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    Summary
    EudraCT Number:2019-001969-33
    Sponsor's Protocol Code Number:TAK-242-2001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-02-03
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-001969-33
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the safety and effectiveness of taking TAK-242 via an Intravenous Drip for patients with Acute Alcoholic Hepatitis which is worsening their existing Chronic Alcohol-related Cirrhosis ( Acute-on-Chronic liver failure)
    A.3.2Name or abbreviated title of the trial where available
    Phase 2a Study of TAK-242 to Treat Acute-on-Chronic Liver Failure
    A.4.1Sponsor's protocol code numberTAK-242-2001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAkaza Bioscience Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUK Government
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAkaza Bioscience Limited
    B.5.2Functional name of contact pointN/A
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ cityN/A
    B.5.3.3Post codeN/A
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone numberN/A N/A N/A
    B.5.5Fax numberN/A N/A N/A
    B.5.6E-mailinfo@akazabio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTAK-242
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTAK-242
    D.3.9.1CAS number 243984-11-4
    D.3.9.2Current sponsor codeTAK-242
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboEmulsion for emulsion for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute Alcoholic Hepatitis Causing Decompensation of Alcohol related Cirrhosis and Acute-on-Chronic Liver Failure
    E.1.1.1Medical condition in easily understood language
    Acute-on-Chronic Liver Failure
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10001627
    E.1.2Term Alcoholic liver disease
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study will be to investigate the effect of intravenous (IV) TAK-242 administered for 7 days in subjects with cirrhosis due to alcoholic liver disease (ALD), and superimposed AH resulting in Grade 1 or 2 ACLF on the Chronic Liver Failure Consortium (CLIF-C) ACLF score.
    E.2.2Secondary objectives of the trial
    To investigate the safety of IV TAK-242 administered for 7 days in subjects with Grade 1 or 2 ACLF.
    To investigate the effects of IV TAK-242 administered for 7 days in subjects with Grade 1 or 2 ACLF on key biomarkers including IL-8, c-reactive protein (CRP), total bilirubin (TB), and urine neutrophil gelatinase-associated lipocalin (NGAL).
    To investigate the effect of IV TAK-242 administered for 7 days in subjects with Grade 1 or 2 ACLF on Day 28 survival.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. In the opinion of the investigator, the subject is deemed capable of understanding and complying with protocol requirements. If the subject is deemed incapable because of encephalopathy, then informed consent can be signed by a representative of the subject, in line with local law and regulation.
    2. The subject or the subject’s representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
    3. The subject is male or female ≥18 and <75 years of age.
    4. The subject meets the definition of ACLF Grade 1 or 2 (using the CLIF-C OF score; Appendix G), OR bilirubin criteria (>20 mg/dL at diagnosis); OR criteria of AKI Stage 1b or 2 (Appendix M) after initial supportive treatment with fluids, albumin, or terlipressin; AND the CLIF-C ACLF score is >35 and <64, which is calculated within 16 hours prior to randomization.
    5. The subject has a history of alcohol-related cirrhosis based on clinical, radiological, and/or histological evidence.
    6. The subject has continued to drink heavily (defined as >40 gm alcohol/day in women and >60 gm alcohol/day in men) for >6 months with <60 days of abstinence before the onset of jaundice.
    7. The subject has a history of an acute decompensating event (including, but not limited to, jaundice, ascites, gastrointestinal bleeding, hepatic encephalopathy, and/or acute bacterial infections), occurring within 6 weeks of screening.
    8. In the judgement of the investigator, the subject does not have a history of previous AH in the past 3 months and present episode is considered a new episode rather than unresolved AH.
    9. The subject has a clinical and/or liver biopsy diagnosis of alcoholic hepatitis (see definition in Appendix O). A liver biopsy is required for the diagnosis if the subject has potential confounders as defined in the exclusion criteria (see exclusion criteria 4, 5, 9, and 10) and the subject should be excluded if the biopsy suggests an alternative cause for decompensated liver disease.
    10. The subject has a total white blood cell count ≥8.0×109/L.
    11. A male subject who is nonsterilized* and sexually active with a female partner of childbearing potential* agrees to use barrier method of contraception (eg, condom with spermicide)* from signing of informed consent throughout the duration of the study. The male participant agrees to inform female partners of participation in the study and the need for effective contraception*.
    12. A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use an effective method of contraception* from signing of informed consent throughout the duration of the study.
    *Definitions and effective methods of contraception are defined in Section 9.1.10 and reporting responsibilities are defined in Section 9.1.11.
    E.4Principal exclusion criteria
    1. The subject has been hospitalized for more than 10 days.
    2. The subject has received any investigational compound within 30 days prior to the first dose of study drug or is scheduled to receive another investigational drug or device in the course of the study. Concomitant observational studies are allowed.
    3. The subject has received TAK-242 in a previous clinical study.
    4. The subject has received corticosteroids for alcohol-induced liver failure within the 4 weeks prior to randomization.
    5. The subject has cirrhosis from other chronic causes including nonalcoholic steatohepatitis (NASH), hepatitis C virus (HCV), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, alpha-1-antitrypsin deficiency, or Wilson’s disease.
