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Trial record 19 of 311 for:    Recruiting, Not yet recruiting, Available Studies | Inhibition

IL-1 Signal Inhibition in Alcoholic Hepatitis (ISAIAH)

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ClinicalTrials.gov Identifier: NCT03775109
Recruitment Status : Recruiting
First Posted : December 13, 2018
Last Update Posted : October 31, 2019
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Imperial College London

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis Drug: Canakinumab 150mg/ml solution for injection Drug: Placebo Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: IL-1 Signal Inhibition in Alcoholic Hepatitis (ISAIAH)
Actual Study Start Date : December 21, 2018
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Canakinumab

Arm Intervention/treatment
Active Comparator: Canakinumab 150mg/ml solution for injection
150mg/ml solution for injection
Drug: Canakinumab 150mg/ml solution for injection
Canakinumab 150mg/ml solution for injection

Placebo Comparator: Dextrose Drug: Placebo
100ml 5% Dextrose




Primary Outcome Measures :
  1. Histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment compared to baseline. [ Time Frame: Baseline and 28 days ]
    Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).


Secondary Outcome Measures :
  1. Improvement of individual components of alcoholic hepatitis on liver histology from baseline to Day 28. [ Time Frame: Baseline and 28 days ]
    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.

  2. Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) from baseline to Day 28 [ Time Frame: Baseline and 28 days ]
    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.

  3. Changes in the components of Nonalcoholic fatty liver disease activity score (NAS) from baseline to Day 28 [ Time Frame: Baseline and 28 days ]
    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.

  4. Changes in hepatic venous pressure gradient (HVPG) between baseline and day 28 [ Time Frame: Baseline and 28 days ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
    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

  8. Change in Glasgow Alcoholic Hepatitis Score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 90 [ Time Frame: 90 days ]
    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.

  9. 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 ]
    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.

  10. Lille score at Day 7 [ Time Frame: 7 days ]

    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%.


  11. 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 ]

    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%

  12. 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 ]

    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%

  13. Mortality rate at Day 90 [ Time Frame: 90 days ]
  14. Incidence of infection and sepsis over 90 days [ Time Frame: 90 days ]
  15. Incidence of acute kidney injury over 90 days [ Time Frame: 90 days ]
  16. Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days [ Time Frame: 90 days ]
  17. Safety and tolerability of canakinumab [ Time Frame: 90 days ]
    The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events.

  18. 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 ]

    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


  19. Changes in CRP over time [ Time Frame: 90 days ]
  20. Length of hospital stay [ Time Frame: 90 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 specified in section 9.6).

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:

    • Evidence of chronic viral hepatitis (Hepatitis B or C)
    • Biliary obstruction
    • Hepatocellular carcinoma
  • Evidence of current malignancy (except non-melanotic skin cancer)
  • Previous entry into the study, or use of either prednisolone or 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 (see below)
  • Patients dependent upon inotropic support (adrenaline or noradrenaline). Terlipressin is allowed
  • Variceal haemorrhage on this admission
  • Untreated sepsis (see below)
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03775109


Contacts
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Contact: Mark Thursz, MBBS MD FRCP 02075940995 isaiah@imperial.ac.uk
Contact: Karolina Bogdanowicz, PhD 02075940995 isaiah@imperial.ac.uk

Locations
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United Kingdom
University Hospitals Bristol NHS Foundation Trust Recruiting
Bristol, United Kingdom
Contact: Anne McCune         
Glasgow Royal Infirmary, Greater Glasgow & Clyde Recruiting
Glasgow, United Kingdom, G4 0SF
Contact: Ewan Forrest         
Queen Elizabeth University Hospital Recruiting
Glasgow, United Kingdom
Principal Investigator: Ewan Forrest         
Leeds Teaching Hospitals NHS Trust Recruiting
Leeds, United Kingdom
Contact: Richard Parker         
Aintree University Hospital Recruiting
Liverpool, United Kingdom
Contact: Cyril SIEBERHAGEN         
Royal Liverpool and Broadgreen University Hospitals NHS Trust Recruiting
Liverpool, United Kingdom
Contact: Paul Richardson         
Imperial College Healthcare NHS Foundation Trust Recruiting
London, United Kingdom, W2 1NY
Contact: Mark Thursz    020 3312 5359      
Chelsea and Westminster Hospital NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Matthew Foxton         
King's College Hospital NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Vishal Patel         
Royal Free London NHS Foundation Trust Recruiting
London, United Kingdom
Contact: David Patch         
The Newcastle Upon Tyne Hospitals NHS Foundation Trust Recruiting
Newcastle Upon Tyne, United Kingdom
Contact: Steve Masson         
Nottingham University Hospitals NHS Trust Recruiting
Nottingham, United Kingdom
Contact: Stephen Ryder         
John Radcliffe Hospital, Oxford University NHS Foundation Trust Recruiting
Oxford, United Kingdom, OX3 9DU
Contact: Jeremy Cobbold         
Plymouth Hospitals NHS Trust Recruiting
Plymouth, United Kingdom
Contact: Ashwin Dhanda         
Sheffield Teaching Hospitals NHS Foundation Trust Not yet recruiting
Sheffield, United Kingdom
Contact: Amer Al-Joudeh         
University Hospital Southampton NHS Foundation Trust Not yet recruiting
Southampton, United Kingdom
Contact: Mark Wright         
Sponsors and Collaborators
Imperial College London
Novartis Pharmaceuticals
Investigators
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Study Director: Mark Thursz Imperial College London

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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT03775109     History of Changes
Other Study ID Numbers: 17SM4152
First Posted: December 13, 2018    Key Record Dates
Last Update Posted: October 31, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Imperial College London:
Canakinumab
Alcoholic Hepatitis
Alcohol Use Disorder
Interleukin
Treatment
Ilaris
Liver disease
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis
Hepatitis, Alcoholic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Liver Diseases, Alcoholic
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Pharmaceutical Solutions
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs