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    Summary
    EudraCT Number:2016-000997-39
    Sponsor's Protocol Code Number:7837
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-05-23
    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 number2016-000997-39
    A.3Full title of the trial
    Eculizumab in Shiga-Toxin producing E. Coli Haemolytic Uraemic Syndrome (ECUSTEC): A Randomised, Double-Blind, Placebo-Controlled Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Eculizumab in Shiga-toxin producing E. Coli Haemolytic Uraemic Syndrome (ECUSTEC): A Randomised, Double-Blind, Placebo-Controlled Trial
    A.3.2Name or abbreviated title of the trial where available
    ECUSTEC
    A.4.1Sponsor's protocol code number7837
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN89553116
    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 SponsorNewcastle Upon Tyne Hospitals NHS Foundation Trust
    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 supportNIHR and MRC Efficacy and Mechanism Evaluation programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle upon Tyne Hospitals NHS Foundation Trust
    B.5.2Functional name of contact pointSean Scott
    B.5.3 Address:
    B.5.3.1Street AddressJoint Research Office, Level 1 Regent Point,
    B.5.3.2Town/ cityRegent Farm Road, Gosforth, Newcastle upon Tyne
    B.5.3.3Post codeNE3 3HD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01912825969
    B.5.6E-mailTnu-tr.sponsormanagement@nhs.net
    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 Yes
    D.2.1.1.1Trade name Soliris
    D.2.1.1.2Name of the Marketing Authorisation holderAlexion Europe SAS
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameSoliris
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEculizumab
    D.3.9.1CAS number 219685-50-4
    D.3.9.2Current sponsor code7837
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Shiga-toxin producing E. Coli Haemolytic Uraemic Syndrome (STEC HUS)
    E.1.1.1Medical condition in easily understood language
    Haemolytic Uraemic Syndrome caused by shiga-toxin producing E. Coli
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10018932
    E.1.2Term Haemolytic uraemic syndrome
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether the severity of Shiga-toxin producing Escherichia Coli Haemolytic Syndrome (STEC HUS) is less in patients who receive eculizumab, compared to those given placebo.
    E.2.2Secondary objectives of the trial
    Secondary study objectives are:

    - assessing the safety of eculizumab in STEC HUS
    - to determine if the incidence of Chronic Kidney Disease (CKD) following STEC HUS is less in those given Ecu compared to placebo
    - to evaluate the cost effectiveness of giving eculizumab in STEC HUS from the perspective of the NHS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The trial population will be children who fulfil the following inclusion criteria:

    1. Age 6 months to <19 years

    2. Weight ≥5kg

    3. Diagnosis of HUS
    a. Micro-angiopathic haemolytic anaemia (indicated by fragmented red cells on blood film OR plasma lactate dehydrogenase above local centre reference range)
    AND
    b. Thrombocytopenia (platelets <150x109/l)
    AND
    c. Acute Kidney Injury (AKI): “injury” or “failure” category of pRIFLE criteria despite correction of hypovolaemia

    4. EITHER
    Reported diarrhoea within 14 days prior to diagnosis of HUS (defined according to World Health Organisation as “the passage of three or more loose or liquid stools per day - or more frequent passage than is normal for the individual”)
    OR
    Passage of blood per rectum within 14 days prior to diagnosis of HUS
    OR
    A stool culture or shiga toxin polymerase chain reaction or STEC serology result indicating STEC in the patient OR Stool culture or shiga toxin polymerase chain reaction (PCR) or STEC serology result indicating STEC in a close contact (household or institutional) setting

    5. Patient intended to be able to receive trial drug within 48 hours of the on-call paediatric nephrologist formally taking over the care of the patient at the trial site providing inclusion criteria 3 is met, or within 48 hours of meeting inclusion criteria 3 if not met at the time the on-call paediatric nephrologist takes over the care of the patient.

    6. Sexually active male or female patients must agree to be practicing an effective, reliable and medically approved contraceptive regimen for 6 months after enrolment.

    7. Sexually active female patient has provided a negative pregnancy test ≤48 hours prior to randomisation.

    8. Patient/parent/guardian reported that vaccinations are up to date according to the routine UK (or equivalent) immunisation schedule.

