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    Clinical Trial Results:
    A Phase II single blind, randomized, placebo controlled trial to study the efficacy and safety of anti-von Willebrand factor Nanobody administered as adjunctive treatment to patients with acquired thrombotic thrombocytopenic purpura.

    Summary
    EudraCT number
    2010-019375-30
    Trial protocol
    BE   AT   GB   DE   IT   ES  
    Global end of trial date
    14 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Mar 2016
    First version publication date
    24 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALX-0681-2.1/10
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01151423
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ablynx
    Sponsor organisation address
    Technologiepark 21, Zwijnaarde, Belgium, B-9052
    Public contact
    Medical Monitor, Ablynx, 32 9262 0000, clinicaltrials@ablynx.com
    Scientific contact
    Medical Monitor, Ablynx, 32 9262 0000, clinicaltrials@ablynx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001157-PIP01-11
    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
    09 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to measure the reduction of time-to-response, defined by the achievement of laboratory blood marker response (platelets), confirmed at 48 hours after the initial reporting of this response (platelets ≥ 150,000/µL and lactate dehydrogenase [LDH] ≤ 2 x ULN).
    Protection of trial subjects
    Only subjects who met all the study inclusion and none of the exclusion criteria were to be randomised to trial treatment. All subjects were free to withdraw from the clinical trial at any time for any reason. Close monitoring of all subjects was adhered to throughout the trial conduct. An independent DSMB monitored accruing safety data during the study (SAEs on an ongoing basis and an ‘early safety look’, per protocol, when 16 subjects, 8 ALX-0081-treated and 8 placebo-treated, had completed treatment with study drug). Based on the ‘early safety look’, the DSMB recommended to the Sponsor that the study continue with no changes to the Protocol. An interim analysis for safety with formal stopping rules was performed when 28 of the ALX-0081 treated subjects had been treated and assessed. Upon review of the interim safety analysis, the DSMB made the recommendation to continue the study with no changes to the protocol. The procedures and responsibilities for the collection, analysis, and review of the data by the DSMB as well as communication and documentation of their opinions and recommendations were defined in the DSMB charter.
    Background therapy
    Subjects received the standard of care and treatment judged appropriate by the Investigator at each site and according to site guidelines for treatment of Thrombotic Thrombocytopenic Purpura (TTP). The principal treatment for acquired TTP was daily plasma exchange (PE). Discontinuation of daily PE depended on normalisation of platelet count, neurological status and other clinical and laboratory parameters. Though not recommended per this protocol, at the discretion of the investigator, the frequency of PE could be tapered rather than stopped completely at the time of platelet count normalisation. Additional treatment was variable depending on local standard practice and could include adjunctive immunosuppressive treatment (e.g., corticosteroids, rituximab).
    Evidence for comparator
    There are currently no specifically approved therapeutics for TTP. Therefore, no active comparator agents are available and a placebo controlled design was used. All subjects received standard care during the study.
    Actual start date of recruitment
    07 Jan 2011
    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
    Switzerland: 3
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Australia: 1
    Worldwide total number of subjects
    75
    EEA total number of subjects
    53
    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)
    73
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with acquired thrombotic thrombocytopenic purpura (TTP) were recruited from 11 countries in Europe, Australia, and US. Only adults were recruited; no adolescent patients were enrolled, although planned. A total of 75 patients were included in the trial.

    Pre-assignment
    Screening details
    76 subjects were screened, 75 subjects were randomized (= ITT population): 36 in the ALX-0081 group, 39 in the placebo group. Three subjects did not receive study drug: 1 subject in the ALX-0081 group (due to participation in another study) and 2 subjects in the placebo group (1 due to protocol violation, 1 due to pregnancy).

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    A single-blinded study design was initiated because the dosing regimen was dependent on the results of the Ristocetin Cofactor (RICO) test following the initial dose. Therefore, a double-blind design was not feasible because the results of the RICO test effectively unblinded the Investigator. Single-blind design was maintained due to the objective nature of the primary endpoint.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Caplacizumab
    Arm description
    Subjects received a first intravenous (i.v.) bolus of 10 mg caplacizumab via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of 10 mg study drug within 30 minutes after the end of the PE procedure.
    Arm type
    Experimental

    Investigational medicinal product name
    caplacizumab
    Investigational medicinal product code
    Other name
    ALX-0081, anti-von Willebrand factor (vWF) nanobody
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous bolus use , Subcutaneous use
    Dosage and administration details
    The first administration of caplacizumab was a single i.v. bolus of 10 mg (filled at 5 mg/mL) caplacizumb, administered by a push injection, 6 hours to 15 minutes prior to the initiation of plasma exchange (PE) on study, followed by s.c. administration within 30 minutes after the end of the PE procedure. All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. Subjects received caplacizumab up to 30 days after the last daily plasma exchange session.

