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    Summary
    EudraCT Number:2013-003200-39
    Sponsor's Protocol Code Number:13/0077
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-04-04
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2013-003200-39
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Investigation of Zibotentan for kidney disease in scleroderma
    A.3.2Name or abbreviated title of the trial where available
    Zibotentan better renal scleroderma outcome study (ZEBRA)
    A.4.1Sponsor's protocol code number13/0077
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUCL Joint Research office
    B.5.2Functional name of contact pointDr Edward Stern
    B.5.3 Address:
    B.5.3.1Street AddressRoyal Free Hospital,Rheumatology Department,Pond Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeNW3 2QG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02073177544
    B.5.5Fax number02077940432
    B.5.6E-maile.stern@ucl.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZibotentan
    D.3.2Product code ZD4054
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZibotentan
    D.3.9.1CAS number 186497-07-4
    D.3.9.2Current sponsor codeZD4054
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Renal complications of systemic sclerosis (scleroderma renal crisis and chronic kidney disease).
    E.1.1.1Medical condition in easily understood language
    Kidney disease in scleroderma
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10064848
    E.1.2Term Chronic kidney disease
    E.1.2System Organ Class 100000004857
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10061087
    E.1.2Term Connective tissue disorder
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10018124
    E.1.2Term Generalized scleroderma
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10069339
    E.1.2Term Acute kidney injury
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary objectives of the trial
    The secondary objectives for this study are:
    •To test whether the zibotentan is safe in patients who have had scleroderma renal crisis (not requiring dialysis) in the last 12 months, and whether it improves their kidney function. (ZEBRA 2A)
    •To see how patients with scleroderma and kidney damage (not on dialysis) respond when they stop taking Zibotentan after 6 months of treatment. (ZEBRA 1 and 2A)
    •To explore how Zibotentan affects other new “biomarkers” of kidney damage in the blood and urine of patients in the study.
    To see how kidney damage from scleroderma affects blood levels of Zibotentan, compared with people with normal kidney function.
    •To test a single dose of Zibotentan in patients with severe kidney damage from scleroderma who are on dialysis and see how well it is tolerated, how safe it is and how blood levels of the drug differ from people with normal kidney function.

    The exploratory objectives for this study are to discover new “biomarkers” of kidney damage in s
    E.2.3Trial contains a sub-study No
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Study consits of three parallel investigations Zebra 1,2a,2b as detailed above

    E.3Principal inclusion criteria
    Inclusion criteria (all substudies)
    1)Patients with either diffuse or limited systemic sclerosis of any disease duration
    2)Male or female age 18 or older.
    3)Women must be either surgically sterilized or post-menopausal or use a highly effective method of birth control.
    4)Females of childbearing potential and males must be willing to use one highly effective and one other method of contraception from the time consent is signed until 6 weeks after treatment discontinuation.
    5)Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment. NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral ophorectomy) or they are postmenopausal.
    6)Provision of signed and dated informed consent prior to any study specific procedures.
    Specific inclusion criteria for ZEBRA1
    1)Patients with CKD2 or CKD3A, with GFR>45 mL/min
    WHO definitions for chronic kidney disease will be used in this study.
    Stage 2: mildly reduced kidney function AND already known to have some kidney damage or disease. People with an eGFR of 60-89 (inclusive) without any known kidney damage or disease are not considered to have CKD2/3.
    Stage 3: moderately reduced kidney function. (With or without a known kidney disease. For example, an elderly person with ageing kidneys may have reduced kidney function without a specific known kidney disease.) 45 mL/min to 59 mL/min (3A) 30 mL/min to 44 ml/min (3B)
    2)Patients who have not had a renal crisis within the previous 12 months at Visit 0.
    Specific inclusion criteria for For ZEBRA 2A and B.
    1)Patients who have experienced a Scleroderma renal crisis. Scleroderma renal crisis will be defined as follows, requiring both of:
    •A new onset of blood pressure >150/85 obtained at least twice over a consecutive 24 hour period. This blood pressure is chosen because it is that defined by the New York Heart Association as significant hypertension.
    •Decline in renal function as defined by an increase of at least 10% from a baseline serum creatinine measured within the previous 12 months. When possible a repeat serum creatinine should be obtained to corroborate the initial result.
    In order to corroborate further the occurrence of acute renal crisis, it would be desirable to have any of the following, if available:
    •Microangiopathic haemolytic anaemia on blood smear
    •Retinopathy typical of acute hypertensive crisis
    •New onset of urinary RBCs (excluding other causes)
    •Flash pulmonary oedema
    •Oliguria or anuria
    •Renal biopsy findings consistent with SRC
    .
    Specific inclusion criteria for ZEBRA2A
    Patients should have experienced an SRC within 1-12 months of the study start. Patients should not be receiving renal dialysis
    Specific inclusion criteria for ZEBRA2B
    Patients should be undergoing regular renal dialysis after experiencing an SRC – any form of dialysis is acceptable.
    E.4Principal exclusion criteria
    Exclusion criteria (all substudies)
    1.Previous use of an endothelin receptor antagonist within 3 months of the study start
    2.Significant abnormalities in liver function testing (ALT, ALP, Bilirubin) more than three times upper limit of normal)
    3.Patients with body weight <40kg.
    4.Patients with conditions which prevent compliance with the protocol or failure to adhere to therapy.
    5.Patients with any other life threatening condition.
    6.Patients with known hypersensitivity to Zibotentan or its excipients
    7.Previous history of epilepsy or other CNS AEs, neurologic symptoms or signs consistent with acute or evolving spinal cord compression, and CNS metastases
    8.Patients with a baseline left ventricular ejection fraction < 40% (prior to any scleroderma renal crisis), patients with acute myocardial infarction within six months or patients who are judged by the trial clinician to be at unacceptable risk from cardiac complications.
    9.History of chronic alcohol or drug abuse or any condition associated with poor compliance as judged by the investigator
    10.Patients receiving cyclosporin A within 1 week of screening or expecting to receive this agent during the study.
    11.Patients who have received an investigational agent in the month prior to screening. These patients may be eligible after a month of washout period (as long as they are still within 1-12 months of the onset of the Scleroderma renal crisis for ZEBRA2A).
    12.Active malignancy or neoplastic disease in the previous 12 months
    13.Women who rely on oestrogen-containing contraceptives (due to potential drug interaction with Zibotentan).
    14.Females who are pregnant or breastfeeding.

