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    Clinical Trial Results:
    A PHASE II PILOT STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY, PHARMACODYNAMICS AND PHARMACOKINETICS OF IDES IN ASYMPTOMATIC ANTIBODY-MEDIATED THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) PATIENTS WITH LOW ADAMTS13 ACTIVITY

    Summary
    EudraCT number
    		 2016-000249-30
    Trial protocol
    		 GB  
    Global end of trial date
    25 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2019
    First version publication date
    04 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15-HMedIdeS-08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02854059
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hansa Biopharma AB (former name Hansa Medical AB)
    Sponsor organisation address
    Scheelevägen 22, Lund, Sweden, 223 63
    Public contact
    Clinical Trials Information, Hansa Biopharma AB (former name Hansa Medical AB), clinicalstudyinfo@hansabiopharma.com
    Scientific contact
    Clinical Trials Information, Hansa Biopharma AB (former name Hansa Medical AB), clinicalstudyinfo@hansabiopharma.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
    02 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess safety and tolerability of single intravenous doses of IdeS in patients diagnosed with asymptomatic antibody-mediated thrombotic thrombocytopenic purpura (TTP) with low ADAMTS13 activity
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory requirements. An internal monitoring committee (IMC) at Hansa Biopharma AB (former name Hansa Medical AB) was established to review safety and tolerability data after the first 3 patients had been dosed and before potential dose escalation. Additionally, if at any time during the study, 2 or more patients had experienced a grade 3 (according to the common terminology criteria for adverse events [CTCAE] v 4.0) related adverse event (AE), the IMC had to be convened. Safety data (clinical chemistry, haematology, coagulation and AEs) collected up to and including day 14 was to be evaluated. Furthermore, efficacy data (ADAMTS13 activity, ADAMTS13 antibodies and CD19) were also planned to be evaluated by the IMC.
    Background therapy
    		 Patients received premedication with paracetamol, hydrocortisone and antihistamine before study drug infusions as well as a 2-week regimen of prophylactic antibiotics (penicillin V or alternatively ciprofloxacin in case of allergy to penicillin), starting pre-dose.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    23 Sep 2016
    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
    United Kingdom: 2
    Worldwide total number of subjects
    2
    EEA total number of subjects
    2
    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)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was a single centre study. 6 patients were planned: 3 patients to recieve 0.25 mg/kg of IdeS and a potential dose escalation to 0.5 mg/kg for additional 3 patients. Two patients were recruited between 25-Sep-2016 and 11-Nov-2016. The study ended prematurely 25-Jan-2017.

    Pre-assignment
    Screening details
    		 The study included adult patients diagnosed with acquired TTP with ADAMTS13 levels of ≤10% in clinical remission and with measurable or previously confirmed ADAMTS13 antibodies. 2 patients were included and completed the study. The study was discontinued prematurely as an non-favourable risk-benefit profile was observed in the first 2 patients.

    Pre-assignment period milestones
    Number of subjects started
    		 2
    Number of subjects completed
    		 2

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group 1 (overall trial)
    Arm description
    		 Single i.v. infusion of IdeS ( 0.25 mg/kg). After review of the initial results from the study that demonstrated a non-favourable risk-benefit profile in the first 2 patients who received single i.v. infusion of IdeS (0.25 mg/kg), the study was prematurely discontinued. The potential dose escalation to i.v. infusion of IdeS (0.5 mg/kg) did not occur.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IdeS
    Investigational medicinal product code
    IdeS
    Other name
    HMed-IdeS, IgG endopeptidase
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single 30-minute i.v. infusion of IdeS (0.25 mg/kg).

    Number of subjects in period 1
    		Group 1 (overall trial)
    Started
    2
    Completed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 2 2
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 2 2
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 1 1
    Race
    Units: Subjects
        Black or African American
    		 1 1
        White
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Group 1 (overall trial)
    Reporting group description
    		 Single i.v. infusion of IdeS ( 0.25 mg/kg). After review of the initial results from the study that demonstrated a non-favourable risk-benefit profile in the first 2 patients who received single i.v. infusion of IdeS (0.25 mg/kg), the study was prematurely discontinued. The potential dose escalation to i.v. infusion of IdeS (0.5 mg/kg) did not occur.

    Primary: Safety assessed as Adverse Events

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    End point title
    		 Safety assessed as Adverse Events [1]
    End point description
    Data on AEs were obtained if spontaneously reported by the patient, if reported in response to an open question from the study personnel or if revealed by observation. A treatment emergent AE (TEAE) was defined as any AE occurring after administration of the IMP and within the time of the residual drug effect period (i.e. 30 days after IMP administration). Severity was graded based on CTCAE version 4.0.
    End point type
    Primary
    End point timeframe
    AEs were collected from subject signing the ICF until end of study visit, incl the follow-up period (=Day 64). AEs reported in EudraCT include TEAEs and post-treatment AEs, i.e. all AEs occurring after admin of the IMP until end of study.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Because of the premature termination of the study and since the sponsor will no longer pursue the indication, the analyses as described in the protocol were not performed. Instead, data collected for the 2 enrolled subjects were listed and presented graphically.
    End point values
    		 Group 1 (overall trial)
    Number of subjects analysed
    2
    Units: Adverse events
        TEAEs
    10
        Mild TEAEs (Grade=1)
    7
        Moderate TEAEs (Grade=2)
    1
        Severe TEAEs (Grade=3)
    1
        Life-threatening TEAEs (Grade=4)
    1
        Related TEAEs
    4
        Serious TEAEs
    2
        Post-TEAEs
    2
        Mild Post-TEAE (Grade=1)
    1
        Moderate Post-TEAE (Grade=2)
    1
        Related Post-TEAEs
    0
        Serious Post-TEAEs
    2
    No statistical analyses for this end point