    Arm title
    Placebo
    Arm description
    Subjects received a first intravenous (i.v.) bolus of placebo via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of placebo within 30 minutes after the end of the PE procedure.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous bolus use , Subcutaneous use
    Dosage and administration details
    The first administration of placebo was a single i.v. bolus, administered by a push injection, 6 hours to 15 minutes prior to the initiation of plasma exchange (PE) on study, followed by s.c. administration within 30 minutes after the end of the PE procedure. All subsequent study drug administrations were daily s.c. injections within 30 minutes after the end of the PE procedure (if applicable) or within 24 hours of the previous dose. Subjects received placebo up to 30 days after the last daily plasma exchange session.

    Number of subjects in period 1
    Caplacizumab Placebo
    Started
    36
    39
    Completed
    20
    21
    Not completed
    16
    18
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    3
         Physician decision
    1
    1
         Study terminated by sponsor for slow recruitment
    9
    10
         Adverse event, non-fatal
    3
    -
         Other
    1
    1
         Pregnancy
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Caplacizumab
    Reporting group description
    Subjects received a first intravenous (i.v.) bolus of 10 mg caplacizumab via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of 10 mg study drug within 30 minutes after the end of the PE procedure.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a first intravenous (i.v.) bolus of placebo via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of placebo within 30 minutes after the end of the PE procedure.

    Reporting group values
    Caplacizumab Placebo Total
    Number of subjects
    36 39 75
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    35 38 73
        From 65-84 years
    1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.6 ± 12.7 42.5 ± 13.2 -
    Gender categorical
    Units: Subjects
        Female
    24 20 44
        Male
    12 19 31
    Race
    Units: Subjects
        Caucasian
    32 34 66
        Black
    4 5 9

    End points

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    End points reporting groups
    Reporting group title
    Caplacizumab
    Reporting group description
    Subjects received a first intravenous (i.v.) bolus of 10 mg caplacizumab via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of 10 mg study drug within 30 minutes after the end of the PE procedure.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a first intravenous (i.v.) bolus of placebo via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of placebo within 30 minutes after the end of the PE procedure.

    Primary: 1. Time-to-response of treatment defined by a confirmed recovery of platelets ≥ 150,000/µL

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    End point title
    1. Time-to-response of treatment defined by a confirmed recovery of platelets ≥ 150,000/µL
    End point description
    Time-to-response, defined by the achievement of platelet count response, confirmed at 48 hours after the initial reporting of this response. Platelet response was defined as recovery of platelets ≥ 150,000/μL. This response had to be confirmed at 48 hours after the initial reporting of platelet recovery ≥ 150,000/μL by a de novo measure of platelets ≥ 150,000/μL and LDH ≤2 x ULN (i.e., ‘confirmed platelet response’).
    End point type
    Primary
    End point timeframe
    From the day of first study drug administration up to 30 days after first study drug administration.
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [1]
    39 [2]
    Units: day
    median (confidence interval 95%)
        YES - One PE Session Prior to Randomisation
    2.4 (1.9 to 3)
    4.3 (2.9 to 5.7)
        NO - No PE Session Prior to Randomisation
    3 (2.7 to 3.9)
    4.9 (3.2 to 6.6)
    Notes
    [1] - Intent-to-treat population
    [2] - Intent-to-treat population
    Statistical analysis title
    Stratified log-rank test; time-to-response
    Statistical analysis description
    The primary analysis consisted of a Kaplan-Meier analysis with time-to-response as endpoint and treatment group as the independent variable and stratified for absence/presence of one PE session prior to randomisation. Caplacizumab was compared to placebo using a one-sided log-rank test in order to assess superiority at 2.5% significance level. The HR was estimated from a Cox proportional Hazards regression model with presence(yes)/absence(no) of 1 PE session prior to randomisation as covariate
    Comparison groups
    Caplacizumab v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [3]
    Method
    Stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.28
         upper limit
    3.78
    Notes
    [3] - p-value from the stratified log-rank test is based on an analysis stratified for presence (YES)/absence (NO) of one plasma exchange (PE) session prior to randomisation.

