Phase II, Double-blind, Randomized, Placebo-controlled, Multicentre Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of TAK-242 and (G-CSF) in Subjects With (sAH) and (ACLF)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- Yaqrit Ltd
- 入组人数
- 78
- 主要终点
- To assess the safety of TAK-242 in combination with G-CSF and alone in subjects with sAH and ACLF compared to placebo
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
The investigational drug blind is maintained by study drug/placebo preparation by an unblinded person (hospital pharmacist, or equivalent).
The study drug blind shall not be broken by the investigator unless information concerning the study drug is necessary for the medical treatment of the subject.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients accepted for inclusion into the study must meet all of the following criteria:
- •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.
排除标准
- •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
研究组 & 干预措施
Standard of care (SOC) plus placebo for TAK-242 plus placebo for G-CSF
干预措施: Placebo (Drug)
Standard of care (SOC) plus TAK-242 plus placebo for G-CSF
干预措施: TAK-242 (Drug)
Standard of Care (SOC) plus TAK-242 plus G-CSF
干预措施: TAK-242 (Drug)
Standard of Care (SOC) plus TAK-242 plus G-CSF
干预措施: G-CSF (Filgrastim) (Drug)
结局指标
主要结局
To assess the safety of TAK-242 in combination with G-CSF and alone in subjects with sAH and ACLF compared to placebo
时间窗: Baseline to Day 14
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).
次要结局
- To investigate transplant free and overall survival in subjects with sAH and ACLF(Upto Day 84)
- To investigate the effect on the Quality of Life(Baseline to Day 84)
- Changes in CLIF-C OF score(Baseline to Day 14)
- Changes in CLIF C ACLF-CRP score(Baseline to Day 84)
- Pharmacokinetics parameters for TAK-242 along with its two main metabolites and G-CSF(Baseline to Day 7)
- 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(From Baseline to Day 4, 7, and 14)
- Change in organ function between different treatment arms.(Baseline to Day 14)