A-TANGO Phase 2 Study

The purpose of this research is to know if a new combination of drugs (TAK-242 and G-CSF) in combination with standard therapy for acute-on-chronic liver failure (ACLF) is more effective than standard therapy for ACLF treatment and is safe.

Description of the population to be studied: ACLF is a syndrome that occurs in patients with chronic liver disease, with or without previously diagnosed cirrhosis, which is characterized by acute hepatic decompensation. Cirrhosis is a chronic disease of the liver marked by degeneration of cells, inflammation, and thickening and scarring (fibrosis) of liver tissue. Hepatic decompensation is a sudden decline in liver function. It is characterized by severe liver damage and complications like jaundice (yellowing of the skin or whites of the eyes), ascites (a condition where excess fluid accumulates in the abdominal cavity and in abdominal organs) and encephalopathy (a group of symptoms that result from damage or dysfunction in the brain, causing a range of cognitive and neurological impairments). It may result in liver failure, one or more organ failures other than liver (renal, brain, coagulation, respiratory, cardiovascular), and is associated with increased mortality within 28-days and up to 3 months from onset. Grade 1 ACLF has a \>15% risk of mortality at 28 days.

Purpose of the study: The investigational medication, TAK-242, is aimed at stopping an "over-reaction" of the immune system (the body's defense system) while G-CSF encourages your liver cells to grow. In patients with severe inflammation of the liver due to alcohol \[severe alcoholic hepatitis (sAH)\] and ACLF, this over-reaction may cause the liver and other organs in the body to suddenly stop working (organ failure). The hypothesis of the study is that by blocking this over-reaction and encouraging your liver cells to grow your condition may improve.

The purpose of this Phase 2 clinical trial is to investigate

* the safety of TAK-242 alone or in combination with G-CSF (G-TAK) in patients with sAH and ACLF.
* the effect of TAK-242 alone or in combination with G-CSF (G-TAK) on the disease severity of ACLF.

Study design:

Multi-center, randomized, double-blind, placebo-controlled trial. Study drug will be administered while subjects are hospitalized. Patients will have been hospitalized for their underlying disease.

78 patients to be randomized (1:1:1) to one of the following three arms:

* Standard of care (SOC) plus placebo for TAK-242 plus placebo for G-CSF
* Standard of care (SOC) plus continuous IV infusion of TAK-242 for 10 days (Day 1-10) plus placebo for G-CSF.
* Standard of Care (SOC) plus continuous IV infusion of TAK-242 for 10 days (Day 1-10) plus daily subcutaneous G-CSF injections for 5 days (Day 1-5) and at Day 8 (6 injections in total)

Follow-up visits will occur on Day 14 (± 4 d), Day 28 (± 5 d), and Day 84 (± 7d). For each patient, the total duration of subject participation in the study, including screening, will be 86 ± 7 days.

The total study duration is estimated to be approximately 42 months from screening of first patient until study completion of the last patient/last visit and data analysis.

The placebo is the same as the investigational medication but does not contain the active ingredient. A placebo is used to check that any effects seen in people taking part in the study are because of the investigational medications and not due to the underlying disease (for safety) or to spontaneous improvement (for efficacy)

The study will also look at how the investigational medications affect the body (known as "pharmacodynamics") and how your body processes the investigational medications (known as "pharmacokinetics").

Investigational product:

* TAK-242 concentrate for solution for infusion (80 mg/mL in 3 mL ethanol): 240 mg TAK-242 per vial. To be reconstituted with 5% dextrose (36 mL) and commercially available 20% intralipid (21 mL).
* Matching placebo: 5% dextrose solution and commercially available lipid emulsion (prepared in hospital pharmacy
* G-CSF(filgrastim): Commercially available vials for subcutaneous injection. Matching placebo: identical to vehicle for filgrastim (prepared for injection by hospital pharmacist, or equivalent)

Management of patients Management of patients enrolled in the study will be performed according to guidelines and best practice of treatments for the management of complications of cirrhosis derived from international societies. Standard medical therapy also means that patients will be clinically assessed daily, including results of clinical chemistry and blood count.

An independent Data and Safety Monitoring Board (DSMB)will review safety and pharmacokinetic data after randomization of 18 patients (n=6 in each treatment arm) with complete PK analysis through Day 4 (±1 d). The DSMB will assess the relevance of drug-related adverse events and drug-drug interactions.

Compliance with Good Clinical Practices The study will be conducted in accordance with all applicable aspects of GCP. Statistical Analysis of Data The primary endpoint - safety - will be evaluated by descriptive statistics.

Secondary endpoints will offer an indication about potential signals in efficacy for future trials. Sample size was estimated to find differences in CLIF-C OF score between G-TAK and placebo, to allow a 90% statistical power to detect a 1.5-point difference between the combination G-TAK and the SOC arm in the reduction of CLIF-C OF score after 14 days from trial enrolment. A 5% Type-I error for a two-sided Student's t-test with repeated measurements is assumed. This sample size includes a dropout rate of 15%.

Eligibility Criteria:
Inclusion Criteria:

* Patients accepted for inclusion into the study must meet all of the following criteria:

  1. Male and female subjects ≥18 of age and ≤75 years of age
  2. Compliance with acceptable contraceptive methods.
  3. With a diagnosis of severe alcoholic hepatitis that is resistant to steroid therapy as defined by a Lille score of \>0.45 and/or in whom steroids are contraindicated.
  4. Eligible subjects will have Grade 1-3 ACLF with a maximum of three organ failures using the CLIF-C OF score AND the CLIF-C ACLF-CRP score of \>35 and \<60.

Exclusion Criteria:

* Patients with any of the following criteria are to be excluded:

  * Refusal to give informed consent
  * Mechanical ventilation due to respiratory failure and/or need for renal replacement therapy and or requiring inotropes for circulatory support with a noradrenaline requirement of \>0.5ug/kg/min to maintain mean arterial pressure \> 70mmHg
  * Subject has received any investigational drug within 30 days of randomization
  * Subject has any of the following conditions:

    * history of liver transplantation
    * postoperative decompensation after partial hepatectomy
    * liver failure without underlying chronic liver injury
  * Any untreated infections (\<48h antibiotic therapy) including gram-positive infections, active tuberculosis or coinfection with HIV.
  * Chronic or pre-existing kidney failure, survival prognosis of \<6 months due to severe co-morbid conditions that might confound study results or compromise subject safety
  * Methemoglobinemia, clinically-significant disseminated intravascular coagulation, uncontrolled bleeding, sickle cell anemia
  * Uncontrolled seizures, Creutzfeldt-Jakob disease, glucose-6-phosphate dehydrogenase deficiency.
  * Active malignancy, premalignant hematological disorders (e.g., myelodysplastic syndrome, chronic myeloid leukemia) or multiorgan failure (≥ 4 organ failures).
  * Pregnancy or nursing women
  * Allergy to eggs