    Secondary: Change from baseline in ADAMTS13 activity

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    End point title
    		 Change from baseline in ADAMTS13 activity
    End point description
    ADAMTS13 is an enzyme which is inhibited in patients with TTP. The efficacy of IdeS on ADAMTS13 activity was measured througout the study as change from baseline.
    End point type
    Secondary
    End point timeframe
    From day of dosing until end of follow up on day 64.
    End point values
    		 Group 1 (overall trial)
    Number of subjects analysed
    2
    Units: Participants
        Change in activity at any time after IdeS
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in ADAMTS13 Antibody Levels (IgG and F(ab’)2)

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    End point title
    		 Change From Baseline in ADAMTS13 Antibody Levels (IgG and F(ab’)2)
    End point description
    The efficacy of IdeS on ADAMTS13 antibody cleaving was measured througout the study as change from baseline in ADAMTS13 antibody concentration.
    End point type
    Secondary
    End point timeframe
    From day of dosing until end of follow up on day 64
    End point values
    		 Group 1 (overall trial)
    Number of subjects analysed
    2
    Units: Participants
        ≥90% decrease 2-24h after IdeS
    2
    No statistical analyses for this end point

    Secondary: Time for ADAMTS13 Activity to Return to Normal Levels

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    End point title
    		 Time for ADAMTS13 Activity to Return to Normal Levels
    End point description
    The ADAMTS13 activity in TTP patients is decreased. The efficacy of IdeS on ADAMTS13 activity was assessed throughout the study to identify the time-point of return to normal levels.
    End point type
    Secondary
    End point timeframe
    From day of dosing until end of follow up on day 64
    End point values
    		 Group 1 (overall trial)
    Number of subjects analysed
    2
    Units: Participants
        Normal activity any time after IdeS
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pharmacodynamics as Measured by Level of IgG

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    End point title
    		 Change From Baseline in Pharmacodynamics as Measured by Level of IgG
    End point description
    IdeS cleaves IgG molecules. The concentration of uncleaved IgG in the patient's serum was measured throughout the study to determine change from baseline following IdeS administration.
    End point type
    Secondary
    End point timeframe
    From day of dosing until end of follow up on day 64
    End point values
    		 Group 1 (overall trial)
    Number of subjects analysed
    2
    Units: Patients
        ≥90% decrease 2-24h after IdeS
    2
        ≥90% decrease 3d after IdeS
    1
        ≥90% decrease 7-64d after IdeS
    0
    No statistical analyses for this end point

    Secondary: Immunogenicity of IdeS by Measuring Anti-drug Antibodies

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    End point title
    		 Immunogenicity of IdeS by Measuring Anti-drug Antibodies
    End point description
    Most humans have been infected with S. pyogenes which is the origin of IdeS. It was therefore expected that patients in this study might have antibodies against IdeS before being exposed to IdeS in the study. The concentration of ant-IdeS antibodies was measured before dosing and throughout the study.
    End point type
    Secondary
    End point timeframe
    From day of dosing until end of follow up on day 64
    End point values
    		 Group 1 (overall trial)
    Number of subjects analysed
    2
    Units: Participants
        Presence of anti-IdeS before IdeS
    2
        Elevated anti-IdeS at day 64
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from subject signing the ICF until end of study visit, incl the follow-up period (=Day 64). AEs reported in EudraCT include TEAEs and post-treatment AEs, i.e. all AEs occurring after admin of the IMP until end of study
    Adverse event reporting additional description
    Data on AEs were obtained if spontaneously reported by the patient, if reported in response to an open question from the study personnel or if revealed by observation. A treatment emergent AE (TEAE) was defined as any AE occurring after administration of the IMP and within the time of the residual drug effect period (i.e. 30 days after IMP adminis
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Group 1 (overall trial)
    Reporting group description
    		 Single i.v. infusion of 0.25 mg IdeS/kg body weight. Initially 3 patients receiving a dose of 0.25 mg/kg body weight of IdeS and after safety evaluation, a potential dose escalation to 0.5 mg/kg for the remaining 3 patients. The study was terminated early by the sponsor following a review of the initial results from the study that demonstrated a non-favourable risk-benefit profile in the first 2 patients.

    Serious adverse events
    		 Group 1 (overall trial)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Serum sickness
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1 (overall trial)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 Jan 2017
    After an internal review of initial results from the study in December 2016, it was decided that the study would be discontinued since a non-favourable risk-benefit profile was observed in the first 2 patients. Although IdeS effectively cleaved IgG antibodies, including a transient reduction in the anti-ADAMTS13 antibodies, an effect on ADAMTS13 enzyme activity was not demonstrated. Thus, the two unexpected events of serum sickness observed caused an overall non-favourable risk-benefit profile for treatment with IdeS in patients with antibody-mediated asymptomatic TTP. The study 15-HMedIdeS-08 was therefore discontinued on 25 Jan 2017 (date of last patient last visit).
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Because of premature study termination and since the sponsor will no longer pursue the indication, the analyses as described in the protocol were not performed. Instead, data collected for the 2 enrolled subjects were listed and presented graphically
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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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