<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03775109</url>
  </required_header>
  <id_info>
    <org_study_id>17SM4152</org_study_id>
    <nct_id>NCT03775109</nct_id>
  </id_info>
  <brief_title>IL-1 Signal Inhibition in Alcoholic Hepatitis</brief_title>
  <acronym>ISAIAH</acronym>
  <official_title>IL-1 Signal Inhibition in Alcoholic Hepatitis (ISAIAH)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by&#xD;
      liver failure in the context of recent and heavy alcohol consumption. The condition carries a&#xD;
      high fatality risk; patients with severe AH have a 30% mortality rate at 90 days after&#xD;
      presentation.&#xD;
&#xD;
      Currently there is no effective treatment for severe alcoholic hepatitis. Based on our&#xD;
      current understanding of the disease pathogenesis IL-1 (interleukin) is a key mediator of&#xD;
      hepatic inflammation responsible for metabolic disturbances, fibrogenesis stellate cell&#xD;
      activation and consequently portal hypertension.&#xD;
&#xD;
      Canakinumab is a licensed monoclonal antibody inhibitor of IL-1 and may consequently reverse&#xD;
      the adverse effects of the cytokine in patients with this disorder. Therefore, the main&#xD;
      objective of the ISAIAH trial is to explore the potential benefits of the IL-1β antibody,&#xD;
      Canakinumab (solution for injection), in the treatment of alcoholic hepatitis.&#xD;
&#xD;
      ISAIAH is a multicentre, double blind, randomized (1:1), placebo controlled trial. The trial&#xD;
      will follow patients up for 90 days and will be conducted in centres across the United&#xD;
      Kingdom. Twenty-six patients will be recruited to each arm of the trial: total 52 patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main objective of the ISAIAH trial is to explore the potential benefits of the IL-1β&#xD;
      antibody, Canakinumab (solution for injection), in the treatment of alcoholic hepatitis.&#xD;
&#xD;
      ISAIAH is a multicentre, double blind, randomized (1:1), placebo controlled trial. The trial&#xD;
      will follow patients up for 90 days and will be conducted in centres across the United&#xD;
      Kingdom. Twenty-six patients will be recruited to each arm of the trial: total 52 patients.&#xD;
&#xD;
      The trial will be conducted in patients with severe alcoholic hepatitis (mDF* ≥ 32 and MELD&#xD;
      ≤27) with treatment initiated during an index hospital admission with the condition.&#xD;
&#xD;
      The primary endpoint of the trial is histological improvement of alcoholic hepatitis on liver&#xD;
      biopsy after 28 days of treatment compared to baseline. Histological improvement is defined&#xD;
      as a reduction in lobular inflammation (regardless of cell type).&#xD;
&#xD;
      Patients meeting the eligibility criteria will be randomized and treated. A single dose of 3&#xD;
      mg/kg Canakinumab or identical placebo will be administered intravenously at baseline (Day&#xD;
      1). Canakinumab will be made up by dilution in 100 ml 5% Dextrose by an unblinded research&#xD;
      personnel at each site.&#xD;
&#xD;
      Patients with AST &gt;2 x ULN on Day 28 will receive a second dose of 3 mg/kg study drug&#xD;
      administered i.v. on Day 28. Patients who received placebo on baseline will receive placebo.&#xD;
      Patients who received canakinumab on baseline will receive canakinumab.&#xD;
&#xD;
      Total follow up time for each patient is 90 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 21, 2018</start_date>
  <completion_date type="Anticipated">May 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment compared to baseline.</measure>
    <time_frame>Baseline and 28 days</time_frame>
    <description>Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement of individual components of alcoholic hepatitis on liver histology from baseline to Day 28.</measure>
    <time_frame>Baseline and 28 days</time_frame>
    <description>Improvement will be recorded as a binary Yes/No outcome. The outcome will be analysed as the percentage of patients, within each treatment group, with improvement on each individual component (polymorphonuclear cell infiltrate, ballooned hepatocytes and steatosis). Analysis will be based on three pairs of percentages which will represent the proportion of patients with improvement for each component.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) from baseline to Day 28</measure>
    <time_frame>Baseline and 28 days</time_frame>
    <description>Four histologic features are combined to create the AHHS score: Fibrosis stage (0-3), bilirubinostasis (0-2), polymorphonuclear infiltration (0-2), and megamitochondria (0-2) for a total of 9 points (Mild 0-3; Intermediate 4-5; Severe 6-9). AHHS score will be compared between active treatment and placebo treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the components of Nonalcoholic fatty liver disease activity score (NAS) from baseline to Day 28</measure>
