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    Clinical Trial Results:
    A phase II, single centre, randomised, placebo-controlled, 3-part trial to assess the safety, tolerability and efficacy of Zibotentan in patients with renal disease secondary to scleroderma

    Summary
    EudraCT number
    2013-003200-39
    Trial protocol
    GB  
    Global end of trial date
    19 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jul 2019
    First version publication date
    05 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13/0077
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02047708
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IRAS number : 136274
    Sponsors
    Sponsor organisation name
    UCL
    Sponsor organisation address
    Joint Research Office , Gower Street , London , United Kingdom, WC1E 6BT
    Public contact
    Dr Edward Stern, UCL Joint Research office , +44 02073177544, e.stern@ucl.ac.uk
    Scientific contact
    Dr Edward Stern, UCL Joint Research office , +44 02073177544, e.stern@ucl.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
    03 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives for this study is to see how safe Zibotentan is in patients with scleroderma and kidney damage and whether it has any effect on their kidney function
    Protection of trial subjects
    Zibotentan has been well tolerated but has been associated with minor side effects including headache, low blood pressure, nausea, vomiting and nasal congestion.These side effects were minimised by keeping within the dosage range as well as regular safety monitoring while on the study. Participants with severe hepatic impairment were excluded as a clinical study detailed in the Zibotentan Investigator's Brochure indicated reduced clearance of Zibotentan in these patients. Participants may experience some local discomfort whilst blood samples are taken. This may include pain, inflammation, infection or a small bruise at the puncture site. The study doctor will follow up if any of these side effects occur.
    Background therapy
    Immunosuppressants such as mycophenolate, cyclophosphamide, and methotrexate are prescribed to manage disease symptoms as there is currently no approved medication.
    Evidence for comparator
    This is a phase II, single centre, randomised, placebo controlled, 3 part trial designed to evaluate the safety, tolerability and efficacy of Zibotentan in patients with renal disease secondary to scleroderma . As there is no approved drug for DcSSC, a placebo arm is the relevant comparator.
    Actual start date of recruitment
    03 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    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)
    14
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment window was 02/10/2014 to 02/02/2017

    Pre-assignment
    Screening details
    28 participants screened for trial. 5 were screening failures therefore 23 participants randomized. 1 participant withdrew.

    Pre-assignment period milestones
    Number of subjects started
    23
    Number of subjects completed
    23

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Zebra 1- Double blind Zebra 2A- Single blind Zebra 2B- Open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Active treatment
    Arm description
    Zibotentan 2.5, 5, 7.5, 10 mg od
    Arm type
    Experimental

    Investigational medicinal product name
    Zibotentan 2.5, 5, 7.5, 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Zibotentan 2.5, 5, 7.5, 10 mg taken orally

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5, 5, 7.5, 10 mg taken orally

    Investigational medicinal product name
    Zibotentan 2.5, 5, 7.5, 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Zibotentan 2.5, 5, 7.5, 10 mg taken orally

    Number of subjects in period 1
    Active treatment Placebo
    Started
    15
    8
    Completed
    14
    8
    Not completed
    1
    0
         Adverse event, serious fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active treatment
    Reporting group description
    Zibotentan 2.5, 5, 7.5, 10 mg od

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Active treatment Placebo Total
    Number of subjects
    15 8 23
    Age categorical
    age 18 or older
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    9 4 13
        From 65-84 years
    6 4 10
        85 years and over
    0 0 0
        18 or older
    0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    64 ± 7.4 68 ± 7.2 -
    Gender categorical
    Units: Subjects
        Female
    8 6 14
        Male
    7 2 9
    Subject analysis sets

    Subject analysis set title
    Zebra 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    A 1:1 randomised parallel group placebo-controlled, double-blind, single centre trial comparing Zibotentan 10 mg once daily orally (with possible dose reductions to a minimum dose of 5mg once daily) with matched placebo in Scleroderma patients with CKD2 and CKD3 (and GFR >45 ml/min) over 26 weeks with a 26 weeks follow up.

    Subject analysis set title
    Zebra 2A
    Subject analysis set type
    Full analysis
    Subject analysis set description
    A parallel group placebo-controlled, single blind, single centre trial comparing Zibotentan once daily orally over 26 weeks, with a 26 week follow up, with matched placebo using 2:1 (active:placebo) randomisation in patients within 1-12 months of SRC (Scleroderma Renal Crisis) not requiring ongoing dialysis. Individual patients will start at 2.5 mg once daily and following weekly monitoring will be dose escalated by 2.5 mg weekly to a maximum of 10 mg once daily over the course of the first 4 weeks.

