Severe alcoholic hepatitis (sAH) and acute-on-chronic liver failure (ACLF) Digestive System Alcoholic hepatitis
Conditions
Interventions
Multicentre, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of TAK-242 alone or in combination with G-CSF in three dosing cohorts.
78 patients to be randomized
Sponsors
Yaqrit Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female subjects =18 years of age and =75 years of age 2. With a diagnosis of severe alcoholic hepatitis defined by a Lille score of >0.45 in those treated with steroids and/or contraindication to steroids 3. 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
Exclusion criteria: 1. Refusal to give informed consent 2. 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 >0.5 ug/kg/min to maintain mean arterial pressure >70 mmHg 3. Subject has received any investigational drug within 30 days of randomization 4. Subject has any of the following conditions: 4.1. History of liver transplantation 4.2. Postoperative decompensation after partial hepatectomy 4.3. Liver failure without evidence of underlying chronic liver disease 5. Any untreated infections (<48h antibiotic therapy) including gram-positive infections, active tuberculosis or coinfection with HIV 6. 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 7. Methemoglobinemia, clinically-significant disseminated intravascular coagulation, uncontrolled bleeding, sickle cell anaemia 8. Uncontrolled seizures, Creutzfeldt-Jakob disease, glucose-6-phosphate dehydrogenase deficiency 9. Active malignancy, premalignant haematological disorders (e.g. myelodysplastic syndrome, chronic myeloid leukaemia) or multiorgan failure (=4 organ failures) 10. Pregnancy or nursing women
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The safety of TAK-242 in combination with G-CSF and alone in subjects with sAH and ACLF compared to placebo from baseline to Day 14, assessed using: 1. The percentage of subjects who experience at least one treatment-emergent AE (TEAE) or SAE 2. The percentage of subjects who discontinue the study drug due to an AE (including methemoglobinemia) 3. The percentage of subjects who experience at least one treatment-emergent clinical laboratory test result or abnormal ECG that meets the Sponsor’s markedly abnormal criteria | — |
Secondary
| Measure | Time frame |
|---|---|
| These secondary endpoints have been chosen in order to better understand the impact of TAK-242 alone or the combination G-CSF and TAK-242 (G-TAK) administration on efficacy, safety, pharmacokinetics, organ function and the development of complications during the course of ACLF. 1. Organ failure measured using CLIF-C OF score in subjects treated with G-TAK compared with placebo from baseline to Day 14 2. Organ failure measured using CLIF-C OF score in patients treated with TAK-242 alone compared with G-TAK as well as CLIF C ACLF-CRP score between all arms from baseline to Day 14 3. Pharmacokinetics of TAK-242 alone or the combination G-TAK in patients with ACLF, measured using plasma Cmax and Cav of TAK-242 and G-CSF and metabolites on Day 1, Day 2, Day 7 and Early Termination 4. Key biomarkers for inflammation, cell death, liver function, regeneration and senescence measured using total bilirubin (TB), Cytokeratin-18 (M30), cleaved Cytokeratin-18 (M65), transforming growth factor beta 1 (TGFb1), interleukin 22 (IL-22) and interleukin 22 binding protein (IL-22BP), high sensitivity CRP (hs-CRP), hepatic growth factor (HGF), SDF-1, soluble urokinase-type plasminogen activator receptor (suPAR), DNA methylation, and circulating RNAs (genes MYLK3, SLC22A13, TPRG1-AS1, AC020633.1, TPRG1-AS1, NUDT4P1 (40) from baseline to Day 14 5. Transplant-free and overall survival measured using patient medical records on Day 28 and Day 84 6. Organ function (hepatic, renal, brain, coagulation, respiratory, cardiovascular) measured using CLIF-C OF, CLIF-C ad, CLIF-C ACLF-CRP scores and Systemic Inflammatory Response Score (SIRS) from Day 1 to Day 10 7. Inflammatory markers and ACLF-related panel including, but not limited to, IL-6, TNF-a, IL-10, M30/M65, sCD163, sCD206 measured using inflammation and plasma/serum biomarkers lab test from baseline to Day 4, 7 and 14 8. Quality of life measured using EQ5D5L from baseline to Day 14 Health economics: 9. Number of days in intensive care/in | — |
Countries
England, France, Germany, Portugal, Spain, United Kingdom
Contacts
Public ContactRajiv Jalan
Outcome results
None listed