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    Clinical Trial Results:
    A single arm, two-stage, multi-centre, phase II clinical trial investigating the safety and activity of the use of BTT1023, a human monoclonal antibody targeting vascular adhesion protein (VAP-1), in the treatment of patients with primary sclerosing cholangitis (PSC)

    Summary
    EudraCT number
    		 2014-002393-37
    Trial protocol
    		 GB  
    Global end of trial date
    18 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2020
    First version publication date
    01 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_13-027
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11233255
    US NCT number
    		 NCT02239211
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CRCTU CAS number: HE2022, Sponsors RG Number: RG_13-027, Sponsors SAF number: ERN_13-1461
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Vincent Drive, Edgbaston, Birmingham, United Kingdom, B15 2TT
    Public contact
    BUTEO Trial Coordinator, University of Birmingham, +44 0121 371 8117, BUTEO@trials.bham.ac.uk
    Scientific contact
    BUTEO Trial Coordinator, University of Birmingham, +44 0121 371 8117, BUTEO@trials.bham.ac.uk
    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
    08 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1) To determine the activity of the anti-VAP-1 antibody BTT1023 in patients with PSC as measured by a decrease in ALP levels (primary endpoint) with secondary endpoints to include various measures of liver injury and fibrosis. 2) To evaluate the safety, effective dose and tolerability of BTT1023 in patients with PSC.
    Protection of trial subjects
    The trial was comprised of two components, an initial run-in period to confirm the therapeutic dose, which followed into a Phase II Simon’s two-stage design. Given the unpredictable nature of PSC and natural variation of ALP levels, a two-stage screening process over 4–7 weeks was incorporated into the trial, whereby the ALP levels must not vary by more than 25% between screening visit 1 and 2 in order to continue trial enrolment. Participants were all patients with a clinical diagnosis of PSC; this was established using recognised eligibility criteria. In order to comply with the Medicines for Human Use (Clinical Trials) Regulations 2004, an accurate record of all Adverse Events reported by Investigators were maintained throughout the trial.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 BTT1023 is a fully-human monoclonal IgG4 immunoglobulin with antigen-binding specificity for human VAP-1. BTT1023 blocks the leucocyte adhesion receptor VAP­1 which helps position inflammatory cells and activated myofibroblasts in areas of ongoing fibrogenesis in the liver. Inhibition of VAP­1  with BTT1023 is expected to impact fibrotic liver disease by reducing inflammatory cell  and activated fibroblast accumulation. Data from previous studies of RA and psoriasis patients supports the use of a therapeutic dose of 8 mg/kg which was well tolerated. BTT1023 was administered as repeated intravenous infusions at weekly to biweekly intervals up to a maximum of 7 consecutive doses at 8 mg/kg body weight over 11 weeks.
    Actual start date of recruitment
    02 Feb 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
    United Kingdom: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    21
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were invited to participate in the BUTEO trial from six NHS hospitals. Potential participants were identified directly by the trial Clinician and/or Research Nurse by using a variety of  methods i.e. hospital clinics, outpatient lists and patient referrals from other NHS hospitals. Recruitment ran between 08-Sep-2015 and 19-Jun-2018.

    Pre-assignment
    Screening details
    		 Screening including any non-standard of care assessments commenced following informed consent and prior to patient registration in order to confirm eligibility. Given the unpredictable nature of PSC and natural variation of ALP levels, a two-stage screening process over 4–7 weeks was incorporated into the trial.

    Pre-assignment period milestones
    Number of subjects started
    		 35 [1]
    Number of subjects completed
    		 23

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Change in ALP level between screening visits: 3
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Patient availability: 1
    Reason: Number of subjects
    		 Elevated ALK Phosphate: 1
    Reason: Number of subjects
    		 ALT levels high: 1
    Reason: Number of subjects
    		 Cholangitis (point 6 of exclusion criteria): 1
    Reason: Number of subjects
    		 Elevated Bilirubin: 1
    Reason: Number of subjects
    		 Parotid lump warranting oncology referral: 1
    Reason: Number of subjects
    		 Positive T-Spot test: 1
    Reason: Number of subjects
    		 On transplant list: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Pre-assignment patients were screened for eligibility, those who did not meet the eligibility criteria were not enrolled into the trial.
    Period 1
    Period 1 title
    Registration
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BTT1023
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BTT1023
    Investigational medicinal product code
    BTT1023
    Other name
    Timolumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BTT1023 was administered as repeated intravenous infusions at weekly to biweekly intervals up to a maximum of 7 consecutive 8 mg/kg doses, therefore the total dose received was 56 mg/kg by all patients in the trial.

    Number of subjects in period 1
    		BTT1023
    Started
    23
    Completed
    22
    Not completed
    1
         patient ineligible post registration
    1
    Period 2
    Period 2 title
    Treated Patients
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BTT1023
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BTT1023
    Investigational medicinal product code
    BTT1023
    Other name
    Timolumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BTT1023 was administered as repeated intravenous infusions at weekly to biweekly intervals up to a maximum of 7 consecutive 8 mg/kg doses, therefore the total dose received was 56 mg/kg by all patients in the trial.