    <time_frame>Baseline and 28 days</time_frame>
    <description>The NAS score combines steatosis grade, lobular inflammation, and liver cell injury (ballooning). Scoring: 0-2 Not steatohepatitis; 3-4 Indeterminate; ≥5, Steatohepatitis. NAS score will be compared between active treatment and placebo treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in hepatic venous pressure gradient (HVPG) between baseline and day 28</measure>
    <time_frame>Baseline and 28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in serum CK18-M30/M65 from baseline to Day 7, 14, 21, 28, 42 and 90</measure>
    <time_frame>Baseline and 7, 14, 21, 28, 42, 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum bilirubin from baseline to Day 7, 14, 28, 21, 42 and 90</measure>
    <time_frame>Baseline and 7, 14, 21, 28, 42, 90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in MELD (Model For End-Stage Liver Disease) score at from baseline to Day 7, 14, 21, 28, 42 and 90</measure>
    <time_frame>Baseline and 7, 14, 21, 28, 42, 90 days</time_frame>
    <description>MELD score is based on the following formula: MELD Score = 10 * ((0.957 * ln(Creatinine)) + (0.378 * ln(Bilirubin)) + (1.12 * ln(INR))) + 6.43</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Glasgow Alcoholic Hepatitis Score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 90</measure>
    <time_frame>90 days</time_frame>
    <description>Predicts mortality in patients with alcoholic hepatitis by laboratory results and age. GAHS score is calculated after Forrest et al., 2007 where a score of 1-3 is assigned based on age, WCC, Urea, PT ratio or INR and bilirubin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Maddrey's Discriminant Function (mDF) score from baseline to Day 7, 14, 21, 28, 42 and 90</measure>
    <time_frame>Baseline and 7, 14, 21, 28, 42, 90 days</time_frame>
    <description>mDF is calculated using the following formula: mDF = 4.6 x (Prothrombin time (PTPATIENT - PTCONTROL) + Serum Bilirubin (μmol/l) / 17.1 (PTCONTROL is defined as the mean value at each site; this mean value may be updated on a weekly or monthly basis), where a higher score is associated with poorer prognosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lille score at Day 7</measure>
    <time_frame>7 days</time_frame>
    <description>Lille score is calculated as Exp(-R)/[1+exp(-R)] where R = [3.19 - (0.101*age in years)] + (1.47*albumin at baseline in g/dL) + [0.28215* (bilirubin at baseline - bilirubin at Day 8 in mg/dL)] - [0.206 * (if creatinine&gt;=1.3 mg/dL at baseline)] - [0.11115*bilirubin baseline in mg/dL] - (0.0096*Prothrombin Time in seconds at baseline).&#xD;
The Lille Model predicts mortality rates within 6 months. Scores &gt;0.45 predict a 6-month survival of 25%. Scores &lt;0.45 predict a 6-month survival of 85%.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 7, 14, 21, 28, 42 and 90 in patients with SIRS at baseline</measure>
    <time_frame>Baseline and 7, 14, 21, 28, 42, 90 days</time_frame>
    <description>Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; where SIRS represents the presence of 2 or more criteria out of following:&#xD;
Temperature &lt; 36 ºC or &gt; 38 ºC&#xD;
Heart rate &gt; 90 beats/minute&#xD;
Respiratory rate &gt; 20 breaths/minute or venous pCO2 &lt;32 mmHg&#xD;
Leukocyte count &gt; 12,000/mm3 or &lt; 4,000/mm3 or band forms &gt; 10%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of SIRS at Day 7, 14, 21, 28, 42 and 90 in patients without SIRS at baseline</measure>
    <time_frame>Baseline and 7, 14, 21, 28, 42, 90 days</time_frame>
    <description>Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; where SIRS represents the presence of 2 or more criteria out of following:&#xD;
Temperature &lt; 36 ºC or &gt; 38 ºC&#xD;
Heart rate &gt; 90 beats/minute&#xD;
Respiratory rate &gt; 20 breaths/minute or venous pCO2 &lt;32 mmHg&#xD;
Leukocyte count &gt; 12,000/mm3 or &lt; 4,000/mm3 or band forms &gt; 10%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality rate at Day 90</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of infection and sepsis over 90 days</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute kidney injury over 90 days</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of canakinumab</measure>
    <time_frame>90 days</time_frame>
    <description>The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum and plasma biomarkers of hepatic function and inflammation including cytokine profiles which may indicate the degree of response to IL-1b inhibition.</measure>
    <time_frame>90 days</time_frame>
    <description>The aim is to monitor baseline levels of cytokines linked to inflammasome activation and their changes after active IMP treatment. The proposed method and cytokines is as follows:&#xD;
