included all participants randomized, who received any dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Relevant Changes in Clinical Chemistry

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    End point title
    		 Number of Participants with Clinically Relevant Changes in Clinical Chemistry
    End point description
    Clinical chemistry assessed alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose. SAS included all participants randomized, who received any dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Relevant Changes in Hematology

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    End point title
    		 Number of Participants with Clinically Relevant Changes in Hematology
    End point description
    Hematology consisted of complete blood count and leukocytes with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC) and platelet count. SAS included all participants randomized, who received any dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    9
    9
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Receiving Rescue Therapy

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    End point title
    		 Percentage of Participants Receiving Rescue Therapy
    End point description
    Rescue therapy was defined as any product with a known interruption to the pharmacokinetic/ pharmacodynamic (PK/PD) relationship between ADAMTS-13 activity, von Willebrand factor (VWF) activity, and platelet count. If rescue therapy was initiated, the administration of IP (SHP655 or placebo) was suspended for the duration of the study. Number of participants experiencing occurrence of receiving rescue therapy was assessed. FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: percentage of participants
        number (not applicable)
    20.0
    0
    22.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting Rescue Criteria

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    End point title
    		 Percentage of Participants Meeting Rescue Criteria
    End point description
    Rescue therapy was defined as any product with a known interruption to the PK/PD relationship between ADAMTS-13 activity, VWF activity, and platelet count. If rescue therapy was initiated, the administration of IP (SHP655 or placebo) was suspended for the duration of the study. Number of participants experiencing occurrence in meeting rescue therapy criteria was assessed. Percentage of participants with rescue therapy initiated are based on laboratory criteria and adverse events. FAS included all enrolled participants with confirmed aTTP diagnosis who were treated with a study product and had an ADAMTS-13 activity reading from at least one post infusion sample.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the EOS (up to approximately 15 months)
    End point values
    		 Standard of Care (SoC) + Placebo SoC + SHP655 + Placebo SoC + SHP655
    Number of subjects analysed
    10
    8
    9
    Units: percentage of participants
        number (not applicable)
    10.0
    0.0
    11.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to end of the study (up to approximately 15 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Standard of Care (SoC) + Placebo
    Reporting group description
    		 Participants received SoC daily plasma exchange (PEX) followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group title
    SoC + SHP655
    Reporting group description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Reporting group title
    SoC + SHP655 + Placebo
    Reporting group description
    		 Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

    Serious adverse events
    		 Standard of Care (SoC) + Placebo SoC + SHP655 SoC + SHP655 + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 9 (33.33%)
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard of Care (SoC) + Placebo SoC + SHP655 SoC + SHP655 + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    6 / 9 (66.67%)
    9 / 9 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Hot flush
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0
    General disorders and administration site conditions
    Catheter site bruise
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Chest discomfort
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    1
    Catheter site related reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Medical device site discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Feeling cold
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Feeling abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    2
    Swelling face
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Dry throat
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    5
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Orthopnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Throat irritation
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Suffocation feeling
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    5
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Delirium
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Procedural anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Panic attack
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    2 / 9 (22.22%)
         occurrences all number
    1
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    2
    Blood pressure increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    3
    Blood glucose increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    White blood cell count abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Anal injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Citrate toxicity
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Contusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    Transfusion related complication
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Extrasystoles
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    5
    1
    1
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    7
    Restless legs syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Taste disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Sensory disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Neutrophilia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    0
    3
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    3 / 9 (33.33%)
         occurrences all number
    1
    1
    4
    Paraesthesia oral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    2
    Nausea
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    5
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Papule
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Ecchymosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    1
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    2
    Skin weeping
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Skin tightness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Urticaria
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    7
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    Back pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    7
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Myopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in jaw
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Abnormal weight gain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperlactacidaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    2

    More information

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

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

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