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    Clinical Trial Results:
    A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Study of Fostamatinib Disodium in the Treatment of Persistent/Chronic Immune Thrombocytopenic Purpura

    Summary
    EudraCT number
    		 2013-005453-76
    Trial protocol
    		 CZ   AT   ES   PL   BG  
    Global end of trial date
    31 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Sep 2021
    First version publication date
    25 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C-935788-048
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02076412
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigel Pharmaceuticals, Inc.
    Sponsor organisation address
    1180 Veterans Blvd, South San Francisco, CA, United States, 94080
    Public contact
    Clinical trials, Rigel Pharmaceuticals, Inc., +1 650-624-1100, clinicaltrials@rigel.com
    Scientific contact
    Clinical trials, Rigel Pharmaceuticals, Inc., +1 650-624-1100, clinicaltrials@rigel.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
    28 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to establish the efficacy of fostamatinib disodium (fostamatinib) as compared with placebo in achieving a stable platelet response in subjects with persistent/chronic immune thrombocytopenic purpura (ITP).
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    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)
    61
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 107 subjects were screened, 33 subjects failed screening (primarily they did not meet inclusion criteria or did meet one or more exclusion criterion), and the remaining 74 subjects were randomized, 50 to the fostamatinib group and 24 to the placebo group (ITT population).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fostamatinib Disodium
    Arm description
    		 Fostamatinib Disodium tablet 100 mg or 150 mg PO bid (morning and evening) over the course of 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostamatinib Disodium
    Investigational medicinal product code
    Other name
    R935788, R788, Fostamatinib
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fostamatinib Disodium tablet 100 mg or 150 mg PO bid (morning and evening) over the course of 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet PO bid (morning and evening) over the course of 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet PO bid (morning and evening)

    Number of subjects in period 1
    		Fostamatinib Disodium Placebo
    Started
    50
    24
    Completed
    13
    2
    Not completed
    37
    22
         Consent withdrawn by subject
    1
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    2
    2
         Lack of efficacy
    33
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fostamatinib Disodium
    Reporting group description
    		 Fostamatinib Disodium tablet 100 mg or 150 mg PO bid (morning and evening) over the course of 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet PO bid (morning and evening) over the course of 24 weeks.

    Reporting group values
    		 Fostamatinib Disodium Placebo Total
    Number of subjects
    		 50 24 74
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.1 ( 15.2 ) 49.5 ( 16.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 31 13 44
        Male
    		 19 11 30

    End points

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    End points reporting groups
    Reporting group title
    Fostamatinib Disodium
    Reporting group description
    		 Fostamatinib Disodium tablet 100 mg or 150 mg PO bid (morning and evening) over the course of 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet PO bid (morning and evening) over the course of 24 weeks.

    Primary: Number of Participants With Stable Platelet Response of at Least 50,000/µL

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    End point title
    		 Number of Participants With Stable Platelet Response of at Least 50,000/µL
    End point description
    Stable platelet response by Week 24 defined as a platelet count of at least 50,000/µL on at least 4 of the 6 visits between Weeks 14-24
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    50
    24
    Units: Number of Participants With Stable Plate
    9
    1
    Statistical analysis title
    		 Statistical Analysis for Primary Outcome
    Comparison groups
    Fostamatinib Disodium v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1519
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    13.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 27.1

    Secondary: Number of Participants With Platelet Count ≥ 50,000/µL at Week 12

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    End point title
    		 Number of Participants With Platelet Count ≥ 50,000/µL at Week 12
    End point description
    Platelet Count ≥ 50,000/µL at Week 12
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    50
    24
    Units: Number of Participants With Platelet Cou
    12
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With Platelet Count ≥ 50,000/µL at Week 24

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    End point title
    		 Number of Participants With Platelet Count ≥ 50,000/µL at Week 24
    End point description
    Platelet Count ≥ 50,000/µL at Week 24
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    50
    24
    Units: Number of Participants With Platelet Cou
    8
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Platelet Count ≥ 30,000/μL and at Least 20,000/μL Above Baseline at Week 12

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    End point title
    		 Number of Participants With Platelet Count ≥ 30,000/μL and at Least 20,000/μL Above Baseline at Week 12
    End point description
    Among subjects with a baseline platelet count < 15,000/μL, achievement of a count ≥ 30,000/μL and at least 20,000/μL above baseline at Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    22
    9
    Units: Number of Participants With Platelet Cou
    6
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Platelet Count ≥ 30,000/μL and at Least 20,000/μL Above Baseline at Week 24

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    End point title
    		 Number of Participants With Platelet Count ≥ 30,000/μL and at Least 20,000/μL Above Baseline at Week 24
    End point description
    Among subjects with a baseline platelet count < 15,000/μL, achievement of a count ≥ 30,000/μL and at least 20,000/μL above baseline at Week 24
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    22
    9
    Units: Number of Participants With Platelet Cou
    3
    0
    No statistical analyses for this end point

    Secondary: Frequency and Severity of Bleeding According to the ITP Bleeding Score (IBLS)

