TAK-242 in Patients With Acute Alcoholic Hepatitis

Study Overview
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Brief Summary
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A phase 2a double-blind, randomized, placebo-controlled, multicenter, proof-of-concept study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of TAK-242 in subjects with acute decompensation of alcohol-related cirrhosis due to alcoholic hepatitis resulting in acute-on-chronic liver failure.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Proof-of-Concept, Phase 2a Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous TAK-242 in Subjects With Acute Alcoholic Hepatitis Causing Decompensation of Alcohol-related Cirrhosis and Acute-on-Chronic Liver Failure

Conditions
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Acute-On-Chronic Liver Failure

Intervention / Treatment
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* Drug: TAK-242
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of alcohol-related cirrhosis who continue to drink heavily History of an acute decompensating event with a clinical and/or liver biopsy diagnosis of alcoholic hepatitis Grade 1 or 2 ACLF using the CLIF-C OF score; OR bilirubin criteria OR criteria of acute kidney injury Stage 1b or 2 after initial supportive treatment with fluids, albumin, or terlipressin; AND CLIF-C ACLF score is >35 and <64 History of alcohol-related cirrhosis based on clinical, radiological, and/or histological evidence Exclusion Criteria: Received certain previous therapies (any investigational drug within 30 days of randomization, corticosteroids for alcohol-induced liver failure within 4 weeks of randomization, or received TAK-242 in any previous study) History of liver cirrhosis from other chronic diseases; liver failure from other causes History of liver transplantation, post-operative decompensation after partial hepatectomy, acute or subacute liver failure without underlying cirrhosis Any untreated infections including gram-positive infections, or active or latent atuberculosis, sepsis or septic shock, or coinfection with hepatitis B virus, hepatitis C virus, hepatitis E virus, or HIV Chronic or pre-existing kidney failure, uncontrolled medical disorder that might confound study results or compromise subject safety, oxygen saturation <90%, or requires mechanical ventilation. Uncorrected anemia, methemoglobinemia, disseminated intravascular coagulation, significant or uncontrolled bleeding, atypical laboratory screening tests. Uncontrolled seizures, Grade 3 or 4 hepatic encephalopathy, Creutzfeldt-Jakob disease, glucose-6-phosphate dehydrogenase deficiency. Active extrahepatic malignancy or survival prognosis of <6 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-242<br>Patients will be administered TAK-242 as a continuous IV infusion with standard care 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 7 days | Drug: TAK-242<br>* TAK-242 concentrate solution 80 mg/mL for dilution and infusion<br>|
| Placebo Comparator: Placebo<br>Patients will be administered placebo as a continuous IV infusion with standard care 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 7 days | Drug: Placebo<br>* Matching placebo concentrate solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CLIF-C ACLF score from baseline to Day 8 |  | Baseline to Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects who experience at least 1 markedly abnormal treatment-emergent AE or SAE | The percentage of subjects who experience at least 1 treatment-emergent AE or SAE that meets the Sponsor's markedly abnormal criteria | To Day 28 | 
| Percentage of subjects who experience at least 1 treatment-emergent clinical laboratory test result or abnormal ECG that meets the Sponsor's markedly abnormal criteria | The percentage of subjects who experience at least 1 treatment-emergent clinical laboratory test result or abnormal ECG that meets the Sponsor's markedly abnormal criteria | To Day 28 | 
| Percentage of subjects who discontinue study drug due to an AE |  | To Day 28 | 
| Change in naturally log-transformed key biomarkers | Change in naturally log-transformed key biomarkers (TB, IL-8, high sensitivity CRP [hs-CRP], and urinary NGAL) | Baseline to day 8 | 
| Survival at Day 28 after initiation of TAK-242 therapy versus placebo |  | Baseline to Day 28 |