    E.5 End points
    E.5.1Primary end point(s)
    •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). (ZEBRA1)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse Events (AEs)
    Electrocardiogram (ECG)
    Physical examination
    Haematology
    Clinical chemistry
    Urinalysis
    Vital signs
    sVCAM-1
    E.5.2Secondary end point(s)
    The secondary objectives for this study are:
    •To assess the tolerability, safety and effect of Zibotentan treatment over 6 months on renal function, (GFR) in patients who have experienced an SRC not requiring dialysis (ZEBRA2A)
    •To assess the efficacy of Zibotentan treatment over 6 months on disease outcome measures in patients with scleroderma associated with CKD2 and CKD3 (GFR>45ml/min) and in patients with scleroderma who have experienced a renal crisis within 1-12 months of the start of treatment not requiring dialysis. (ZEBRA1 and 2A only)
    •To assess response to Zibotentan withdrawal after 6 months treatment (ZEBRA1 and 2A only)
    •To explore the impact of Zibotentan on novel candidate biomarkers of renal involvement in patients with scleroderma.
    •To evaluate the effect of renal impairment in scleroderma on the PK of Zibotentan
    •To evaluate the effect of severe renal dysfunction and dialysis on the tolerability, safety and pharmacokinetic profile of a single dose of Zibotentan in patients with scleroderma (ZEBRA 2B only)

    The exploratory objectives for this study are
    •To compare the biomarkers and clinical outcome measures between the patients in ZEBRA1 and ZEBRA2, and with other existing datasets (e.g. the BIRD1 dataset (Penn 2013)
    •Additional exploratory biomarkers relevant to renal disease and scleroderma may be measured and are to be defined based on an ongoing observational cross sectional study
    E.5.2.1Timepoint(s) of evaluation of this end point
    As per CKD2/3 patients above
    Glomerular filtration rate at 6 and 12 months (assessed by eGFR or isotope GRF if clinically indicated)
    HAQ-DI with Scleroderma specific VAS
    Scleroderma Functional score
    SF-36
    Physician and patient global disease activity score
    Digital ulcers will be counted and recorded and skin involvement assessed by modified Rodnan skin score
    Examination of proteinuria (tubular, glomerular), creatinine clearance and eGFR
    Maintenance anti-hypertensive therapy
    Mortality, frequency and duration of dialysis, at 6 and 12 months
    Blood pressure, ET1, eGFR, need for additional use of anti-hypertensive treatment and biomarkers at 1 and 4 weeks after stopping Zibotentan treatment. (Biomarkers at 4 weeks only)
    sVCAM-1
    Serum Nt-pro-BNP
    VEGF, vWF, ET-1, creatinine, sIC
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind Yes
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last patient, last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 72
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state72
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    As Zibotentan is an unlicenced drug,it will not be available for the patients after the study has concluded. Patient will be aware of this at time of consent as it is detailed in the patient information sheet.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-19
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