    Secondary: 2. Proportion of subjects with complete remission following initial daily PE

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    End point title
    2. Proportion of subjects with complete remission following initial daily PE
    End point description
    Proportion of subjects with complete remission (defined as confirmed platelet response and absence of exacerbation) following initial daily plasma exchange
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 30 days after stop of the study drug treatment.
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [4]
    39 [5]
    Units: Subjects
    29
    18
    Notes
    [4] - Intent-to-treat population
    [5] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: 3. Proportion of subjects with exacerbations of TTP

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    End point title
    3. Proportion of subjects with exacerbations of TTP
    End point description
    Proportion of subjects with exacerbations of TTP (defined as recurrent thrombocytopenia following a confirmed platelet response and requiring a re-initiation of daily PE treatment after ≥ 1 day but ≤ 30 days of no daily PE treatment. Time to first exacerbation of TTP was also examined as part of this end point analysis; the median time to first exacerbation could not be determined because of the small number of events.
    End point type
    Secondary
    End point timeframe
    Within 30 days of last day of initial daily PE
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [6]
    39 [7]
    Units: Subjects
    3
    11
    Notes
    [6] - Intent-to-treat population
    [7] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: 4. Proportion of subjects with relapse of TTP

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    End point title
    4. Proportion of subjects with relapse of TTP
    End point description
    The proportion of subjects with relapse of TTP (defined as de novo TTP event that occurred later than 30 days after the last daily PE) was evaluated.
    End point type
    Secondary
    End point timeframe
    Later than 30 days after the last daily PE
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [8]
    39 [9]
    Units: Subjects
    11
    3
    Notes
    [8] - Intent-to-treat population
    [9] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: 5a. Number of daily plasma exchange (PE) sessions during the initial daily plasma exchange period

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    End point title
    5a. Number of daily plasma exchange (PE) sessions during the initial daily plasma exchange period
    End point description
    Number of daily plasma exchange sessions during the initial daily plasma exchange (PE) period which could include more than 1 PE per day was evaluated.
    End point type
    Secondary
    End point timeframe
    During the initial daily plasma exchange (PE) period
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [10]
    37 [11]
    Units: PE sessions
        arithmetic mean (standard deviation)
    6.7 ± 3.69
    8.4 ± 6.74
    Notes
    [10] - Number of subjects from the Intent-to-treat population, with data available.
    [11] - Number of subjects from the Intent-to-treat population, with data available.
    No statistical analyses for this end point

    Secondary: 5b. Total volume of plasma administered during the initial daily PE period

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    End point title
    5b. Total volume of plasma administered during the initial daily PE period
    End point description
    The total volume of plasma administered during the initial daily PE period was measured
    End point type
    Secondary
    End point timeframe
    During the initial daily PE period
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    34 [12]
    37 [13]
    Units: mL
        arithmetic mean (standard deviation)
    22481.8 ± 15914.85
    28358.4 ± 21344.16
    Notes
    [12] - Number of subjects from the intent-to-treat population, with data available.
    [13] - Number of subjects from the intent-to-treat population, with data available.
    No statistical analyses for this end point

    Secondary: 5c. Number of days with at least one PE administration during the total course of the study

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    End point title
    5c. Number of days with at least one PE administration during the total course of the study
    End point description
    Number of days for plasma exchange was evaluated. This implies the number of days with at least one PE administration during the total course of the study.
    End point type
    Secondary
    End point timeframe
    During the total course of the study
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [14]
    37 [15]
    Units: day
        arithmetic mean (standard deviation)
    11.8 ± 7.43
    12.6 ± 9.15
    Notes
    [14] - Number of subjects from the intent-to-treat population, with data available.
    [15] - Number of subjects from the intent-to-treat population, with data available.
    No statistical analyses for this end point

    Secondary: 5d. The maximum number of consecutive days per subject where there was no interruption of PE during the initial daily PE period

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    End point title
    5d. The maximum number of consecutive days per subject where there was no interruption of PE during the initial daily PE period
    End point description
    The maximum number of consecutive days per subject of PE where there was no interruption of PE during the initial daily PE period.
    End point type
    Secondary
    End point timeframe
    During the initial daily PE period
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [16]
    37 [17]
    Units: day
        arithmetic mean (standard deviation)
    6.6 ± 3.35
    8.1 ± 6.46
    Notes
    [16] - Number of subjects from the intent-to-treat population, with data available.
    [17] - Number of subjects from the intent-to-treat population, with data available.
    No statistical analyses for this end point

    Secondary: 6. Resolution of non-focal neurological symptoms

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    End point title
    6. Resolution of non-focal neurological symptoms
    End point description
    Resolution of non-focal neurological symptoms as defined by neurocognitive function at complete remission, measured by a neurocognitive test battery (adults only). The CNTB was completed by a low proportion of subjects with baseline data available only for 3 subjects in the caplacizumab and 4 subjects in the placebo group. Therefore, the results obtained are not considered representative of the overall study population and an analysis was not performed.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Subjects
    Notes
    [18] - Analysis was not performed, see also end point description
    [19] - Analysis was not performed, see also end point description
    No statistical analyses for this end point

