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    Summary
    EudraCT Number:2017-003724-79
    Sponsor's Protocol Code Number:17SM4152
    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:2018-04-13
    Trial 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 number2017-003724-79
    A.3Full title of the trial
    IL-1 Signal Inhibition in Alcoholic Hepatitis (Isaiah)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    IL-1 Signal Inhibition in Alcoholic Hepatitis
    A.3.2Name or abbreviated title of the trial where available
    IL-1 Signal Inhibition in Alcoholic Hepatitis (Isaiah)
    A.4.1Sponsor's protocol code number17SM4152
    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 SponsorImperial 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 supportNovartis Pharmaceuticals UK Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College
    B.5.2Functional name of contact pointProfessor Mark Thursz
    B.5.3 Address:
    B.5.3.1Street AddressNorfolk Place
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW2 1NY
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02033126454
    B.5.6E-mailm.thursz@imperial.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 Yes
    D.2.1.1.1Trade name Ilaris
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameIlaris
    D.3.4Pharmaceutical form Solution for injection/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 INNCanakinumab
    D.3.9.1CAS number 914613-48-2
    D.3.9.2Current sponsor codeACZ885
    D.3.9.3Other descriptive nameEV substance code: SUB30137
    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 number150
    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) No
    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 injection/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
    Alcoholic Hepatitis
    E.1.1.1Medical condition in easily understood language
    Inflammation of the liver caused by excessive alcohol consumption
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10001624
    E.1.2Term Alcoholic hepatitis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective is to explore the potential benefits of the IL-1β antibody, Canakinumab, in the treatment of alcoholic hepatitis
    E.2.2Secondary objectives of the trial
    We wish to determine whether Canakinumab reduces mortality rates in patients with severe alcoholic hepatitis at 90 days, increases the rate of recovery of liver function, reduces the risk of acute kidney injury and reduces the risk of the systemic inflammatory response syndrome (SIRS).
    We wish to determine the safety and tolerability of Canakinumab and establish whether Canakinumab influences the risk of infection. We will evaluate whether identification of patients with a high infection risk using bacterial DNA measurement coupled with antibiotic prophylaxis is a successful strategy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    * Male and female patients aged 18 years or older at screening
    * Clinical diagnosis of alcoholic hepatitis at screening:
    - Serum bilirubin > 80μmol/L
    - History of excess alcohol (> 80g/day male, > 60g/day female) to within 6 weeks before screening visit
    - Less than 4 weeks since admission to hospital at baseline visit
    * mDF ≥ 32 and MELD ≤ 27 at baseline visit
    * Informed consent
    * Women of child-bearing potential have to use an effective contraception method (as defined in detail in study protocol)
    E.4Principal exclusion criteria
    • Alcohol abstinence of >6 weeks prior to randomization/baseline visit
    • Duration of clinically apparent jaundice > 3 months before baseline visit
    • Other causes of liver disease including:
    o Evidence of chronic viral hepatitis (Hepatitis B or C)
    o Biliary obstruction
    o Hepatocellular carcinoma
    • Evidence of current malignancy (except non-melanotic skin cancer)
    • Previous entry into the study, or use of either prednisolone any systemic steroids (equivalent to a dose of systemic prednisolone >20mg) within 6 weeks of screening.
    • AST >500 U/L or ALT >300 U/L (not compatible with alcoholic hepatitis)
    • Patients with a serum creatinine >220 μmol/L (2.5 mg / dL) or requiring renal support
    • Patients dependent upon inotropic support (adrenaline or noradrenaline). Terlipressin is allowed
    • Variceal haemorrhage on this admission
    • Untreated sepsis
    • Patients with known hypersensitivity or contraindications to Canakinumab
    • Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction (within the last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation)
    • Pregnant or lactating women
    • Patients treated with other IL-1 inhibitors and biologics or any other immunosuppressants within 3 months of study participation.
    • Known infection with HIV at screening or randomization
    History or evidence of tuberculosis (TB) (active or latent) infection
    • History or evidence of tuberculosis (TB) (active or latent) infection
    • Active ongoing inflammatory diseases other than AAH that might confound the evaluation of the benefit of canakinumab therapy
    • Underlying metabolic, hematologic, renal, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions, including neutropenia (ANC >1.5) and leukopenia, which in the opinion of the investigator immune-compromises the subject and/or places the subject at unacceptable risk for participation in an immunomodulatory therapy.
    • Significant medical problems or diseases, including but not limited to the following: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure [New York Heart Association status of class III or IV], uncontrolled diabetes
    • Vaccination with a live vaccine within 3 month before baseline
    E.5 End points
    E.5.1Primary end point(s)
    Histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment compared to baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days after baseline / randomisation into the study
    E.5.2Secondary end point(s)
    • Improvement of individual components (polymorphonuclear cell infiltrate, ballooned hepatocytes and steatosis) of alcoholic hepatitis on liver histology from baseline to Day 28
    • Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) (1) from baseline to Day 28
    • Changes in the components of Nonalcoholic fatty liver disease activity score (NAS) score from baseline to Day 28
    • Changes in hepatic venous pressure gradient (HVPG) between baseline and day 28
    • Changes of serum CK18-M30/M65 from baseline to Day 7, 14, 21, 28, 42 and 90
    • Change in serum bilirubin from baseline to Day 7, 14, 28, 21, 42 and 90
    • Change in MELD score at from baseline to Day 7, 14, 21, 28, 42 and 90
    • Change in Glasgow alcoholic hepatitis score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 90
    • Change in mDF score from baseline to Day 7, 14, 21, 28, 42 and 90
    • Lille score at Day 7
    • Resolution of systemic inflammatory response syndrome (SIRS) at Day 7, 14, 21, 28, 42 and 90 in patients with SIRS at baseline
    • Incidence of SIRS at Day 7, 14, 21, 28, 42 and 90 in patients without SIRS at baseline
    • Mortality rate at Day 90
    • Incidence of infection and sepsis over 90 days
    • Incidence of acute kidney injury over 90 days
    • Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days
    • safety and tolerability of canakinumab
    • Serum and plasma biomarkers of hepatic function and inflammation including cytokine profiles which may indicate the degree of response to IL-1b inhibition.
    • Changes in CRP over time
    • Length of hospital stay
    E.5.2.1Timepoint(s) of evaluation of this end point
    As detailed in the above box
    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 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 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 No
    E.8.1.3Single blind No
    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.8.2.4Number 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 concerned18
    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
    90 days after randomisation of the last patient (last patient last visit).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days30
    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: 52
    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 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 state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 52
    F.4.2.2In the whole clinical trial 52
    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)
    Patients will return to their routine care and clinic appointments at the end of the trial and no longer provided with the research treatment after their last research visit.

    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 Decision2018-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-10
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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