    Number of subjects in period 2
    		BTT1023
    Started
    22
    Completed
    22
    Period 3
    Period 3 title
    Efficacy
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BTT1023
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BTT1023
    Investigational medicinal product code
    BTT1023
    Other name
    Timolumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BTT1023 was administered as repeated intravenous infusions at weekly to biweekly intervals up to a maximum of 7 consecutive 8 mg/kg doses, therefore the total dose received was 56 mg/kg by all patients in the trial.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Analysis will be carried out on a modified intention-to-treat basis in which only patients who have received at least one infusion at the confirmed dose of BTT1023 will be analysed.
    Number of subjects in period 3 [3]
    		BTT1023
    Started
    22
    Completed
    19
    Not completed
    3
         Consent withdrawn by subject
    2
         Missing one treatment visit
    1
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Analysis will be carried out on a modified intention-to-treat basis in which only patients who have received at least one infusion at the confirmed dose of BTT1023 will be analysed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Efficacy
    Reporting group description
    		 -

    Reporting group values
    		 Efficacy Total
    Number of subjects
    		 22 22
    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)
    		 20 20
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
        Adults
    		 0 0
        Adult
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 48 (38 to 51.7) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 18 18
    Ethnicity
    Units: Subjects
        Caucasian
    		 20 20
        South Asian
    		 2 2
    Alcohol Consumption
    Units: Subjects
        0 units
    		 7 7
        1-7 units
    		 12 12
        7-14 units
    		 2 2
        15-21
    		 1 1
        >22 units
    		 0 0
    Alcohol History
    Units: Subjects
        Have consumed alcohol
    		 4 4
        Never consumed alcohol
    		 1 1
        Not applicable
    		 15 15
        Missing
    		 2 2
    Cardiovascular Event
    Units: Subjects
        No
    		 14 14
        Yes
    		 8 8
    Myocardial Infarction
    Units: Subjects
        No
    		 7 7
        Yes
    		 0 0
        Not Applicable
    		 14 14
        Missing
    		 1 1
    Cerebrovascular Accident
    Units: Subjects
        No
    		 7 7
        Yes
    		 0 0
        Not Applicable
    		 14 14
        Missing
    		 1 1
    Peripheral Vascular Disease
    Units: Subjects
        No
    		 7 7
        Yes
    		 0 0
        Not Applicable
    		 14 14
        Missing
    		 1 1
    Hypertension
    Units: Subjects
        No
    		 5 5
        Yes
    		 2 2
        Not Applicable
    		 14 14
        Missing
    		 1 1
    Hyperlipidaemia
    Units: Subjects
        No
    		 7 7
        Yes
    		 0 0
        Not Applicable
    		 14 14
        Missing
    		 1 1
    Other Medical Condition
    Units: Subjects
        No
    		 0 0
        Yes
    		 8 8
        Missing
    		 0 0
        Not applicable
    		 14 14
    Current Symptoms of Primary Sclerosing Cholangistis
    Current symptoms of Primary Sclerosing Cholangistis experienced by patients at time of screening
    Units: Subjects
        No
    		 5 5
        Yes
    		 17 17
        Not applicable
    		 0 0
    Current PSC Symptom: Tiredness
    Units: Subjects
        No
    		 4 4
        Yes
    		 13 13
        Not applicable
    		 5 5
    Current PSC Symptom: Jaundice
    Units: Subjects
        No
    		 17 17
        Yes
    		 0 0
        Not applicable
    		 5 5
    Current PSC Symptom: Fever
    Units: Subjects
        No
    		 17 17
        Yes
    		 0 0
        Not applicable
    		 5 5
    Current PSC Symptom: Abdominal Pain
    Units: Subjects
        No
    		 13 13
        Yes
    		 4 4
        Not applicable
    		 5 5
    Current PSC Symptom: Bowel Movement
    Units: Subjects
        No
    		 12 12
        Yes
    		 4 4
        Not Applicable
    		 5 5
        Missing
    		 1 1
    Current PSC Symptom: Skin Irritation
    Units: Subjects
        No
    		 3 3
        Yes
    		 14 14
        Not applicable
    		 5 5
    Current PSC Symptom: Nausea
    Units: Subjects
        No
    		 16 16
        Yes
    		 1 1
        Not applicable
    		 5 5
    Current PSC Symptom: Vomiting
    Units: Subjects
        No
    		 16 16
        Yes
    		 1 1
        Not applicable
    		 5 5
    Smoking History: Current Smoker
    Patient smoking status and history at date of screening.
    Units: Subjects
        No
    		 22 22
        Yes
    		 0 0
    Smoking History: Previous Smoker
    Patient smoking status and history at date of screening.
    Units: Subjects
        No
    		 17 17
        Yes
    		 5 5
    History of Inflammatory Bowel Disease
    Units: Subjects
        No
    		 8 8
        Yes
    		 14 14
    Previous/Known Drug Allergies
    Units: Subjects
        No
    		 17 17
        Yes
    		 5 5
    Diagnosis of Disease
    Units: Subjects
        Established
    		 12 12
        New
    		 8 8
        Not Applicable
    		 2 2
    Response to Previous UDCA
    Units: Subjects
        UDCA naive
    		 3 3
        UDCA non-responder
    		 7 7
        UDCA responder
    		 8 8
        Not Applicable
    		 4 4
    Basis for Diagnosis
    Units: Subjects
        Blood work
    		 3 3
        Histology
    		 6 6
        Imaging
    		 12 12
        Not Applicable
    		 1 1
    History of Autoimmune Disease
    Units: Subjects
        No
    		 17 17
        Yes
    		 5 5
    History of Prior Surgery
    Units: Subjects
        No
    		 10 10
        Yes
    		 12 12
    Medication Taken
    History of medication taken within the three months prior to trial registration.
    Units: Subjects
        No
    		 2 2
        Yes
    		 19 19
        Not Applicable
    		 1 1
    Allergy History: Allergic Rhinitis
    Units: Subjects
        No
    		 22 22
        Yes
    		 0 0
    Allergy History: Allergic Asthma
    Units: Subjects
        No
    		 19 19
        Yes
    		 3 3
    Allergy History: Allergic Eczema
    Units: Subjects
        No
    		 20 20
        Yes
    		 2 2
    Allergy History: Food Allergies
    Units: Subjects
        No
    		 20 20
        Yes
    		 2 2
    Allergy History: Other Allergies
    Units: Subjects
        No
    		 19 19
        Yes
    		 3 3
    Absolute ALP Percentage Change
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    		 5.65 (4.06 to 16.2) -
    Period of Alcohol Abstinence
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 8.5 (6.25 to 11.5) -
    Previous Smoking Duration
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 7.5 (2.75 to 14) -
    Previous Smoking Amount
    Units: Cigarettes per day
        median (inter-quartile range (Q1-Q3))
    		 10 (7.5 to 10) -
    Age of Inflammatory Bowel Disease onset
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 23 (19.25 to 35.25) -
    Onset Age of Primary Sclerosing Cholangitis
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 37 (25 to 41.75) -