    Secondary: 7. Resolution of TTP-related signs or symptoms

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    End point title
    7. Resolution of TTP-related signs or symptoms
    End point description
    Resolution or improvement (improvement of ≥ 1 grade in the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 scale) of TTP-related signs and symptoms as captured on physical examination and as adverse events. This endpoint was only evaluated for “resolution".
    End point type
    Secondary
    End point timeframe
    End of daily PE treatment period, end of study treatment period and at 1 month follow-up.
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [20]
    39 [21]
    Units: Subjects
        End of daily PE treatment period
    29
    29
        End of study treatment period
    30
    33
        At 1 month follow-up
    31
    27
    Notes
    [20] - Intent-to-treat population.
    [21] - Intent-to-treat population.
    No statistical analyses for this end point

    Secondary: 8. Mortality

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    End point title
    8. Mortality
    End point description
    Total mortality up to 1 month follow-up
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [22]
    39 [23]
    Units: Deaths
    0
    2
    Notes
    [22] - Intent-to-treat population
    [23] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: 9a. Number of plasma exchange (PE) related adverse events

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    End point title
    9a. Number of plasma exchange (PE) related adverse events
    End point description
    Number of plasma exchange (PE) treatment-related adverse events (AE)
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [24]
    39 [25]
    Units: Adverse event
    72
    44
    Notes
    [24] - Intent-to-treat population
    [25] - Intent-to-treat population.
    No statistical analyses for this end point

    Secondary: 9b. Number of subjects with plasma exchange related adverse events

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    End point title
    9b. Number of subjects with plasma exchange related adverse events
    End point description
    Number of subjects with plasma exchange (PE) related adverse events (AE)
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    36 [26]
    39 [27]
    Units: Adverse events
    20
    20
    Notes
    [26] - Intent-to-treat population
    [27] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: 10a. Number of treatment-emergent adverse events by severity

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    End point title
    10a. Number of treatment-emergent adverse events by severity
    End point description
    Number and severity of treatment-emergent adverse events (AEs) were evaluated. The severity grades of AEs were defined as: mild, moderate, severe. Note: the numbers listed do not include the treatment-emergent adverse events with missing severity
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [28]
    37 [29]
    Units: Adverse event
        Mild
    348
    299
        Moderate
    154
    173
        Severe
    37
    23
    Notes
    [28] - Safety population
    [29] - Safety population
    No statistical analyses for this end point

    Secondary: 10b. Number of subjects with treatment-emergent adverse events by severity

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    End point title
    10b. Number of subjects with treatment-emergent adverse events by severity
    End point description
    Number of subjects with treatment-emergent adverse events (AEs) by severity. The severity grades of AEs were defined as: mild, moderate, severe.
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [30]
    37 [31]
    Units: Subject
        Mild
    31
    36
        Moderate
    27
    31
        Severe
    18
    14
    Notes
    [30] - Safety population
    [31] - Safety population
    No statistical analyses for this end point

    Secondary: 10c. Number of treatment-emergent adverse events and their relationship to study drug

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    End point title
    10c. Number of treatment-emergent adverse events and their relationship to study drug
    End point description
    Number of treatment-emergent AEs and their relationship to study drug were evaluated. Relationship of AEs to study drug was: related, possibly related, unlikely/not related.
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [32]
    37 [33]
    Units: Adverse events
        Related
    12
    6
        Possibly related
    59
    9
        Unlikely/Not related
    486
    524
    Notes
    [32] - Safety population
    [33] - Safety population
    No statistical analyses for this end point

    Secondary: 11. Immunogenicity

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    End point title
    11. Immunogenicity
    End point description
    The development of anti-drug antibodies was monitored from the start of the study until last follow-up visit.
    End point type
    Secondary
    End point timeframe
    From the start of the study until last follow-up visit.
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    32 [34]
    30 [35]
    Units: subjects
    3
    0
    Notes
    [34] - Number of subjects from the Safety population with data available
    [35] - Number of subjects from the Safety population with data available
    No statistical analyses for this end point