    Subject analysis set title
    Zebra 2B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    An open label single ascending dose administration pharmacokinetic study of Zibotentan 2.5 mg to 10 mg orally in patients requiring dialysis. Individual patients can receive up to two single doses of Zibotentan (at different dose levels).

    Subject analysis sets values
    Zebra 1 Zebra 2A Zebra 2B
    Number of subjects
    13
    4
    6
    Age categorical
    age 18 or older
    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)
    6
    2
    5
        From 65-84 years
    7
    2
    1
        85 years and over
    0
    0
        18 or older
    0
    0
    Age continuous
    Units: years
        median (standard deviation)
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    10
    3
    1
        Male
    3
    1
    5

    End points

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    End points reporting groups
    Reporting group title
    Active treatment
    Reporting group description
    Zibotentan 2.5, 5, 7.5, 10 mg od

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Zebra 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    A 1:1 randomised parallel group placebo-controlled, double-blind, single centre trial comparing Zibotentan 10 mg once daily orally (with possible dose reductions to a minimum dose of 5mg once daily) with matched placebo in Scleroderma patients with CKD2 and CKD3 (and GFR >45 ml/min) over 26 weeks with a 26 weeks follow up.

    Subject analysis set title
    Zebra 2A
    Subject analysis set type
    Full analysis
    Subject analysis set description
    A parallel group placebo-controlled, single blind, single centre trial comparing Zibotentan once daily orally over 26 weeks, with a 26 week follow up, with matched placebo using 2:1 (active:placebo) randomisation in patients within 1-12 months of SRC (Scleroderma Renal Crisis) not requiring ongoing dialysis. Individual patients will start at 2.5 mg once daily and following weekly monitoring will be dose escalated by 2.5 mg weekly to a maximum of 10 mg once daily over the course of the first 4 weeks.

    Subject analysis set title
    Zebra 2B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    An open label single ascending dose administration pharmacokinetic study of Zibotentan 2.5 mg to 10 mg orally in patients requiring dialysis. Individual patients can receive up to two single doses of Zibotentan (at different dose levels).

    Primary: sVCAM-1 serum level

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    End point title
    sVCAM-1 serum level
    End point description
    To assess the tolerability, safety and effect of Zibotentan treatment over 6 months on renal biomarkers (sVCAM1) in patients with scleroderma associated with CKD2 and CKD3 (GFR>45 mL/min).
    End point type
    Primary
    End point timeframe
    26 weeks after baseline
    End point values
    Active treatment Placebo
    Number of subjects analysed
    7
    6
    Units: mL/min
    median (standard deviation)
        Placebo
    0 ± 0
    0.23 ± 0.15
        Active treatment
    0.20 ± 0.13
    0 ± 0
    Statistical analysis title
    VCAM1 urine /creatinine
    Statistical analysis description
    Descriptive statistical analysis did not show any difference between active treatment and placebo
    Comparison groups
    Active treatment v Placebo
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.1 [1]
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - less than 0.1

    Primary: Number and severity of adverse events Zebra 1

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    End point title
    Number and severity of adverse events Zebra 1
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks from baseline
    End point values
    Active treatment Placebo Zebra 1
    Number of subjects analysed
    7
    6
    13
    Units: whole number
    20
    26
    46
    Statistical analysis title
    Number of AE's
    Comparison groups
    Placebo v Active treatment
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    > 0.1
    Method
    ANCOVA
    Confidence interval
    Notes
    [2] - Descriptive analysis did not show significant difference at 24 weeks between treatment arms

    Primary: eGFR level Zebra 2A

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    End point title
    eGFR level Zebra 2A
    End point description
    The primary analysis will be to graphically evaluate GFR changes in the 26 weeks from baseline. This will be compared using eGFR as a continuous variable.
    End point type
    Primary
    End point timeframe
    26 weeks after baseline visit
    End point values
    Active treatment Placebo
    Number of subjects analysed
    2
    1
    Units: ml/min
    number (not applicable)
        Active treatment
    34
    0
        Placebo
    71
    51
    Statistical analysis title
    eGFR level
    Statistical analysis description
    Drug levels provide information about potential dosing in dialysis patients in any future study
    Comparison groups
    Active treatment v Placebo
    Number of subjects included in analysis
    3
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.1 [4]
    Method
    ANCOVA
    Confidence interval
    Notes
    [3] - The primary analysis will be to graphically evaluate GFR changes in the 26 weeks from baseline. This will be compared using eGFR as a continuous variable.
    [4] - less than 0.1