MSD 7-plex kit will be used for the detection of the following cytokines: IL-18, IL-1β*, IL-1ra, IL-6, IL-8, IFNγ** and TNF-α&#xD;
ELLA 1-plex will be used for the detection of the following cytokines: IL-18Bpa</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in CRP over time</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">1300</enrollment>
  <condition>Alcoholic Hepatitis</condition>
  <arm_group>
    <arm_group_label>Canakinumab 150mg/ml solution for injection</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>150mg/ml solution for injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dextrose</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Canakinumab 150mg/ml solution for injection</intervention_name>
    <description>Canakinumab 150mg/ml solution for injection</description>
    <arm_group_label>Canakinumab 150mg/ml solution for injection</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>100ml 5% Dextrose</description>
    <arm_group_label>Dextrose</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female patients aged 18 years or older at screening&#xD;
&#xD;
          -  Clinical diagnosis of alcoholic hepatitis at screening:&#xD;
&#xD;
               -  Serum bilirubin &gt; 80μmol/L&#xD;
&#xD;
               -  History of excess alcohol (&gt; 80g/day male, &gt; 60g/day female) to within 6 weeks&#xD;
                  before screening visit&#xD;
&#xD;
               -  Less than 4 weeks since admission to hospital at baseline visit&#xD;
&#xD;
          -  mDF* ≥ 32 and MELD ≤ 27 at baseline visit&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
          -  Women of child-bearing potential have to use an effective contraception method (as&#xD;
             specified in section 9.6).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Alcohol abstinence of &gt;6 weeks prior to randomization/baseline visit&#xD;
&#xD;
          -  Duration of clinically apparent jaundice &gt; 3 months before baseline visit&#xD;
&#xD;
          -  Other causes of liver disease including:&#xD;
&#xD;
               -  Evidence of chronic viral hepatitis (Hepatitis B or C)&#xD;
&#xD;
               -  Biliary obstruction&#xD;
&#xD;
               -  Hepatocellular carcinoma&#xD;
&#xD;
          -  Evidence of current malignancy (except non-melanotic skin cancer)&#xD;
&#xD;
          -  Previous entry into the study, or use of either prednisolone or any systemic steroids&#xD;
             (equivalent to a dose of systemic prednisolone &gt;20mg) within 6 weeks of screening.&#xD;
&#xD;
          -  AST &gt;500 U/L or ALT &gt;300 U/L (not compatible with alcoholic hepatitis)&#xD;
&#xD;
          -  Patients with a serum creatinine &gt;220 μmol/L (2.5 mg / dL) or requiring renal support&#xD;
             (see below)&#xD;
&#xD;
          -  Patients dependent upon inotropic support (adrenaline or noradrenaline). Terlipressin&#xD;
             is allowed&#xD;
&#xD;
          -  Variceal haemorrhage on this admission&#xD;
&#xD;
          -  Untreated sepsis (see below)&#xD;
&#xD;
          -  Patients with known hypersensitivity or contraindications to Canakinumab&#xD;
&#xD;
          -  Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial&#xD;
             infarction (within the last 6 weeks) or severe cardiac arrhythmias (not including&#xD;
             atrial fibrillation)&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Patients treated with other IL-1 inhibitors and biologics or any other&#xD;
             immunosuppressants within 3 months of study participation.&#xD;
&#xD;
          -  Known infection with HIV at screening or randomization&#xD;
&#xD;
          -  History or evidence of tuberculosis (TB) (active or latent) infection&#xD;
&#xD;
          -  Active ongoing inflammatory diseases other than AAH that might confound the evaluation&#xD;
             of the benefit of canakinumab therapy&#xD;
&#xD;
          -  Underlying metabolic, hematologic, renal, pulmonary, neurologic, endocrine, cardiac,&#xD;
             infectious or gastrointestinal conditions, including neutropenia (ANC &lt;1.5) and&#xD;
             leukopenia, which in the opinion of the investigator immune-compromises the subject&#xD;
             and/or places the subject at unacceptable risk for participation in an&#xD;
             immunomodulatory therapy.&#xD;
&#xD;
          -  Significant medical problems or diseases, including but not limited to the following:&#xD;
             uncontrolled hypertension (≥160/95 mmHg), congestive heart failure [New York Heart&#xD;
             Association status of class III or IV], uncontrolled diabetes&#xD;
&#xD;
          -  Vaccination with a live vaccine within 3 month before baseline&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark Thursz</last_name>
    <role>Study Director</role>
    <affiliation>Imperial College London</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mark Thursz, MBBS MD FRCP</last_name>
    <phone>02075940995</phone>
    <email>isaiah@imperial.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Justyna Czyzewska-Khan</last_name>
    <phone>02075941687</phone>
    <email>isaiah@imperial.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospitals Bristol NHS Foundation Trust</name>
      <address>
        <city>Bristol</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anne McCune</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Glasgow Royal Infirmary, Greater Glasgow &amp; Clyde</name>
      <address>
        <city>Glasgow</city>
        <zip>G4 0SF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ewan Forrest</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth University Hospital</name>
      <address>
        <city>Glasgow</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Leeds Teaching Hospitals NHS Trust</name>
      <address>
        <city>Leeds</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Richard Parker</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Aintree University Hospital</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cyril SIEBERHAGEN</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Liverpool and Broadgreen University Hospitals NHS Trust</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paul Richardson</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Imperial College Healthcare NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>W2 1NY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mark Thursz</last_name>
      <phone>020 3312 5359</phone>
    </contact>
  </location>
  <location>
    <facility>
      <name>Chelsea and Westminster Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gavin Whitehouse</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>King's College Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vishal Patel</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal Free London NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Patch</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>St George's University Hospitals NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arjuna Singanayagam</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Newcastle Upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle Upon Tyne</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Steve Masson</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Nottingham University Hospitals NHS Trust</name>
      <address>
        <city>Nottingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stephen Ryder</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>John Radcliffe Hospital, Oxford University NHS Foundation Trust</name>
      <address>
        <city>Oxford</city>
        <zip>OX3 9DU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeremy Cobbold</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Plymouth Hospitals NHS Trust</name>
      <address>
        <city>Plymouth</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ashwin Dhanda</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Southampton NHS Foundation Trust</name>
      <address>
        <city>Southampton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mark Wright</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 13, 2018</study_first_posted>
  <last_update_submitted>February 9, 2023</last_update_submitted>
  <last_update_submitted_qc>February 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Canakinumab</keyword>
  <keyword>Alcoholic Hepatitis</keyword>
  <keyword>Alcohol Use Disorder</keyword>
  <keyword>Interleukin</keyword>
  <keyword>Treatment</keyword>
  <keyword>Ilaris</keyword>
  <keyword>Liver disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Hepatitis, Alcoholic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03775109
org study id: 17SM4152
nct id: NCT03775109
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by
      liver failure in the context of recent and heavy alcohol consumption. The condition carries a
      high fatality risk; patients with severe AH have a 30% mortality rate at 90 days after
      presentation.

      Currently there is no effective treatment for severe alcoholic hepatitis. Based on our
      current understanding of the disease pathogenesis IL-1 (interleukin) is a key mediator of
      hepatic inflammation responsible for metabolic disturbances, fibrogenesis stellate cell
      activation and consequently portal hypertension.

      Canakinumab is a licensed monoclonal antibody inhibitor of IL-1 and may consequently reverse
      the adverse effects of the cytokine in patients with this disorder. Therefore, the main
      objective of the ISAIAH trial is to explore the potential benefits of the IL-1β antibody,
      Canakinumab (solution for injection), in the treatment of alcoholic hepatitis.