    Secondary: 12a. Pharmacokinetics

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    End point title
    12a. Pharmacokinetics
    End point description
    The concentration of caplacizumab in plasma was determined at different time points. PK Population: The PK Population consisted of all subjects who received the study drug and for whom the primary PK data are considered to be sufficient and interpretable.
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [36]
    0 [37]
    Units: ng/mL
    arithmetic mean (standard error)
        Baseline
    100 ± 0
    ±
        Day 1 of daily PE, 5 – 10 min postdose
    1765.9 ± 185.04
    ±
        Day 1 of daily PE, 3 - 6 hours postdose
    450.4 ± 36.15
    ±
        Day 1 of daily PE, 8 - 24 hours postdose
    562 ± 36.8
    ±
        Day 2 of daily PE, predose
    288 ± 24.05
    ±
        Day 2 of daily PE, 1 – 6 hrs postdose
    415.8 ± 24.75
    ±
        Day 2 of daily PE, 6 – 12 hrs postdose
    570.7 ± 52.22
    ±
        Day 2 of daily PE, 18 – 24 hrs postdose
    489.3 ± 32.54
    ±
        Last day of daily PE, predose
    348.4 ± 38.32
    ±
        Day 1 after daily PE
    521.9 ± 31.52
    ±
        Week 1 after daily PE
    490.6 ± 36.11
    ±
        Week 2 after daily PE
    524.9 ± 39.37
    ±
        Week 3 after daily PE
    499.6 ± 35.1
    ±
        Week 4 after daily PE
    503.4 ± 31.21
    ±
        Day 3 of follow-up period
    346.7 ± 25.43
    ±
        Day 7 of follow-up period
    162.3 ± 20.2
    ±
        1 month follow-up
    100 ± 0
    ±
    Notes
    [36] - PK population
    [37] - No PK data were generated for the subjects in the placebo group
    No statistical analyses for this end point

    Secondary: 12b. Pharmacodynamics: Ristocetin cofactor (RICO) activity over time

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    End point title
    12b. Pharmacodynamics: Ristocetin cofactor (RICO) activity over time
    End point description
    The change from baseline in ristocetin cofactor (RICO) activity was measured at different time points
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [38]
    37 [39]
    Units: Percentage
    arithmetic mean (standard deviation)
        Baseline
    76.2 ± 4.95
    82.1 ± 3.76
        Day 1 of daily PE, post dose
    16.2 ± 0.72
    84.4 ± 6.09
        Day 2 of daily PE, post dose
    21.4 ± 3.64
    94.4 ± 3.69
        Last day of daily PE, post dose
    15.4 ± 0.39
    118.2 ± 1.78
        Day 1 after daily PE
    19.2 ± 3.94
    105.2 ± 4.31
        Week 1 after daily PE
    15 ± 0
    107.3 ± 3.05
        Week 2 after daily PE
    18.9 ± 2.87
    109.2 ± 2.8
        Week 3 after daily PE
    17.4 ± 2.34
    104 ± 3.46
        Week 4 after daily PE
    15.1 ± 0.07
    105.5 ± 3.59
        Day 3 of follow-up period
    42.3 ± 6.33
    99.1 ± 4.56
        Day 7 of follow-up period
    88.3 ± 4.99
    99.7 ± 4.06
        1 month follow-up
    94.6 ± 3.78
    94.7 ± 5.35
    Notes
    [38] - Safety population
    [39] - Safety population
    No statistical analyses for this end point

    Secondary: 12c. Pharmacodynamics: vWF:Ag over time

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    End point title
    12c. Pharmacodynamics: vWF:Ag over time
    End point description
    The change from baseline in vWF:Ag concentration was measured at different time points.
    End point type
    Secondary
    End point timeframe
    From the start of the study drug up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [40]
    37 [41]
    Units: Percentage
    arithmetic mean (standard deviation)
        Baseline
    185.1 ± 15.09
    204.4 ± 14.52
        Day 1 of daily PE, post dose
    120.6 ± 7.98
    166.6 ± 9.24
        Day 2 of daily PE, post dose
    94.6 ± 4.83
    140.2 ± 6.16
        Last day of daily PE, post dose
    93.6 ± 6.01
    151.2 ± 14.25
        Day 1 after daily PE
    86.2 ± 6.15
    166 ± 10.05
        Week 1 after daily PE
    93.4 ± 6.4
    234.9 ± 20.91
        Week 2 after daily PE
    115.9 ± 12.42
    242.6 ± 19.43
        Week 3 after daily PE
    102.4 ± 6.45
    224.2 ± 18.62
        Week 4 after daily PE
    100.1 ± 5
    204.3 ± 17.08
        Day 3 of follow-up period
    137.8 ± 9.32
    184.1 ± 13.89
        Day 7 of follow-up period
    190.2 ± 12.9
    190.3 ± 14.81
        1 month follow-up
    176.3 ± 15.63
    167.2 ± 15.46
    Notes
    [40] - Safety population
    [41] - Safety population
    No statistical analyses for this end point