    End points

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    End points reporting groups
    Reporting group title
    BTT1023
    Reporting group description
    		 -
    Reporting group title
    BTT1023
    Reporting group description
    		 -
    Reporting group title
    BTT1023
    Reporting group description
    		 -

    Primary: Response at visit 10

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    End point title
    		 Response at visit 10 [1]
    End point description
    Primary Outcome: To determine the activity of the anti-VAP-1 antibody BTT1023 in patients with PSC as measured by a decrease in ALP levels (primary endpoint). Primary Outcome Measure: Response at Day 99: a reduction in serum alkaline phosphatase (ALP) by 25% or more from baseline to Day 99. Percentage change in ALP was calculated as: (ALP(visit 10) - ALP(visit 3, pre-infusion))/ALP(visit 3, pre-infusion). The target reduction in ALP was 25%. Statistical analysis description: This trial was designed with a Simon's two-stage using the following parameters: alpha = 0.10 (type I error), beta = 0.2 (1-beta=power), P0 = 0.15, P1 = 0.30. P0 and P1 correspond to the required reduction in patients experiencing raised levels of ALP from 85%to 70%, i.e. 1-0.85=0.15 and 1-0.70=0.30. The Simon’s two-stage minimax design requires 3 responses out of 18 evaluable patients at the interim analysis to continue, and 9 of 37 at the final analysis.
    End point type
    Primary
    End point timeframe
    Percentage change in ALP measured between visit 3 pre-infusion (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    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: This is a single arm trial with a Simon's two-stage design therefore interpretation is made with respect to desirable characteristics.
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Response
        Reduction of 25% or greater
    2
        No reduction of 25% or greater
    19
        Data missing
    1
    No statistical analyses for this end point

    Secondary: Treatment Compliance

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    End point title
    		 Treatment Compliance
    End point description
    If a patient had been fully compliant with the protocol, they would have attended 11 visits: screening visits 1 & 2; treatment visits 3-9; and follow-up visits 10 & 11. Here we present counts of patients who complied with trial visits per protocol
    End point type
    Secondary
    End point timeframe
    Treatment compliance during the trial period.
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Persons
        Attended all trial visits
    19
        Did not attend all trial visits
    3
    No statistical analyses for this end point

    Secondary: Treatment Compliance

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    End point title
    		 Treatment Compliance
    End point description
    If a patient had been fully compliant with the protocol, they would have attended 11 visits: screening visits 1 & 2; treatment visits 3-9; and follow-up visits 10 & 11. Here we present descriptive summary information regarding the number of visits attended.
    End point type
    Secondary
    End point timeframe
    Treatment compliance within trial period.
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Visits
        arithmetic mean (full range (min-max))
    10.64 (5 to 11)
    No statistical analyses for this end point

    Secondary: Treatment Compliance

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    End point title
    		 Treatment Compliance
    End point description
    End point type
    Secondary
    End point timeframe
    Withdrawals from trial treatment during trial period.
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Withdrawals
        Withdrew consent to treatment
    2
        Did not withdraw consent to treatment
    20
    No statistical analyses for this end point

    Secondary: Treatment Compliance

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    End point title
    		 Treatment Compliance
    End point description
    End point type
    Secondary
    End point timeframe
    The length of time on trial treatments calculated as the time (in days) between the first treatment with BTT1023 and the last treatment with BTT1023.
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Days
        arithmetic mean (full range (min-max))
    73.14 (1 to 80)
    No statistical analyses for this end point

