Phase2, double-blind, randomized, placebo-controlled, multicentre study to evaluation the safety, efficacy, and pharmacokinetics of TAK-242 and Granulocyte Colony-Stimulating Factor (G-CSF) (G-TAK) in subjects with severe alcoholic hepatitis (sAH) and acute-on-chronic liver failure (ACLF).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alpha Bioresearch S.L., Yaqrit Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Decision date (initial)

2023-03-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Yaqrit Ltd

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

The primary objective of this Phase 2 clinical trial is to investigate the safety of TAK-242 in combination with G-CSF (G-TAK) in patients with sAH and ACLF.

Secondary objectives 2

1. The effect of TAK-242 in combination with G-CSF (G-TAK) on the disease severity of ACLFtiene menú contextual
2. To explore disease mechanisms being modulated by the G-TAK

Conditions and MedDRA coding

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 resulting in liver failure (jaundice and prolongation of INR), one or more extrahepatic organ failures (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. The study population will consist of up to 78 subjects with Grade 1- 3 ACLF limited to 3 organ failures and a baseline CLIF-C ACLF-CRP score of >35 and <60.

Study design 1 period

Regulatory references

Scientific advice from competent authorities

The Spanish Agency Of Medicines And Medical Devices, National Authority Of Medicines And Health Products

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male and female subjects ≥18 of age and ≤75 years of age
2. Compliance with acceptable contraceptive methods.
3. With a diagnosis of severe alcoholic hepatitis (APPENDIX 12) that is resistant to steroid therapy as defined by a Lille score of >0.45 (APPENDIX 9) and/or in whom steroids are contraindicated.
4. 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. APPENDIX 2

Exclusion criteria 10

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 >0.5ug/kg/min to maintain mean arterial pressure > 70mmHg
3. Subject has received any investigational drug within 30 days of randomization
4. Subject has any of the following conditions: o history of liver transplantation o postoperative decompensation after partial hepatectomy o liver failure without underlying chronic liver injury
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 (according to BAVENO V; APPENDIX 16), 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The percentage of subjects who experience at least 1 treatment-emergent AE (TEAE) or SAE.
2. The percentage of subjects who discontinue the study drug due to an AE (including methemoglobinemia).

Secondary endpoints 10

1. Change in CLIF-C OF score in subjects treated with G-TAK compared to placebo from baseline to Day 14. APPENDIX 2
2. Change in CLIF-C OF score in subjects treated with TAK-242 alone compared with G-TAK as well as CLIF C ACLF-CRP score between all arms
3. Define the pharmacokinetics of TAK-242 alone or the combination G-TAK in patients with ACLF: Plasma Cmax and Cav of TAK-242 and G-CSF and metabolites.
4. To investigate the effects TAK-242 alone or the combination G-TAK compared with placebo and each other in subjects with sAH and ACLF on key biomarkers for inflammation, cell death, liver function, regeneration and senescence: Change in naturally log-transformed key biomarkers total bilirubin (TB), cleaved Cytokeratin-18 (M30)/ Cytokeratin-18 (M65), transforming growth factor beta 1 (TGFb1), interleukin 22 (IL-22) and interleukin 22 binding protein (IL-22BP), CRP, hepatic growth factor (HGF), SDF
5. To investigate the effect of a) TAK-242 alone or b) the combination TAK-242/G-CSF (G-TAK) on Day 28 and Day 84 transplant free and overall survival versus placebo in subjects with sAH and ACLF.
6. To investigate the effect of TAK-242 alone or the combination G-TAK compared with placebo and each other administered for 10 days in subjects with sAH and ACLF on organ function (hepatic, renal, brain, coagulation, respiratory, cardiovascular): Regular assessments of organ failure, systemic inflammation, and ACLF including CLIF-C organ failure score (CLIF-C OF), CLIF-C acute decompensation score (CLIF-C AD), CLIF-C ACLF-CRP score and Systemic Inflammatory Response Score (SIRS) (APPENDIX 2 and AP
7. Change in inflammatory markers and ACLF-related panel including, but not limited to, IL-6, TNF-α, IL-10, M30/M65, sCD163, sCD206 from baseline to Day 4, 7 and 14.
8. To investigate the effect of TAK-242 alone or the combination G-TAK compared with placebo and each other on the Quality of Life in subjects with sAH and ACLF. The scoring system that will be used is EQ5D5L, which allows assessment of QoL changes in sick patients (see APPENDIX 14).
9. Number of days in intensive care/intensive therapy unit.
10. Total costs of hospital treatment with a time horizon of 90 days across treatment arms. The cost analysis is limited to hospital care.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alpha Bioresearch S.L.

Sponsor organisation

Alpha Bioresearch S.L.

Address

Calle De Lopez De Hoyos N 155 3º Piso, Poligono Lopez De Hoyos Poligono Lopez De Hoyos

City

Madrid

Postcode

28002

Country

Spain

Scientific contact point

Organisation

Yaqrit Limited

Contact name

Rajiv Jalan

Public contact point

Organisation

Alpha Bioresearch S.L.

Contact name

Cornelius Engelmann

Yaqrit Limited

Sponsor organisation

Yaqrit Limited

Address

Interchange Triangle, Stables Market, Chalk Farm Road Stables Market Chalk Farm Road

City

London

Postcode

NW1 8AB

Country

United Kingdom

Sponsor responsibilities

Contact point sponsor

Alpha Bioresearch S.L.

Locations

3 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications