Study Description

A-TANGO - NOVEL TREATMENT OF ACUTE ON CHRONIC LIVER FAILURE USING SYNERGISTIC ACTION OF G-CSF AND TAK-242 (G-TAK)

A-TANGO

Alcohol related liver disease is a frequent chronic disease with a high risk of death. Many patients with superimposed severily inflamed liver develop a newly described syndrome, which is called acute-on-chronic liver failure. Patients present with failing organ function and frequently die despite intensive therapy. The A-TANGO consortium aims to perform a phase 2 clinical trial using a novel, patented and innovative therapeutic strategy, which consists of two compounds, one to block inflammation and another compound to boost regeneration. Additionally, A-TANGO aims to discover novel
biomarkers for patient selection and defining prognosis. The A-TANGO Consortium includes the inventors of G-TAK (UCL, Charité, ULEI and LUMC) and will deliver the project aims through EFCLIF, which has a network of 110 European hospitals. YAQ and HPX are SME's that own the background IP and will ensure regulatory approval, study Sponsorship and drug supply. APHP and IMAC will deliver the economic models. Concentris will manage the project and together with EASL, CHX and ELPA will engage with patients, initiate
widespread dissemination activities and allow exploitation of the results. Gender balance will be maintained throughout the project
duration. A-TANGO will achieve the expected impacts of producing meaningful advances in clinical practice by reducing the
mortality and improving the quality of life of patients with ACLF whilst reducing disease burden of individual patients and health
care systems following validation in late stage clinical trials.

In Europe, about 30,000 people die every year from alcohol related cirrhosis, a form of chronic, non- communicable disease. The
patients that are at highest risk of death are those with superimposed alcoholic hepatitis (AH) who do not respond to therapy and
develop acute on chronic liver failure (ACLF), a newly described syndrome characterised by multiorgan failure. Treatment of ACLF is
an unmet need. Based upon their clinical and pre-clinical studies, The A-TANGO consortium aims to perform Phase 2 clinical trials of a
novel, patented and innovative therapeutic strategy by repurposing a toll-like 4 receptor antagonist (TAK242, Technology Readiness
Level (TRL) 8), which targets inflammation, and combining it with granulocyte colony-stimulating factor (G-CSF, TRL9) that improves
hepatocyte proliferation (G-TAK, TRL4). A successful trial will advance G-TAK to TRL8. Additionally, A-TANGO aims to discover novel
biomarkers for patient selection and defining prognosis, building health economics models and reimbursement strategies to allow
maximal dissemination and exploitation. The A-TANGO Consortium includes the inventors of G-TAK (UCL, Charité, ULEI and LUMC)
and will deliver the project aims through EFCLIF, which has a network of 110 European hospitals. YAQ and HPX are SME's that own
the background IP and will ensure regulatory approval, study Sponsorship and drug supply. APHP and IMAC will deliver the
economic models. Concentris will manage the project and together with EASL, CHX and ELPA will engage with patients, initiate
widespread dissemination activities and allow exploitation of the results. Gender balance will be maintained throughout the project
duration. A-TANGO will achieve the expected impacts of producing meaningful advances in clinical practice by reducing the
mortality and improving the quality of life of patients with ACLF whilst reducing disease burden of individual patients and health
care systems following validation in late stage clinical trials.

Investigated Disease, Health Issue

• K70.4 - Alkoholisches Leberversagen
• K70.1 - Alkoholische Hepatitis

Inclusion Criteria

18 - 99

All

1. Male and female subjects ≥18 of age
2. with a diagnosis of alcoholic hepatitis (Annex 14) that is resistant to steroid therapy defined by a Lille
score of >0.45 (Annex 12) and/or contraindication to steroids.
3. Eligible subjects will have Grade 1- 3a ACLF with a maximum of three organ failures using the CLIF-C
OF score AND the CLIF-C ACLF score of >35 and <60.
Acute-on-chronic liver failure (ACLF) will be defined according to the criteria validated by the EF-CLIF
consortium (1). Subjects with acute decompensation of cirrhosis [defined as acute development of one or
more of the following: ascites (onset and/or worsening), hepatic encephalopathy (onset and/or worsening),
gastrointestinal haemorrhage, bacterial infection] (Annex 13) are classified as ACLF if one of the following
applies:
single kidney failure (serum creatinine level ≥ 2 mg/dl) (ACLF Grade 1) or
single failure of one of the following organ systems: liver, coagulation, circulation, or
respiration, together with a serum creatinine level ranging from 1.5 to < 2.0 mg/dl and/or
mild to moderate hepatic encephalopathy or single cerebral failure together with serum
creatinine level ranging from 1.5 to < 2.0 mg/dl or (ACLF Grade 1)
two or more organ failures (ACLF Grade 2 or 3)
Organ failures are defined according to the CLIF-C OFs

Exclusion Criteria

1. Refusal or inability (lack of capacity) to give informed consent
3. Hepatic encephalopathy grade 3 and 4
4. Mechanical ventilation and/or renal replacement therapy
5. Subject has received certain previous therapies (any investigational drug within 30 days of
randomization)
6. Subject has any of the following conditions:
liver cirrhosis from other etiologies
liver failure from other causes
history of liver transplantation
postoperative decompensation after partial hepatectomy
liver failure without underlying chronic liver injury
7. Any untreated infections including gram-positive infections, active tuberculosis, sepsis or septic shock,
or coinfection with hepatitis B virus, hepatitis C virus or HIV.
8. Chronic or pre-existing kidney failure, uncontrolled medical disorder that might confound study results
or compromise subject safety
9. Methemoglobinemia, disseminated intravascular coagulation, significant and/or uncontrolled bleeding,
sickle cell anaemia
10. uncontrolled seizures, Creutzfeldt-Jakob disease, glucose-6-phosphate dehydrogenase deficiency.
11. active malignancy or survival prognosis of <6 months due to co-morbid conditions.
12. Pregnancy or nursing women

Characteristics

Interventional

2b