    Secondary: EQ-5D Health Questionnaire: EQ-5D 5L

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    End point title
    		 EQ-5D Health Questionnaire: EQ-5D 5L
    End point description
    The EQ-5D-5L (EuroQol 5-Dimensional 5 Levels) descriptive system comprises of five dimensions (mobility; self-care; usual activities; pain or discomfort; and anxiety/depression). Each dimension has five response levels: no problems; slight problems; moderate problems; severe problems; unable to/extreme problems. Responses are coded as single-digit numbers (1-5) expressing the severity level selected in each dimension with lower numbers equating to better functionality (and vice versa). The digits for the five dimensions can be combined in a 5-digit code that describes the respondent’s health state. Each health state is then transformed to an index score using England specific estimates attained from Devlin et al. (2018). The maximum index score is 1.00, while the minimum index score is -0.285. For EQ-5D 5L index scores, higher scores equate to better functionality. Percentage change in EQ-5D 5L index score is calculated as: (EQ-5D 5L(visit 10) - EQ-5D 5L(visit 3))/EQ-5D 5L(visit 3)
    End point type
    Secondary
    End point timeframe
    Percentage change in EQ-5D 5L index score measured between visit 3 pre-infusion (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    21 [2]
    Units: Percentage Change(test unit: index score
        arithmetic mean (full range (min-max))
    -5.52 (-59.24 to 20.63)
    Notes
    [2] - One patient had information pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: EQ-5D Health Questionnaire: EQ-VAS

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    End point title
    		 EQ-5D Health Questionnaire: EQ-VAS
    End point description
    The EQ-VAS (EuroQol Visual Analogue Scale) records the respondent’s overall current health today on a vertical visual analogue scale, where the endpoints are labelled ‘The best health you can imagine’ (corresponding to a score of 100) and ‘The worst health you can imagine’ (corresponding to a score of 0). The EQ-VAS provides a quantitative measure of the patient’s perception of their overall health. Percentage change in EQ-VAS was calculated as: (EQ-VAS(visit 10) - EQ-VAS(visit 3))/EQ-VAS(visit 3).
    End point type
    Secondary
    End point timeframe
    Percentage change in EQ-VAS measured between visit 3 (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    21 [3]
    Units: Percentage Change (Test Units: EQ-VAS)
        arithmetic mean (full range (min-max))
    -3.76 (-40.98 to 23.08)
    Notes
    [3] - One patient had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Fatigue Severity Scale (FSS)

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    End point title
    		 Fatigue Severity Scale (FSS)
    End point description
    The Fatigue Severity Scale (FSS) is a method of evaluating the impact of fatigue on a patient through methods of a short questionnaire that requires patients to rate their level of fatigue. The FSS questionnaire contains nine statements, graded from 1 to 7 based on how accurately the statement reflects the patient condition during the past week and the extent to which they agree or disagree that the statement applies to them. A low value (e.g.1) indicates strong disagreement with the statement, whereas a high value (e.g. 7) indicates a strong agreement. Percentage change in FSS score is calculated as: (FSS(visit 10) - FSS(visit 3))/FSS(visit 3).
    End point type
    Secondary
    End point timeframe
    Percentage change in Fatigue Severity Scale (FSS) score measured between visit 3 (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    21 [4]
    Units: Percentage Change (Test Units: FSS)
        arithmetic mean (full range (min-max))
    -2.28 (-41.67 to 33.33)
    Notes
    [4] - One patient had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Pruritus Visual Analogue Scale (VAS)

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    End point title
    		 Pruritus Visual Analogue Scale (VAS)
    End point description
    The purpose of the visual analogue scale (VAS) was to measure the amount of pruritus (itching) that patients experience while participating in the BUTEO trial. The following reference was given “Mark with a pen on the line below how much you were bothered by itchiness over the past 24 hours. The far left indicates ‘no itching’ and far right indicates ‘intolerable/severe itching’." Percentage change in pruritus VAS was calculated as (pruritus VAS(visit 10) - pruritus VAS(visit 3))/pruritus VAS(visit 3).
    End point type
    Secondary
    End point timeframe
    Percentage change in Pruritus Visual Analogue Scale (VAS) measured between visit 3 (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    20 [5]
    Units: Percentage Change(Test Unit:Pruritus VAS
        arithmetic mean (full range (min-max))
    115.97 (-98.15 to 2550.00)
    Notes
    [5] - Two patients had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Inflammatory Bowel Disease (IBD) Diary: Number of Stools

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    End point title
    		 Inflammatory Bowel Disease (IBD) Diary: Number of Stools
    End point description
    The Inflammatory Bowel Disease (IBD) diary was completed by 14 people. All participants who completed the diary had IBD and the 8 patients who did not complete the diary did not have IBD. As the diary was completed on 7 consecutive days before visit, for the descriptive analyses provided here, the median average is first calculated for each time point, to give the median number of stools per day, and then the difference in averages calculated. The median was used due to the highly skewed nature of this outcome. The percentage change in number of stools could not be calculated for one patient as at the reference period, screening visit 2, they had a median average of 0 stools per day. This patient has been excluded from the analysis otherwise the mean and upper bound of the range cannot formally be quantified. The percentage change in median number of stools per day is calculated as: (Stools per day(visit 10) - Stools per day(visit 2))/Stools per day(visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in the median number of stools per day measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    12 [6]
    Units: Percentage Change in No of Stools a day
        arithmetic mean (full range (min-max))
    25.79 (-33.33 to 200)
    Notes
    [6] - One patient had outcome data missing. Percentage change could not be calculated for one patient.
    No statistical analyses for this end point

    Secondary: Inflammatory Bowel Disease (IBD) Diary: Frequency of Blood in Stool

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    End point title
    		 Inflammatory Bowel Disease (IBD) Diary: Frequency of Blood in Stool
    End point description
    The Inflammatory Bowel Disease (IBD) diary was completed by 14 people. All participants who completed the diary had IBD and the 8 patients who did not complete the diary did not have IBD. As the diary was completed on 7 consecutive days before visit, for the descriptive analyses provided here, the median average is first calculated for each time point, to give the median frequency of blood in stools per day, and then the difference in averages calculated. The median is used due to the skewed nature of the outcome. Due to the high presence of there being on average 0 instances of blood in the stools per day at both time points, the difference between the two time points is instead used (as '0/0' cannot be evaluated). The difference in the median frequency of blood in stools per day is calculated as: Blood in Stools per day(visit 10) - Blood in Stools per day(visit 2)
    End point type
    Secondary
    End point timeframe
    Difference in the median frequency of blood in stools per day measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    13 [7]
    Units: Difference in Freq Blood in Stools a day
        arithmetic mean (full range (min-max))
    0 (0 to 0)
    Notes
    [7] - One patient had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Inflammatory Bowel Disease (IBD) Diary: Abdominal Pain/Cramp

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    End point title
    		 Inflammatory Bowel Disease (IBD) Diary: Abdominal Pain/Cramp
    End point description
    The Inflammatory Bowel Disease (IBD) diary was completed by 14 people. All participants who completed the diary had IBD and the 8 patients who did not complete the diary did not have IBD. Patients were asked to rate their abdominal pain/cramp score on a scale of 0 to 3 where: 0 = none; 1 = mild; 2 = moderate; and 3 = severe. As the diary was completed on 7 consecutive days before visit, for the descriptive analyses provided here, the median average is first calculated for each time point to give the median abdominal pain per day, and then the difference in averages calculated. Furthermore, by using the median, the summary measure should always fall on an integer, giving a more meaningful value given the categorical of the data. Many individuals reported their abdominal pain to be 'good' (graded 0) at either/both visit(s). Therefore, the percentage change cannot often be calculated. To give a more meaningful sample size, the difference has instead been used.
    End point type
    Secondary
    End point timeframe
    Difference in the median abdominal pain/cramp between screening visit 2 and visit 10 (the first follow-up visit, day 99). Calculated as: median abdominal pain/cramp score per day(visit 10) - median abdominal pain/cramp score per day(screening visit 2)
    End point values
    		 BTT1023
    Number of subjects analysed
    13 [8]
    Units: Median Abdominal Pain/Cramp Score
        arithmetic mean (full range (min-max))
    0.08 (-1 to 1)
    Notes
    [8] - One patient had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Inflammatory Bowel Disease (IBD) Diary: General Wellbeing

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    End point title
    		 Inflammatory Bowel Disease (IBD) Diary: General Wellbeing
    End point description
    The Inflammatory Bowel Disease (IBD) diary was completed by 14 people. All participants who completed the diary had IBD and the 8 patients who did not complete the diary did not have IBD. Patients were asked to rate their general wellbeing score on a scale of 0 to 3 where: 0 = good; 1 = average; 2 = poor; and 3 = very poor. As the diary was completed on 7 consecutive days before visit, for the descriptive analyses provided here, the median average is first calculated for each time point to give the median general wellbeing score, and then the difference in averages calculated. Furthermore, by using the median, the summary measure should always fall on an integer, giving a more meaningful value given the categorical of the data. Many individuals reported their general wellbeing to be 'good' (graded 0) at either/both visit(s). Therefore, the percentage change cannot often be calculated. To give a more meaningful sample size and values, the difference has instead been used.
    End point type
    Secondary
    End point timeframe
    Difference in the median general wellbeing between screening visit 2 and visit 10 (the first follow-up visit, day 99). Calculated as: median general wellbeing score per day(visit 10) - median general wellbeing per day(screening visit 2)
    End point values
    		 BTT1023
    Number of subjects analysed
    13 [9]
    Units: Difference in General Wellbeing score
        arithmetic mean (full range (min-max))
    0 (-1 to 1)
    Notes
    [9] - One patient had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Enhanced Liver Fibrosis (ELF)

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    End point title
    		 Enhanced Liver Fibrosis (ELF)
    End point description
    Percentage change in Enhanced Liver Fibrosis (ELF) score is calculated as: (ELF(visit 10) - ELF(screening visit 2))/ELF(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in the enhanced liver fibrosis score measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    0 [10]
    Units: Percentage Change(Test Units:ELF result)
        arithmetic mean (full range (min-max))
    ( to )
    Notes
    [10] - Data pertinent to this outcome was unavailable at the time of preparation of this report.
    No statistical analyses for this end point

    Secondary: Fibroscan: kPa

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    End point title
    		 Fibroscan: kPa
    End point description
    Percentage change in Fibroscan kPa score is calculated as: (kPa (visit 10) - kPa (screening visit 2))/kPa (screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in the Fibroscan kPa result measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Percentage Change (Test Units: kPa)
        arithmetic mean (full range (min-max))
    13.58 (-54.75 to 122.86)
    No statistical analyses for this end point

    Secondary: Fibroscan: IQR

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    End point title
    		 Fibroscan: IQR
    End point description
    Percentage change in Fibroscan IQR score is calculated as: (IQR (visit 10) - IQR (screening visit 2))/IQR (screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in the Fibroscan IQR result measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Percentage Change (Test Units: IQR)
        arithmetic mean (full range (min-max))
    65.72 (-53.33 to 400)
    No statistical analyses for this end point