    Secondary: 12d. Pharmacodynamics: Coagulation Factor VIII:C over time

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    End point title
    12d. Pharmacodynamics: Coagulation Factor VIII:C over time
    End point description
    The change from baseline in Factor VIII clotting activity concentration was measured at different time points.
    End point type
    Secondary
    End point timeframe
    From the start of the study up to 1 month follow-up
    End point values
    Caplacizumab Placebo
    Number of subjects analysed
    35 [42]
    37 [43]
    Units: percentage
    arithmetic mean (standard deviation)
        Baseline
    144.18 ± 11.14
    156.8 ± 12.54
        Day 1 of daily PE, post dose
    104 ± 6.95
    149 ± 9.16
        Day 2 of daily PE, post dose
    90.7 ± 5.49
    152.9 ± 9.41
        Last day of daily PE, post dose
    102.4 ± 10.91
    169.5 ± 17.79
        Day 1 after daily PE
    116.3 ± 13.33
    234.2 ± 16.05
        Week 1 after daily PE
    116.4 ± 11.73
    296.8 ± 26.07
        Week 2 after daily PE
    125.2 ± 16.88
    291.1 ± 18.25
        Week 3 after daily PE
    106.3 ± 9.7
    273.1 ± 20.35
        Week 4 after daily PE
    95.8 ± 6.09
    249.1 ± 18.27
        Day 3 of follow-up period
    146.3 ± 12.59
    227.7 ± 17.32
        Day 7 of follow-up period
    208.6 ± 15.54
    237.5 ± 15.65
        1 month follow-up
    212.2 ± 17.33
    200.1 ± 17.11
    Notes
    [42] - Safety population
    [43] - Safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For the entire study period and up to 12 months follow-up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Caplacizumab (active drug)
    Reporting group description
    Subjects received a first intravenous (i.v.) bolus of 10 mg caplacizumab via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of 10 mg study drug within 30 minutes after the end of the PE procedure.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a first intravenous (i.v.) bolus of placebo via push injection within 6 h to 15 min prior to the initiation of PE on study. The first plasma exchange (PE) on study could either be the very first PE session for the current episode of acquired TTP (if the subject was randomised prior to the initiation of PE) or the second PE session (if the subject was randomised after a single PE session). The first PE on study was followed by subcutaneous (s.c.) administration of 10 mg study drug within 30 minutes after the end of the PE procedure.