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    End point title
    		 Frequency and Severity of Bleeding According to the ITP Bleeding Score (IBLS)
    End point description
    The ITP Bleeding Scale (IBLS) is an immune thrombocytopenic purpura (ITP)-specific bleeding score used to analyze the correlation of clinical and laboratory platelet variables with bleeding. The IBLS comprises of 11 grades from 0 (none) to 2 (marked bleeding) by history over the previous week or by exam; 2 being worse. These 11 grades include: skin by physical exam, oral by physical exam, skin by history, oral by history, epistaxis, gastrointestinal, urinary, gynecological, pulmonary, intracranial hemorrhage, and subconjunctival hemorrhage. After each grade is scored, the mean value for all 11 grades is calculated (lowest score being 0 and highest score being 2) for each subject visit. LOCF method was used to impute any missing data. The mean of the IBLS scores across visits during the 24-week treatment period was summarized by treatment group using descriptive statistics. A 2-sided, 2-sample t-test was used to test for a difference in means between treatments for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    50
    24
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.04 ( 0.08 )
    0.06 ( 0.07 )
    Statistical analysis title
    		 Statistica Analysis for ITP Bleeding Score
    Comparison groups
    Placebo v Fostamatinib Disodium
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4927 [1]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.02
    Notes
    [1] - P-value from a two-sided two-sample t-test, testing for a difference in means between fostamatinib and placebo.

    Secondary: Frequency and Severity of Bleeding According to the World Health Organization (WHO) Bleeding Scale

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    End point title
    		 Frequency and Severity of Bleeding According to the World Health Organization (WHO) Bleeding Scale
    End point description
    The World Health Organization (WHO) bleeding scale is a standardized grading scale created to measure the severity of bleeding. The scale is a clinical investigator-assessed five-point scale with a score range starting at the lowest 0=No bleeding, 1 = Petechiae, 2=Mild blood loss, 3=Gross blood loss, to the worse 4=Debilitating blood loss. The WHO bleeding scale is scored by history over the previous-week or by exam. After each grade is scored, the mean value is calculated (lowest score being 0 [no bleeding] to the highest score being 4 [debilitating blood loss]) for each visit. LOCF method was used to impute any missing data. The mean of the WHO bleeding scale across visits during the 24-week treatment period was summarized by treatment group using descriptive statistics. A 2-sided, 2-sample t-test was used to test for a difference in means between treatments for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Fostamatinib Disodium Placebo
    Number of subjects analysed
    50
    24
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.26 ( 0.38 )
    0.38 ( 0.47 )
    Statistical analysis title
    		 Statistica Analysis for WHO Bleeding Scale
    Comparison groups
    Fostamatinib Disodium v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2499 [2]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.09
    Notes
    [2] - P-value from a two-sided two-sample t-test, testing for a difference in means between fostamatinib and placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Adverse event reporting additional description
    One patient randomized to the placebo group was given the wrong treatment kit, and was treated with fostamatinib for 2 weeks. This patient's efficacy data were analyzed with the placebo arm, but his safety data were analyzed with the fostamatinib arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Fostamatinib Recipient
    Reporting group description
    		 Fostamatinib (100 mg PO bid or 150 mg PO bid)

    Reporting group title
    Placebo Recipient
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Fostamatinib Recipient Placebo Recipient
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 51 (9.80%)
    6 / 23 (26.09%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Muscle rupture
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 23 (13.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 23 (4.35%)
         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
    		 Fostamatinib Recipient Placebo Recipient
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 51 (68.63%)
    15 / 23 (65.22%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    4
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 51 (13.73%)
    3 / 23 (13.04%)
         occurrences all number
    7
    4
    Haematoma
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 23 (13.04%)
         occurrences all number
    4
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 51 (17.65%)
    3 / 23 (13.04%)
         occurrences all number
    15
    3
    Nausea
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 23 (13.04%)
         occurrences all number
    5
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    6 / 51 (11.76%)
    1 / 23 (4.35%)
         occurrences all number
    7
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 23 (4.35%)
         occurrences all number
    3
    1
    Petechiae
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 23 (4.35%)
         occurrences all number
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2014
    The protocol version 2.0 dated 08 April 2014 included the following main changes: • Revision of inclusion and exclusion criteria • Addition of D-dimer testing to Visit 1 • Clarification that subjects who require a washout period greater than 30 days should sign the informed consent form at a prescreening visit prior to beginning washout • Clarification that the Visit 3 SF-36 assessment would be administered after the Visit 2 assessments are complete in the event that Visit 2 and Visit 3 occur on the same day • Subjects who have a dose reduction to due adverse events may be allowed to have their dose re-escalated after the adverse event has resolved following consultation with the Medical Monitor • Removal of measurement of IgD and IgE levels.
    09 Dec 2014
    The protocol version 3.0 dated 09 December 2014 included the following main changes: • Revision of inclusion and exclusion criteria • Revision of washout requirements to clarify that subjects must discontinue all therapeutic agents, other than those allowed as ITP concomitant therapy • Clarification that subjects may continue the specific concurrent therapies for ITP that are allowed at study entry • Definition of requirements for the withdrawal visit assessments in order to facilitate smooth transition to Study C-935788-049, if applicable • Clarification that testing for D-dimer is only required for subjects that have a history of DVT.

    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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