    9. Written informed consent obtained from the patient's parents/guardians and written assent obtained from patient (where age appropriate). Patient's aged 16 years and above will provide their own written consent.

    E.4Principal exclusion criteria
    Patients will not be entered if they fulfil any of the following exclusion criteria:
    1. Family history of atypical HUS
    2. Previous episode of HUS
    3. Known pre-existing eGFR <90ml/min/1.73m2
    4. Known or suspected pneumococcal infection
    5. Known or suspected meningococcal infection
    6. Prior to diagnosis, patient taking a drug known to be associated with HUS, e.g. calcineurin inhibitors, chemotherapy, quinine, oral contraceptive pill
    7. Hypersensitivity to Ecu, murine proteins or any of the excipients listed in the Summary of Product Characteristics
    8. Pregnancy or lactation
    9. Malignancy
    10. Known Disseminated Intravascular Coagulopathy
    11. Refusal of consent, including consent for pregnancy testing, meningococcal vaccination or antibiotic prophylaxis
    12. Currently participating in another clinical trial of an investigational medicinal product.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is a purpose-developed, multi-domain clinical severity score. A single score is designated at day 60 to reflect cumulative morbidity up until that point. The STEC HUS clinical severity score is a multi-domain score comprising severity of AKI and extra-renal events, developed by the protocol contributors for use as an outcome measure. The score has a range of 1 to 69, with higher scores indicating greater disease severity. Since severity of acute kidney injury (AKI) is a significant prognostic factor, the score is weighted for severity of the AKI. Pilot data shows mean severity score 13.16 with standard deviation (SD) 9.66. The clinical severity score is presented in Appendix 1 of the protocol. ECUSTEC is powered to detect a 5 point difference between arms in the severity score with 80% power.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 60.
    E.5.2Secondary end point(s)
    1. Overall survival
    2. Duration of renal replacement therapy (days)
    3. Duration of thrombocytopenia (number of consecutive days until platelet count >150x109/l)
    4. Duration of haemolysis (number of days until lactate dehydrogenase (LDH) within local centre reference range)
    5. Number of packed red blood cell transfusions required and volume (ml/kg)
    6. Duration markers of inflammation present (number of days until neutrophil cell count and C-reactive protein are in normal range for that centre)
    7. CKD at 52 weeks (a composite endpoint of the presence of hypertension [average of 3 readings by manual method using centile charts for age/sex/height], albuminuria [urine albumin-creatinine ratio >2.5mg/mmol on early morning urine] or estimated Glomerular Filtration Rate eGFR<90ml/min/1.73m2 at 52 weeks). Presence of any of these will constitute CKD at 1 year.
    8. eGFR measurement using a centralised cystatin C assay at 52 weeks.
    9. Persistent neurological defect at day 60 measured by structured expert assessment to include CNS examination, vision, hearing and neuropsychological assessment
    10. Economic evaluation of cost per clinical severity score point, and cost per QALY gained, using Paediatric Quality of Life Inventory (PedsQL) and Child Health Utility- 9D (CHU-9D) assessments to measure health related quality of life (HR QoL).
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary outcome measures will be analysed up to the point the patient completes the follow-up period of 12 months. (All participants will be followed-up for 52 weeks from randomisation, with daily trial assessments until up until either hospital discharge or day 14 (whichever is soonest). If hospital admission lasts >14 days, then assessments will continue to be taken weekly from day 14 to discharge or day 60 (whichever is soonest). All patients will be assessed at 30 and 60 days, and then at 26 and 52 weeks post randomisation for trial follow-up assessments).
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    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 Yes
    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
    The end of trial will be 6 months after the last data capture. The last data capture will be 12 months following recruitment of the last patient. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trials Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 50
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 70
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state134
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 134
    F.4.2.2In the whole clinical trial 134
    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)
    If the trial were to show eculizumab is successful in reducing the severity of STEC HUS, it would be the first treatment proven to alter the disease course and will have a significant impact on the knowledge of STEC HUS.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR Clinical Research Network: North East and North Cumbria
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-03-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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