    Primary: Number and severity of adverse events Zebra 2A

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    End point title
    Number and severity of adverse events Zebra 2A
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks from baseline
    End point values
    Active treatment Placebo Zebra 2A
    Number of subjects analysed
    2
    2
    4
    Units: whole numbers
    5
    5
    10
    Statistical analysis title
    Number and severity of adverse events Zebra 2A
    Comparison groups
    Active treatment v Placebo
    Number of subjects included in analysis
    4
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.1
    Method
    ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to end of study
    Adverse event reporting additional description
    Safety and tolerability of Zibotentan in CKD2/3 patients assessed by ECG, Physical examination, vital signs, haematology, clinical chemistry and Urinalysis. Study doctor also enquired about adverse events at every study visit between baseline and end of study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Zebra 1
    Reporting group description
    1:1 randomised parallel group placebo-controlled, double-blind, single centre trial comparing Zibotentan 10 mg once daily orally (with possible dose reductions to a minimum dose of 5mg once daily) with matched placebo in Scleroderma patients with CKD2 and CKD3 (and GFR >45 ml/min) over 26 weeks with a 26 weeks follow up.

    Reporting group title
    Zebra 2A
    Reporting group description
    A parallel group placebo-controlled, single blind, single centre trial comparing Zibotentan once daily orally over 26 weeks, with a 26 week follow up, with matched placebo using 2:1 (active:placebo) randomisation in patients within 1-12 months of SRC (Scleroderma Renal Crisis) not requiring ongoing dialysis. Individual patients will start at 2.5 mg once daily and following weekly monitoring will be dose escalated by 2.5 mg weekly to a maximum of 10 mg once daily over the course of the first 4 weeks

    Reporting group title
    Zebra 2B
    Reporting group description
    An open label single ascending dose administration pharmacokinetic study of Zibotentan 2.5 mg to 10 mg orally in patients requiring dialysis. Individual patients can receive up to two single doses of Zibotentan (at different dose levels).

    Serious adverse events
    Zebra 1 Zebra 2A Zebra 2B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    pseudoaneurysm
    Additional description: Pseudoaneurysm Left AVF
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    High INR
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia Community Acquired
    Additional description: Community acquired pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pneumonia
    Additional description: Hospital acquired pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Zebra 1 Zebra 2A Zebra 2B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 13 (84.62%)
    4 / 4 (100.00%)
    3 / 6 (50.00%)
    General disorders and administration site conditions
    General symptom
         subjects affected / exposed
    11 / 13 (84.62%)
    4 / 4 (100.00%)
    3 / 6 (50.00%)
         occurrences all number
    46
    10
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2014
    1. All patients will have pre and treatment echocardiogram in all parts of the study. Patients in ZEBRA 1 and ZEBRA 2A will also have an end of treatment echocardiogram. Updated following MHRA review. 2. All patients will have NT pro-BNP measured as part of the panel of monthly safety bloods. Updated following MHRA review. 3. End of treatment (week 26) pharmacokinetics analysis is to be omitted from ZEBRA 1 and ZEBRA 2A. Additional PK testing at this stage would not have any safety value for study participants or add to the scientific quality of the study.
    06 Jul 2016
    1. Update to the Investigator’s brochure (current version 15). 2. Minor changes to the layout of the Scleroderma Health assessment questionnaire. 3. Updates to the Protocol to reflect change in named statistician and contact details as well as update to sponsor's representative's contact details.
    07 Dec 2016
    1. Changes to the inclusion criteria for the ZEBRA 2B sub-study, removing the requirement that patients have a diagnosis of scleroderma or scleroderma renal crisis. 2. At all study visits where a 24-hour urine collection was mandated, will be replaced by a spot urine sample for protein:creatinine ratio. It is well established in clinical practice that this measurement method is at least as accurate as 24-hour collection and it is much better tolerated by patients. 3. The visit schedules for all three studies contain an error that has persisted through earlier protocol versions: as described in the endpoints for these studies, the trial design requires experimental biomarkers to be collected at start of treatment visit (visit 1), end of treatment visit (26 weeks) and end of follow-up visit (52 weeks), but the protocol shows biomarker sample collection at all study visits. This error been corrected in the latest version. Only routine safety blood and urine samples will be collected at interim study visits.
    25 Jul 2017
    1. The removal of follow up visits for Zebra 2B renal crisis patients which are not relevant for either safety or research outcomes as well as clarification on dose escalation. 2. Updated the information sheet and Protocol in line with the previously REC approved substantial amendment 5 i.e. the removal of Echocardiograms for 2B patients which is not relevant for non-Scleroderma patients.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Aug 2015
    Recruitment freeze due to potential interruption of IMP supply
    03 Sep 2015
    01 Nov 2015
    Decision by sponsor to freeze recruitment to allow data to be migrated from one database to another. Initial database shut down unexpectedly.
    11 Mar 2016

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Challenging to recruit patients within the recruitment window due to limitations mentioned above. Recruitment target in the 2 arms of the study therefore not met. Statistical analysis plan updated accordingly.
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