      ISAIAH is a multicentre, double blind, randomized (1:1), placebo controlled trial. The trial
      will follow patients up for 90 days and will be conducted in centres across the United
      Kingdom. Twenty-six patients will be recruited to each arm of the trial: total 52 patients.
The main objective of the ISAIAH trial is to explore the potential benefits of the IL-1β
      antibody, Canakinumab (solution for injection), in the treatment of alcoholic hepatitis.

      ISAIAH is a multicentre, double blind, randomized (1:1), placebo controlled trial. The trial
      will follow patients up for 90 days and will be conducted in centres across the United
      Kingdom. Twenty-six patients will be recruited to each arm of the trial: total 52 patients.

      The trial will be conducted in patients with severe alcoholic hepatitis (mDF* ≥ 32 and MELD
      ≤27) with treatment initiated during an index hospital admission with the condition.

      The primary endpoint of the trial is histological improvement of alcoholic hepatitis on liver
      biopsy after 28 days of treatment compared to baseline. Histological improvement is defined
      as a reduction in lobular inflammation (regardless of cell type).

      Patients meeting the eligibility criteria will be randomized and treated. A single dose of 3
      mg/kg Canakinumab or identical placebo will be administered intravenously at baseline (Day
      1). Canakinumab will be made up by dilution in 100 ml 5% Dextrose by an unblinded research
      personnel at each site.

      Patients with AST >2 x ULN on Day 28 will receive a second dose of 3 mg/kg study drug
      administered i.v. on Day 28. Patients who received placebo on baseline will receive placebo.
      Patients who received canakinumab on baseline will receive canakinumab.

      Total follow up time for each patient is 90 days.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment compared to baseline.
time frame: Baseline and 28 days
description: Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).
measure: Improvement of individual components of alcoholic hepatitis on liver histology from baseline to Day 28.
time frame: Baseline and 28 days
description: Improvement will be recorded as a binary Yes/No outcome. The outcome will be analysed as the percentage of patients, within each treatment group, with improvement on each individual component (polymorphonuclear cell infiltrate, ballooned hepatocytes and steatosis). Analysis will be based on three pairs of percentages which will represent the proportion of patients with improvement for each component.
measure: Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) from baseline to Day 28
time frame: Baseline and 28 days
description: Four histologic features are combined to create the AHHS score: Fibrosis stage (0-3), bilirubinostasis (0-2), polymorphonuclear infiltration (0-2), and megamitochondria (0-2) for a total of 9 points (Mild 0-3; Intermediate 4-5; Severe 6-9). AHHS score will be compared between active treatment and placebo treatment groups.
measure: Changes in the components of Nonalcoholic fatty liver disease activity score (NAS) from baseline to Day 28
time frame: Baseline and 28 days
description: The NAS score combines steatosis grade, lobular inflammation, and liver cell injury (ballooning). Scoring: 0-2 Not steatohepatitis; 3-4 Indeterminate; ≥5, Steatohepatitis. NAS score will be compared between active treatment and placebo treatment groups.
measure: Changes in hepatic venous pressure gradient (HVPG) between baseline and day 28
time frame: Baseline and 28 days
measure: Changes in serum CK18-M30/M65 from baseline to Day 7, 14, 21, 28, 42 and 90
time frame: Baseline and 7, 14, 21, 28, 42, 90 days
measure: Change in serum bilirubin from baseline to Day 7, 14, 28, 21, 42 and 90
time frame: Baseline and 7, 14, 21, 28, 42, 90 days
measure: Change in MELD (Model For End-Stage Liver Disease) score at from baseline to Day 7, 14, 21, 28, 42 and 90
time frame: Baseline and 7, 14, 21, 28, 42, 90 days
description: MELD score is based on the following formula: MELD Score = 10 * ((0.957 * ln(Creatinine)) + (0.378 * ln(Bilirubin)) + (1.12 * ln(INR))) + 6.43
measure: Change in Glasgow Alcoholic Hepatitis Score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 90
time frame: 90 days
description: Predicts mortality in patients with alcoholic hepatitis by laboratory results and age. GAHS score is calculated after Forrest et al., 2007 where a score of 1-3 is assigned based on age, WCC, Urea, PT ratio or INR and bilirubin.