    Secondary: Liver Function Tests: AST

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    End point title
    		 Liver Function Tests: AST
    End point description
    Percentage change in Aspartate Transaminase (AST, IU/L) score is calculated as: (AST(visit 10) - AST(screening visit 2))/AST(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Aspartate Transaminase (AST, IU/L) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    20 [11]
    Units: Percentage Change (Test Units: IU/L)
        arithmetic mean (full range (min-max))
    -2.52 (-36.56 to 56.67)
    Notes
    [11] - Data pertinent to this outcome was missing for two patients.
    No statistical analyses for this end point

    Secondary: Liver Function Tests: ALT

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    End point title
    		 Liver Function Tests: ALT
    End point description
    Percentage change in Alanine Transaminase (ALT, IU/L) score is calculated as: (ALT(visit 10) - ALT(screening visit 2))/ALT(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Alanine Transaminase (ALT, IU/L) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    21 [12]
    Units: Percentage Change (Test Units: IU/L)
        arithmetic mean (full range (min-max))
    1.14 (-45.07 to 88.64)
    Notes
    [12] - One patient had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Liver Function Tests: ALP

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    End point title
    		 Liver Function Tests: ALP
    End point description
    Percentage change in Alkaline Phosphatase (ALP, IU/L) score is calculated as: (ALP(visit 10) - ALP(screening visit 2))/ALP(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Alkaline Phosphatase (ALP, IU/L) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Percentage Change (Test Units: IU/L)
        arithmetic mean (full range (min-max))
    -3.57 (-34.26 to 49.19)
    No statistical analyses for this end point

    Secondary: Liver Function Tests: GGT

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    End point title
    		 Liver Function Tests: GGT
    End point description
    Percentage change in Gamma Glutamyl Transferase (GGT, IU/L) score is calculated as: (AST(visit 10) - AST(screening visit 2))/AST(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Gamma Glutamyl Transferase (GGT, IU/L) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    20 [13]
    Units: Percentage Change (Test Units: IU/L)
        arithmetic mean (full range (min-max))
    -8.73 (-37.48 to 24.64)
    Notes
    [13] - Two patients had data pertinent to this outcome missing.
    No statistical analyses for this end point

    Secondary: Liver Function Tests: Albumin

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    End point title
    		 Liver Function Tests: Albumin
    End point description
    Percentage change in Albumin (g/L) score is calculated as: (Albumin (visit 10) - Albumin (screening visit 2))/Albumin (screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Albumin (g/L) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Percentage Change (Test Units: g/L)
        arithmetic mean (full range (min-max))
    -2.45 (-12.77 to 10.26)
    No statistical analyses for this end point

    Secondary: Liver Function Tests: Direct Bilirubin

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    End point title
    		 Liver Function Tests: Direct Bilirubin
    End point description
    Percentage change in Direct Bilirubin (umol/l) score is calculated as: (Direct Bilirubin(visit 10) - Direct Bilirubin(screening visit 2))/Direct Bilirubin(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Direct Bilirubin (umol/l) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    18 [14]
    Units: Percentage Change (Test Units: umol/l)
        arithmetic mean (full range (min-max))
    5.92 (-66.67 to 300.00)
    Notes
    [14] - Data pertinent to this outcome was missing for four patients.
    No statistical analyses for this end point

    Secondary: Liver Function Tests: Indirect Bilirubin

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    End point title
    		 Liver Function Tests: Indirect Bilirubin
    End point description
    Percentage change in Indirect Bilirubin (umol/l) score is calculated as: (Indirect Bilirubin(visit 10) - Indirect Bilirubin(screening visit 2))/Indirect Bilirubin(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Indirect Bilirubin (umol/l) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    15 [15]
    Units: Percentage Change (Test Units: umol/l)
        arithmetic mean (full range (min-max))
    -10.66 (-62.5 to 66.67)
    Notes
    [15] - Data pertinent to this outcome was missing for 7 patients.
    No statistical analyses for this end point

    Secondary: Liver Function Tests: International Normalised Ratio

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    End point title
    		 Liver Function Tests: International Normalised Ratio
    End point description
    Percentage change in International Normalised Ratio (INR) score is calculated as: (INR(visit 10) - INR(screening visit 2))/INR(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in International Normalised Ratio (INR) measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    22
    Units: Percentage Change (Test Units: Ratio)
        arithmetic mean (full range (min-max))
    -0.32 (-11.11 to 11.11)
    No statistical analyses for this end point

    Secondary: Model for End Stage Liver Disease (MELD)

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    End point title
    		 Model for End Stage Liver Disease (MELD)
    End point description
    The Model for End Stage Liver Disease (MELD) is a summary demographic of component parts: creatinine (umol/L), bilirubin (umol/L), and international normalised ratio (INR). Percentage change in MELD score is calculated as: (MELD (visit 10) - MELD (screening visit 2))/MELD (screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Model for End Stage Liver Disease (MELD) score measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    20 [16]
    Units: Percentage Change (Test Unit:MELD Score)
        arithmetic mean (full range (min-max))
    -1.58 (-30 to 83.33)
    Notes
    [16] - Data pertinent to this outcome was missing for two patients.
    No statistical analyses for this end point

    Secondary: Mayo PSC Risk Score

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    End point title
    		 Mayo PSC Risk Score
    End point description
    Percentage change in Mayo PSC Risk Score) score is calculated as: (Mayo PSC Risk Score(visit 10) - Mayo PSC Risk Score(screening visit 2))/Mayo PSC Risk Score(screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in Mayo PSC Risk Score measured between screening visit 2 and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    20 [17]
    Units: Percentage Change (Test Unit:Risk Score)
        arithmetic mean (full range (min-max))
    0.38 (-91.38 to 390.16)
    Notes
    [17] - Data pertinent to this outcome was missing for two patients.
    No statistical analyses for this end point