    6. The subject has tested positive for SARS-CoV-2 infection within 7 days prior to randomization and administration of study drug.
    7. The subject has a medical history of co-infection with HIV, hepatitis B virus (HBV), HCV, or hepatitis E virus (HEV). Subjects with a previous diagnosis of hepatitis C treated with a documented course of an approved antiviral therapy for HCV who have achieved a sustained virologic response (defined as an undetectable HCV RNA level 12 weeks after completion of therapy) may be enrolled.
    8. The subject has proven untreated gram-positive bacterial infection including sepsis, bacterial peritonitis, pneumonia, cellulitis, septic arthritis, osteomyelitis or other gram-positive infection. These subjects can be included once they are culture negative.
    9. The subject has evidence of untreated infection, including gram negative infection. If a subject has 1 or more underlying infections, he or she may be entered into the study provided that he or she is clinically responding to treatment as judged by clinical and laboratory assessments. Subjects with chronic infections will be excluded.
    10. The subject has acute or subacute liver failure without underlying cirrhosis.
    11. The subject has medical history of liver failure due to other causes, including, but not limited, to autoimmune hepatitis, PBC and PSC, drug-induced liver injury, and infections causing liver damage.
    12. The subject has atypical laboratory screening tests including AST or ALT >400 IU/L, AST:ALT ratio <1.5, and AST <50 or >400 IU/mL unless a liver biopsy has confirmed the diagnosis of AH.
    13. The subject has a history of liver transplant.
    14. The subject has developed decompensation at any time in the postoperative period following partial hepatectomy.
    15. The subject has clinically significant hemolysis or disseminated intravascular coagulation (DIC).
    16. The subject has chronic and/or pre-existing kidney disease defined as estimated glomerular filtration rate (eGFR) <30 mL/min for 3 months or longer prior to screening.
    17. The subject has a hemoglobin <8 g/dL and is asymptomatic; subjects may be entered into the study after correction of the anemia by transfusion, with stable hemoglobin and hematocrit for 48 hours.
    18. The subject has oxygen saturation <90% despite supportive therapy. No subjects who require mechanical ventilation (MV) will be randomized.
    19. The subject has septic shock (defined as sepsis-induced hypotension [systolic blood pressure <90 mmHg or mean arterial pressure (MAP) <70 mmHg or a SBP decrease >40 mmHg] persisting despite adequate fluid resuscitation). No subjects who require vasopressors to maintain a MAP >70 mmHg will be randomized. Subjects on treatment with terlipressin for the treatment of AKI can be included.
    20. The subject has evidence of significant and/or uncontrolled bleeding. Subjects with gastrointestinal bleeding can be enrolled 48 hours after the bleeding has been controlled, as demonstrated by stable hemoglobin and hematocrit and not requiring transfusion. In subjects treated with terlipressin, treatment with terlipressin must have been discontinued at least 24 hours prior to calculation of the predose, Day 1 CLIF-ACLF scores.
    21. The subject has Grade 3 or 4 hepatic encephalopathy according to West Haven criteria (Appendix I).
    22. The subject has known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
    23. The subject has a methemoglobin ≥5% at screening or a known history of methemoglobinemia.
    24. The subject has active or history of extrahepatic malignancy unless adequately treated or in complete remission for 5 or more years. Subjects with liver cancer outside the Milan criteria (Appendix N) will be excluded.
    25. The subject has active or latent tuberculosis based on history, symptoms, physical examination and chest x-ray or previous positive interferon gamma release assay.
    26. The subject has a survival prognosis of <6 months because of a chronic disease other than liver disease (eg, metastatic cancer) that was present before the acute event that led to hospitalization.
    27. The subject has uncontrolled seizures.
    28. The subject has a diagnosis of Creutzfeldt-Jakob disease.
    E.5 End points
    E.5.1Primary end point(s)
    Change in CLIF-C ACLF score from baseline to Day 8.
    E.5.1.1Timepoint(s) of evaluation of this end point
    baseline to Day 8.
    E.5.2Secondary end point(s)
    • 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).
    • The percentage of subjects who experience at least 1 treatment-emergent clinical laboratory test result or abnormal ECG that meets the Akaza Bioscience Limited markedly abnormal criteria.
    • Change in naturally log-transformed key biomarkers (TB, IL-8, high sensitivity CRP (hs CRP), M30, and urinary NGAL) from baseline to Day 8.
    • Survival at Day 28 after the initiation of TAK-242 therapy versus placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • LPLV
    • Day 8
    • LPLV
    • baseline to Day 8
    • baseline to Day 28
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the last visit of the last subject in the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days21
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If the subject is deemed incapable due to encephalopathy, then the subject’s legal representative may sign the informed consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Study drug will not be available upon completion of the subject’s participation in the treatment period. The subject should be returned to the care of a physician and standard therapies as required.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-02-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-28
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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