measure: Change in Maddrey's Discriminant Function (mDF) score from baseline to Day 7, 14, 21, 28, 42 and 90
time frame: Baseline and 7, 14, 21, 28, 42, 90 days
description: mDF is calculated using the following formula: mDF = 4.6 x (Prothrombin time (PTPATIENT - PTCONTROL) + Serum Bilirubin (μmol/l) / 17.1 (PTCONTROL is defined as the mean value at each site; this mean value may be updated on a weekly or monthly basis), where a higher score is associated with poorer prognosis.
measure: Lille score at Day 7
time frame: 7 days
description: Lille score is calculated as Exp(-R)/[1+exp(-R)] where R = [3.19 - (0.101*age in years)] + (1.47*albumin at baseline in g/dL) + [0.28215* (bilirubin at baseline - bilirubin at Day 8 in mg/dL)] - [0.206 * (if creatinine>=1.3 mg/dL at baseline)] - [0.11115*bilirubin baseline in mg/dL] - (0.0096*Prothrombin Time in seconds at baseline).
The Lille Model predicts mortality rates within 6 months. Scores >0.45 predict a 6-month survival of 25%. Scores <0.45 predict a 6-month survival of 85%.
measure: Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 7, 14, 21, 28, 42 and 90 in patients with SIRS at baseline
time frame: Baseline and 7, 14, 21, 28, 42, 90 days
description: Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; where SIRS represents the presence of 2 or more criteria out of following:
Temperature < 36 ºC or > 38 ºC
Heart rate > 90 beats/minute
Respiratory rate > 20 breaths/minute or venous pCO2 <32 mmHg
Leukocyte count > 12,000/mm3 or < 4,000/mm3 or band forms > 10%
measure: Incidence of SIRS at Day 7, 14, 21, 28, 42 and 90 in patients without SIRS at baseline
time frame: Baseline and 7, 14, 21, 28, 42, 90 days
description: Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; where SIRS represents the presence of 2 or more criteria out of following:
Temperature < 36 ºC or > 38 ºC
Heart rate > 90 beats/minute
Respiratory rate > 20 breaths/minute or venous pCO2 <32 mmHg
Leukocyte count > 12,000/mm3 or < 4,000/mm3 or band forms > 10%
measure: Mortality rate at Day 90
time frame: 90 days
measure: Incidence of infection and sepsis over 90 days
time frame: 90 days
measure: Incidence of acute kidney injury over 90 days
time frame: 90 days
measure: Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days
time frame: 90 days
measure: Safety and tolerability of canakinumab
time frame: 90 days
description: The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events.
measure: Serum and plasma biomarkers of hepatic function and inflammation including cytokine profiles which may indicate the degree of response to IL-1b inhibition.
time frame: 90 days
description: The aim is to monitor baseline levels of cytokines linked to inflammasome activation and their changes after active IMP treatment. The proposed method and cytokines is as follows:
MSD 7-plex kit will be used for the detection of the following cytokines: IL-18, IL-1β*, IL-1ra, IL-6, IL-8, IFNγ** and TNF-α
ELLA 1-plex will be used for the detection of the following cytokines: IL-18Bpa
measure: Changes in CRP over time
time frame: 90 days
measure: Length of hospital stay
time frame: 90 days
arm group label: Canakinumab 150mg/ml solution for injection
arm group type: Active Comparator
description: 150mg/ml solution for injection
arm group label: Dextrose
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Canakinumab 150mg/ml solution for injection
description: Canakinumab 150mg/ml solution for injection
arm group label: Canakinumab 150mg/ml solution for injection
intervention type: Drug
intervention name: Placebo
description: 100ml 5% Dextrose
arm group label: Dextrose
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark Thursz
role: Study Director
affiliation: Imperial College London
last name: Mark Thursz, MBBS MD FRCP
phone: 02075940995
email: isaiah@imperial.ac.uk
last name: Justyna Czyzewska-Khan
phone: 02075941687
email: isaiah@imperial.ac.uk
facility: 
status: Recruiting
contact: 
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status: Terminated
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status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis
mesh term: Hepatitis, Alcoholic
mesh term: Antibodies, Monoclonal
sharing ipd: No