    Secondary: PK Data

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    End point title
    		 PK Data
    End point description
    For all PK data measurements, the percentage change in blood serum is calculated as: (PK (visit 10) - PK (visit 3))/PK (visit 3).
    End point type
    Secondary
    End point timeframe
    Percentage change in PK data in blood serum measured between visit 3 (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    0 [18]
    Units: Percentage Change
        arithmetic mean (full range (min-max))
    ( to )
    Notes
    [18] - Data pertinent to this outcome was unavailable at the time of preparation of this report.
    No statistical analyses for this end point

    Secondary: LiverMultiscan MRI Imaging

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    End point title
    		 LiverMultiscan MRI Imaging
    End point description
    Percentage change in LiverMultiscan MRI Imaging scoree is calculated as: (LiverMultiscan (visit 11) - LiverMultiscan (screening visit 2))/LiverMultiscan (screening visit 2).
    End point type
    Secondary
    End point timeframe
    Percentage change in LiverMultiscan MRI Imaging score measured between screening visit 2 and visit 11 (the second follow-up visit).
    End point values
    		 BTT1023
    Number of subjects analysed
    0 [19]
    Units: Percentage Change
        arithmetic mean (full range (min-max))
    ( to )
    Notes
    [19] - Data pertinent to this outcome was unavailable at the time of preparation of this report.
    No statistical analyses for this end point

    Secondary: s-VAP1/SSAO Biomarker

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    End point title
    		 s-VAP1/SSAO Biomarker
    End point description
    Percentage change in s-VAP1/SSAO Biomarker is calculated as: (s-VAP1/SSAO(visit 10) - s-VAP1/SSAO(visit 3))/s-VAP1/SSAO(screening visit 3).
    End point type
    Secondary
    End point timeframe
    Percentage change in s-VAP1/SSAO Biomarker measured between visit 3 (the first treatment visit) and visit 10 (the first follow-up visit, day 99).
    End point values
    		 BTT1023
    Number of subjects analysed
    0 [20]
    Units: Percentage Change
        arithmetic mean (full range (min-max))
    ( to )
    Notes
    [20] - Data pertinent to this outcome was unavailable at the time of preparation of this report.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe: Date of consent, (Visit 1: screening) and continued until the final follow-up visit (Visit 11: day 120), or alternatively up to 45 days post last drug infusion if the patient withdrew from the trial prior to completion of all 7 drug infusions.
    Adverse event reporting additional description
    Adverse Events (AEs) were reported on an AE form and returned to the Trials Office. AE's were reviewed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4. SAE forms were faxed to the Trials Office; seriousness and causality were determined independently by a by a Clinical Coordinator.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    BTT1023- All patients
    Reporting group description
    		 All patients registered on the trial.