    Serious adverse events
    Caplacizumab (active drug) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 35 (57.14%)
    19 / 37 (51.35%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoantibody test
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Traumatic fracture
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    13 / 35 (37.14%)
    13 / 37 (35.14%)
         occurrences causally related to treatment / all
    2 / 16
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Caplacizumab (active drug) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 35 (94.29%)
    37 / 37 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    4 / 35 (11.43%)
    4 / 37 (10.81%)
         occurrences all number
    4
    4
    Hypertension
         subjects affected / exposed
    5 / 35 (14.29%)
    6 / 37 (16.22%)
         occurrences all number
    6
    7
    Phlebitis
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 37 (5.41%)
         occurrences all number
    3
    2
    Deep vein thrombosis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Hypotension
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 37 (5.41%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 35 (2.86%)
    6 / 37 (16.22%)
         occurrences all number
    1
    8
    Catheter site pain
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Chest pain
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    Fatigue
         subjects affected / exposed
    6 / 35 (17.14%)
    5 / 37 (13.51%)
         occurrences all number
    10
    6
    Injection site bruising
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Injection site haemorrhage
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 37 (2.70%)
         occurrences all number
    6
    1
    Local swelling
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Malaise
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 35 (11.43%)
    0 / 37 (0.00%)
         occurrences all number
    5
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 37 (8.11%)
         occurrences all number
    3
    5
    Pain
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    6 / 35 (17.14%)
    6 / 37 (16.22%)
         occurrences all number
    7
    6
    Chills
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    3
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Metrorrhagia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 35 (14.29%)
    2 / 37 (5.41%)
         occurrences all number
    6
    2
    Dyspnoea
         subjects affected / exposed
    4 / 35 (11.43%)
    4 / 37 (10.81%)
         occurrences all number
    5
    4
    Epistaxis
         subjects affected / exposed
    11 / 35 (31.43%)
    4 / 37 (10.81%)
         occurrences all number
    16
    8
    Oropharyngeal pain
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 37 (8.11%)
         occurrences all number
    3
    3
    Productive cough
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    3 / 35 (8.57%)
    5 / 37 (13.51%)
         occurrences all number
    3
    5
    Anxiety
         subjects affected / exposed
    4 / 35 (11.43%)
    5 / 37 (13.51%)
         occurrences all number
    5
    7
    Depression
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Disorientation
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Insomnia
         subjects affected / exposed
    5 / 35 (14.29%)
    5 / 37 (13.51%)
         occurrences all number
    5
    8
    Restlessness
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Sleep disorder
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Confusional state
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    3
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 37 (0.00%)
         occurrences all number
    5
    0
    Blood potassium decreased
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 37 (8.11%)
         occurrences all number
    2
    3
    Brain natriuretic peptide increased
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    2
    C-reactive protein increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Haptoglobin decreased
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Neutrophil count increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 37 (8.11%)
         occurrences all number
    3
    11
    White blood cell count increased
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    AST increased
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    2
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 37 (5.41%)
         occurrences all number
    8
    2
    Transfusion reaction
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 37 (5.41%)
         occurrences all number
    8
    3
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Cardiac disorder
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    Palpitations
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 37 (5.41%)
         occurrences all number
    3
    2
    Tachycardia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    6 / 35 (17.14%)
    3 / 37 (8.11%)
         occurrences all number
    6
    3
    Headache
         subjects affected / exposed
    11 / 35 (31.43%)
    10 / 37 (27.03%)
         occurrences all number
    19
    26
    Migraine
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0
    Paraesthesia
         subjects affected / exposed
    7 / 35 (20.00%)
    8 / 37 (21.62%)
         occurrences all number
    13
    14
    Syncope
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    4
    Transient ischaemic attack
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    3
    2
    Tremor
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    8 / 37 (21.62%)
         occurrences all number
    2
    34
    Leukocytosis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Neutrophilia
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    Vision blurred
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 37 (10.81%)
         occurrences all number
    3
    27
    Abdominal pain upper
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 37 (8.11%)
         occurrences all number
    3
    4
    Constipation
         subjects affected / exposed
    7 / 35 (20.00%)
    10 / 37 (27.03%)
         occurrences all number
    8
    10
    Diarrhoea
         subjects affected / exposed
    6 / 35 (17.14%)
    3 / 37 (8.11%)
         occurrences all number
    10
    3
    Dyspepsia
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 37 (2.70%)
         occurrences all number
    4
    1
    Gingival bleeding
         subjects affected / exposed
    5 / 35 (14.29%)
    2 / 37 (5.41%)
         occurrences all number
    6
    2
    Nausea
         subjects affected / exposed
    10 / 35 (28.57%)
    10 / 37 (27.03%)
         occurrences all number
    20
    12
    Paraesthesia oral
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 37 (2.70%)
         occurrences all number
    5
    1
    Vomiting
         subjects affected / exposed
    7 / 35 (20.00%)
    7 / 37 (18.92%)
         occurrences all number
    11
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    Ecchymosis
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Erythema
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    2
    Hyperhidrosis
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    Petechiae
         subjects affected / exposed
    4 / 35 (11.43%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0
    Pruritus
         subjects affected / exposed
    4 / 35 (11.43%)
    3 / 37 (8.11%)
         occurrences all number
    4
