A-TANGO Phase 2 Study
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18-75
SponsorYaqrit Ltd
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Male and female subjects ≥18 of age and ≤75 years of age
Compliance with acceptable contraceptive methods.
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.
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.
Disqualifiers
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
history of liver transplantation
Trial design
Design model
Parallel
Treatments tested in this trial
Placebo
DrugMatching placebo for TAK-242: 5% dextrose solution and commercially available 20% intralipid (prepared by hospital pharmacy staff) Matching placebo for G-CSF: identical to vehicle for filgrastim (prepared for injection by hospital pharmacy staff)
TAK-242
DrugTAK-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). TAK-242) will be administered as a continuous IV infusion starting with a loading dose of 0.9 mg/kg administered over 30 minutes, followed by a continuous, constant rate infusion of 1.8 mg/kg/day for 10 days. PLUS placebo for G- CSF
G-CSF (Filgrastim)
DrugCommercially available vials for subcutaneous injection. Quantitative composition (per mL): Filgrastim: 300 mcg Acetate: 0.59 mg Sorbitol: 50.0 mg Tween® 80: 0.04 mg Sodium: 0.035 mg Water for Injection USP q.s. ad 1.0 mL G-CSF will be given subcutaneously once daily at a dose of 5 µg/kg for 5 days (Day 1-5) and at Day 8 (6 injections in total)
Treatment groups
78 Participants
are divided into 3 treatment groupsGroup A: Standard of care (SOC) plus placebo for TAK-242 plus placebo for G-CSFPlacebo comparator 1 intervention
Group B: Standard of care (SOC) plus TAK-242 plus placebo for G-CSFActive comparator 1 intervention
Group C: Standard of Care (SOC) plus TAK-242 plus G-CSFActive comparator 2 interventions
Trial outcomes
Primary outcomes
1
To assess the safety of TAK-242 in combination with G-CSF and alone in subjects with sAH and ACLF compared to placebo
To assess the safety of TAK-242 in combination with G-CSF (G-TAK) and alone in subjects with sAH and ACLF compared to placebo from baseline to Day 14: * The percentage of subjects who experience at least 1 treatment-emergent AE (TEAE) or SAE. * The percentage of subjects who discontinue the study drug due to an AE (including methemoglobinemia).
Time frame
Baseline to Day 14Secondary outcomes
1
Changes in CLIF-C OF score
Changes in CLIF-C OF score in subjects treated with G-TAK compared with placebo from baseline to Day 14 CLIF-C OF (Chronic Liver Failure Organ Failure) - The CLIF-C organ failure (OF) score is used to diagnose acute-on-chronic liver failure (ACLF) in patients with acute decompensation of cirrhosis. Each organ system is scored on a scale to generate the overall CLIF-C OF score, ranging from 0 to 18. A higher CLIF-C OF score translates into a higher ACLF grade.
Time frame
Baseline to Day 142
Changes in CLIF C ACLF-CRP score
Changes in CLIF-C OF score in patients treated with TAK-242 alone compared with G-TAK and placebo, as well as changes in CLIF C ACLF-CRP score between all arms CLIF-C Acute-on-chronic liver failure - c-reactive protein (CLIF-C ACLF-CRP) will be calculated using this formula: CLIF-C ACLF-CRP score = 10 x (0.293 x CLIF-C OF score + 0.034 x Age\[years\] + 0.292 x log(CRP) - 0.8)
Time frame
Baseline to Day 843
Pharmacokinetics parameters for TAK-242 along with its two main metabolites and G-CSF
tmax(hr): Time point where the peak plasma concentration is maximum will be calculated
Time frame
Baseline to Day 74
To Investigate the effects of TAK-242 alone or in combination with G-CSF, compared with placebo and between active treatment groups, on key biomarkers for inflammation, cell death, liver function, regeneration and senescence
Changes from baseline after 14 days in naturally log-transformed key liver function biomarkers will include: * total bilirubin (TB) * cleaved Cytokeratin-18 (M30)/ Cytokeratin-18 (M65) * transforming growth factor beta 1 (TGFb1) * interleukin 22 (IL-22) * interleukin 22 binding protein (IL-22BP) * C-reactive protein (CRP) * hepatic growth factor (HGF) * stromal cell-derived factor 1 (SDF-1), * soluble urokinase-type plasminogen activator receptor (suPAR)) * DNA methylation * circulating RNAs (genes MYLK3, SLC22A13, TPRG1-AS1, AC020633.1, TPRG1-AS1, NUDT4P1 Biomarkers of Humoral Inflammation and Cell Death, Cellular inflammation, regeneration \& senescence, metabolic and genetics and mitochondrial function are assessed individually between treatment groups as well as overall, global trends between treatment groups. They are not aggregated to arrive at one reported value.
Time frame
From Baseline to Day 4, 7, and 14Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Yaqrit Ltd
Lead sponsor
European Foundation for Study of Chronic Liver Failure
Collaborator
University College, London
Collaborator
HEPYX LIMITED
Collaborator
CROWDHELIX LIMITED
Collaborator
Charite University, Berlin, Germany
Collaborator
University of Leipzig
Collaborator
Concentris research management gmbh
Collaborator
Assistance Publique - Hôpitaux de Paris
Collaborator
Leiden University Medical Center
Collaborator
INTERNATIONAL MARKET ACCESS CONSULTING GMBH
Collaborator
KlinEra Global Services
Collaborator
European Association for the Study of the Liver
Collaborator
EUROPEAN LIVER PATIENTS ASSOCIATION
Collaborator
Source ClinicalTrials.gov