    Serious adverse events
    		 BTT1023- All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 23 (17.39%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Infusion related reaction
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 BTT1023- All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    8 / 23 (34.78%)
         occurrences all number
    14
    Surgical and medical procedures
    Other: Insertion of artificial urinary sphincter
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Localized edema
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Aching chest, right side of body
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Bilateral rash to arms where cannula dressings were placed
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    2
    Other: Cold, cough and tickly throat
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Emotional
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Hay fever
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Infusion reaction
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Intermittent bursitis left shoulder
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Intermittent pharyngeal fascitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Left side groin pain during infusion
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Night sweats
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Pain in left shoulder / back /hip
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Right shoulder pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Sluggish/Aching
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Flu like symptoms
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Infusion related reaction
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    10 / 23 (43.48%)
         occurrences all number
    20
    Chills
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Other: Intermittent phlegm sitting in throat
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Mild inspiratory wheeze on right middle lobe chest
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Asthma
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    6
    Sore throat
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Investigations
    Blood corticotrophin decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Aspartate transaminase decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Bilirubin increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Calcium decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: CRP increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Estimated Glomerular Filtration Rate decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Ferritin increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Haemoglobin decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    2
    Other: Hypercholestraemia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Hypoalbuminemia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Indirect bilirubin increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Non significant raised QTC left ventricular hypertrophy
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Phosphates decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Platelets increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    4
    Other: Reduced Ferritin levels
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Sodium decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: C-reactive protein increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Other: Urea increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Other: APTT decreased
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Other: Direct bilirubin increased
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    5
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    9
    White blood cell decreased
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    25
    Other: Urea decreased
         subjects affected / exposed
    7 / 23 (30.43%)
         occurrences all number
    21
    Platelet count decreased
         subjects affected / exposed
    8 / 23 (34.78%)
         occurrences all number
    18
    Other: Creatinine decreased
         subjects affected / exposed
    11 / 23 (47.83%)
         occurrences all number
    29
    Blood bilirubin increased
         subjects affected / exposed
    14 / 23 (60.87%)
         occurrences all number
    59
    Lymphocyte count decreased
         subjects affected / exposed
    16 / 23 (69.57%)
         occurrences all number
    92
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 23 (91.30%)
         occurrences all number
    59
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 23 (91.30%)
         occurrences all number
    71
    Alkaline phosphatase increased
         subjects affected / exposed
    22 / 23 (95.65%)
         occurrences all number
    49
    GGT increased
         subjects affected / exposed
    22 / 23 (95.65%)
         occurrences all number
    50
    Other: Monocytes increased
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    10
    Other: Monocytes decreased
         subjects affected / exposed
    13 / 23 (56.52%)
         occurrences all number
    43
    Other: Mean cell volume increased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Basophils decreased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    6
    Other: Mean cell haemoglobin increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Other: Red blood cell increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    4
    Other: White blood cell increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    7
    Other: Total protein decreased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    8
    Other: Neutrophils decreased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    6
    Other: Mean cell volume decreased
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Other: Eosinophils decreased
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    25
    Other: INR decreased
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    5
    Other: Red blood cell count decreased
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    12
    Other: Mean cell haemoglobin decreased
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    6
    Other: Red blood cell distribution width increased
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    14
    Other: Eosinophils increased
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    26
    Other: Total protein increased
         subjects affected / exposed
    10 / 23 (43.48%)
         occurrences all number
    19
    Other: Neutrophils increased
         subjects affected / exposed
    12 / 23 (52.17%)
         occurrences all number
    30
    Other: Red blood cells decreased
         subjects affected / exposed
    14 / 23 (60.87%)
         occurrences all number
    27
    Other: Haematocrit decreased
         subjects affected / exposed
    17 / 23 (73.91%)
         occurrences all number
    44
    Injury, poisoning and procedural complications
    Wrist fracture
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Cardiac disorders
    Other: Borderline prolonged OT interval
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Borderline QTc on ECG
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Low grade hypertension
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    4
    Other: Sinus rhythm- abnormal ECG
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Sinus bradycardia
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Diplopia in all directions
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Presyncope
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    6
    Anemia
         subjects affected / exposed
    17 / 23 (73.91%)
         occurrences all number
    44
    Eye disorders
    Other: allergic retinitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Gastrointestinal disorders
    Anal pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Gastrointestinal pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: 4 columns of varices seen. The columns of varix seem to become bigger at 35cm. Grade 3
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Barrett's Oesophagus
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Increased stool frequency due to pouchitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Intermittent tenesmus
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Loss of appetite
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Mouth ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Oesophageal Candidiasis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Portal hypertensive gastropathy
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Spider naevi
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Ulcerative colitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    7
    Colitis
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    5
    Other: Loose bloody stools x2
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Hepatobiliary disorders
    Other: Cholangitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Chronic liver failure requiring pre-emptive liver transplantation
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Mild hepatomegaly
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Right upper quadrant pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Hepatomegaly
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Other: Chronic Venous eczema on both lower limbs
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Creatinine decreased
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Dry mouth
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Itchy chest
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Itchy scalp
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Mild foliculitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Psoriasis on legs and hands
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Rash on forehead
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Redness around umbilicus
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Removal of Viral wart on left ankle
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Right side of head above ear, insect bite with swelling and discharge
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Sensitive skin over varicose vein on calves
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Sunburn
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Vitiligo eczema
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    10 / 23 (43.48%)
         occurrences all number
    14
    Other: Poriasis
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    2
    Hypothyroidism
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Type I diabetes
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Chest wall pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    2
    Other: Osteoarthritic nodes in fingers on of the right hand
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Osteoathritis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Polyarthralgia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Swelling of both hands
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Vertebral haemangioma
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Worsening right knee pain
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    8
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    3
    Gallbladder infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Viral infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Upper respiratory infection
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypercalcemia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    4
    Hypernatremia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Other: Vitamin D Deficiency
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Hyperglycemia
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Hypokalemia
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    8
    Hyponatremia
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Hypocalcemia
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    12
    Hypoalbuminemia
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    37

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2015
    This amendment contained: - Changes to Section 7.6.1 – wording updated to prevent additional samples being taken - Grammatical errors and line spacing errors corrected
    27 Nov 2015
    This amendment contained: - Updates to contact details throughout the protocol - Trial inclusion and exclusion criteria updated and clarified - Screening period reduced to 6-8 weeks - Schedule of Events updated: 1) Enhanced Liver Fibrosis (ELF) test included as a research sample; 2) Central alkaline phosphatase (ALP) tests included for Visits 3-11; 3) Tests for Anti-Drug Antibodies (ADA) and Pharmacodynamics (PD) and Quality of Life (QoL) assessment not performed at Screening Visits 1 & 2 and 4) Clarification of MRI Scans - Inclusion of Screening Number and addition of Section 7.11- Contraception and Pregnancy
    16 Mar 2016
    This amendment contained: - Clarification of inclusion criteria; ALP value reduced from >2 x ULN to >1.5 x ULN - Pre-medications updated to include hydrocortisone at Visits 3-5 - Section 8.1.2 “Hypersensitivity, Infusion Reactions and Infusion Related Reactions” added - Additional telephone number for Trial Office added throughout the protocol
    27 Mar 2018
    Clarification of inclusion criteria; minimum patient's weight criteria added and validity of colonoscopy results altered from within 1 year to within the patient’s standard of care. Timing of interim analysis clarified - Information added regarding Acorda, Biotie’s parent company and correction of grammatical errors.
    31 Jul 2018
    This amendment concerns the change of Chief Investigator and Trial Coordinator. Change in Data Protection Regulations, updated text regarding GDPR.

    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.
    This report fulfills the criteria and structure for EudraCT. A full analysis and study publication are being processed to better express the results for dissemination.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28674140
    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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