    5
    Rash
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 37 (10.81%)
         occurrences all number
    6
    4
    Urticaria
         subjects affected / exposed
    4 / 35 (11.43%)
    3 / 37 (8.11%)
         occurrences all number
    6
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 37 (5.41%)
         occurrences all number
    6
    2
    Muscle spasms
         subjects affected / exposed
    3 / 35 (8.57%)
    5 / 37 (13.51%)
         occurrences all number
    6
    7
    Musculoskeletal pain
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 37 (5.41%)
         occurrences all number
    3
    2
    Myalgia
         subjects affected / exposed
    7 / 35 (20.00%)
    1 / 37 (2.70%)
         occurrences all number
    8
    2
    Pain in extremity
         subjects affected / exposed
    5 / 35 (14.29%)
    7 / 37 (18.92%)
         occurrences all number
    7
    11
    Arthralgia
         subjects affected / exposed
    3 / 35 (8.57%)
    8 / 37 (21.62%)
         occurrences all number
    4
    11
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    3
    Influenza
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 37 (5.41%)
         occurrences all number
    3
    2
    Urinary tract infection
         subjects affected / exposed
    5 / 35 (14.29%)
    0 / 37 (0.00%)
         occurrences all number
    6
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 37 (5.41%)
         occurrences all number
    3
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    Fluid retention
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    5 / 37 (13.51%)
         occurrences all number
    3
    11
    Hypocalcaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         occurrences all number
    6
    2
    Hypokalaemia
         subjects affected / exposed
    9 / 35 (25.71%)
    8 / 37 (21.62%)
         occurrences all number
    18
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2010
    Protocol Version 3.0 dated 01 Oct 2010 - main changes: • updating the primary endpoint (from ‘reduction of time-to-recovery, defined by the achievement of laboratory blood marker response, confirmed at 48 hours after the initial reporting of this response’ to ‘time to response, based on the recovery of platelets ≥ 150,000/µL which must be confirmed at 48 hours after the initial reporting of platelet recovery ≥ 150,000/µL by a de novo measure of platelets ≥ 150,000/µL and LDH ≤ 2 x ULN’), • adding 2 exclusion criteria (known hypersensitivity to the active substance or to excipients of the study drug and severe liver impairment), • adjustment of time points for ECG measurements during the treatment phase • adding a paragraph on participation in concurrent clinical studies, • the use of an electronic diary was replaced by a nurse sheet and/or diary and additional time points for recuperating these documents were added.
    05 Apr 2011
    Protocol Version 5.0 dated 05 Apr 2011 - main changes: • change the description of the patient population (from ‘patients with a clinical diagnosis of TTP necessitating PE’ to ‘symptomatic patients with acute episodes of acquired TTP, requiring treatment with PE’), • to add a better description of how to interpret ‘clinically relevant bleeding’ (i.e., ‘moderate to severe [including life-threatening] bleeding requiring urgent medical and/or surgical intervention’) and • to rephrase actions to be taken in case of clinically relevant bleeding, to adjust the section on withdrawal of subjects from the study (to include pregnancy as reason for withdrawal and to note that subject withdrawal due to AEs were not to be replaced) • to add clarifications/specifications in several sections of the Study protocol (exclusion criteria, DSMB [summarize their function], study drug administration, management of overdose, allowed time windows for assessment, updated time points of lab assessments and dosing, AEs). • In case the FVIII:C assay was not available at the local laboratory, it could be replaced by an alternative method.
    21 Oct 2011
    Protocol Version 8.0 dated 21-Oct-2011 - main changes: • clarify wording on endpoints (i.e., add the words ‘confirmed platelet response’ to the primary endpoint description and rewording of secondary/tertiary endpoints), • add an exclusion criterion to exclude severe chronic renal impairment, • change the dosing schedule (dose increase based on local RICO measurements is no longer included), • to delete local RICO measurements from the schedule of assessments, • to note possibility of PE tapering (which although not recommended is also not precluded and resulting in a redefinition of different time intervals during treatment phase [relative to end of daily PE instead of hospital discharge]) • delete the PK/PD substudy (resulting in an adjustment of the PK/PD sampling schedule), • change the duration of hospitalisation, • to add clarifications/specifications in several sections (e.g., exclusion criteria [further clarification of liver impairment added], DSMB, handling of clinical relevant bleeding, the list of clinical outcome criteria for evaluation, PD criteria for evaluation, PE tapering, statistics).
    25 Sep 2012
    Protocol Version 10.0 dated 25-Sep-2012 - main changes: • to add clarifications for the case of TTP exacerbation and TTP relapse (definitions of exacerbations and relapses in the endpoints and objectives were clarified to ‘recurrent thrombocytopenia following a response and requiring a re-initiation of daily PE treatment after ≥ 1 day but ≤ 30 days after the last daily PE’ and ‘de novo event of TTP that occurs later than 30 days after the last daily PE”, respectively, relating to daily PE instead of “no PE treatment’) • clarifications on the timeframe of assessments in view of potential tapering of PE (which is not recommended per this protocol, but it is allowed if considered necessary by the Investigator) resulting in the fact that study drug administration is no longer coinciding with the 30 days post PE period for tapered subjects • to add more details on the planned statistical analysis • to add clarifications/specifications in several sections • the vWF multimers test was no longer to be performed
    25 Sep 2012
    Protocol Version 11.0 dated 25 Sep 2012 reflects the changes in Protocol Version 10.0 and in addition: • opening of the study to adolescents (12 to < 18 years), in line with the obligations and commitments outlined in EMA decision P/0060/2012, relating to PIP EMEA-001157-PIP01-11. Version 11.0 was created only in those centres where both the EC or IRB and the Investigator agreed to include adolescents. Affected sections include the synopsis, Introduction (e.g., safety/risk profile, rationale for dose selection), Trial design, Selection and Withdrawal of subjects, Study drug preparation and administration, Treatment, Study assessments and procedures, Statistical procedures, Patient information and consent/assent and Insurance/liability.
    24 Jun 2013
    Protocol Version 12.0 dated 24 Jun 2013: • revising the protocol to allow enrolment of subjects who have received one prior PE (within an acceptable time frame). (Protocol Version 13.0 also dated 24-Jun-2013 is based on protocol Version 11.0 and in addition reflects the changes in Protocol Version 12.0)

    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.
    Due to recruitment challenges, the study did not meet its enrollment target.
    For support, Contact us.
    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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