This trial will evaluate the safety and efficacy of HepaStem compared to placebo in patients with a cirrhotic liver condition called Acute on Chronic Liver Failure (ACLF). The study will be performed in multiple centers and in a double-blinded manner, meaning neither the patients nor the treating physicians know who is on placebo or the study drug.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cellaïon SA

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

17 Dec 2019 → 10 May 2024

Decision date (initial)

2022-07-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Cellaïon

External identifiers

EU CT number

2022-500252-28-00

EudraCT number

2019-003051-11

ClinicalTrials.gov

NCT04229901

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective is to demonstrate the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million cells per kg (7-day interval) on the overall survival proportion 90 days post-first infusion.

Secondary objectives 2

1. To assess the safety of 2 infusions (i.v.) of HepaStem at 1.0 million of cells per kg BW (7 days apart) through 90 days post first infusion
2. To assess the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million of cells per kg BW (7 days apart): on the percentage of patients alive and free of liver transplantation (LT) at 90 days post first infusion; on the percentage of patients alive, free of LT and free of ACLF at 90 days post first infusion; on the percentage of patients alive and free of LT with Model for End- Stage Liver Disease (MELD)-Na score < 15 at 90 days post first infusion; on the number of intensive care unit (ICU)-free days during the index hospitalization up to 90 days post first infusion; on the number of hospital-free days during the index hospitalization up to 90 days post first infusion

Conditions and MedDRA coding

Cirrhotic patients who are hospitalized for Acute on chronic liver failure (ACLF), ACLF combines an acute deterioration of liver function in an individual with pre-existing chronic liver disease and extrahepatic organ failures characterized by high short-term mortality (30-40% at 28 days). The development of ACLF is associated with exacerbated systemic inflammation that may indeed cause organ failures.

Regulatory references

Scientific advice from competent authorities

Paul Ehrlich Institute, European Medicines Agency, Federal Agency For Medicines And Health Products

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 1. Are adults aged between 18 and 75 years old.
2. 2. Have an initial diagnosis of ACLF at the investigational site.
3. 3. Have ACLF grade 1 or 2 according to the EASL-CLIF Consortium definition.
4. 4. Have a total bilirubin more or equal 5 mg per dL.
5. 5. Are able to read, understand and give written informed consent. Only in case of hepatic encephalopathy (HE) due to ACLF, if the patient is unable to fully understand the study and based on the investigator’s judgment, the ICF must be signed by a legal or authorized representative of the patient according to local regulation. After encephalopathy improvement, if possible, the ICF must be signed by the patient.

Exclusion criteria 33

1. 1. Have a MELD-Na score more than 35.
2. 10. Have a previous history of myocardial infarction and/or cardiac failure, with an ejection fraction rate (EFR) ≤ 40%.
3. 2. Have underlying cirrhosis due to biliary disease.
4. 3. Have underlying cirrhosis due to autoimmune hepatitis.
5. 4. Have active bleeding at a non-compressible site or at a compressible site that, in the opinion of the investigator, poses an unacceptable risk for the patient's participation in the study.
6. 5. Have received treatment for bleeding complications during the current hospitalization and has a persistent high risk for re-bleeding that, in the opinion of the investigator, poses an unacceptable risk for the patient's participation in the study.
7. 6. Have a complete portal vein thrombosis.
8. 7. Have coagulation disturbances defined as: fibrinogen < 80 mg/dL; platelets < 50 x 10³/mm³
9. 8. Are requiring chronic dialysis therapy.
10. 9. Have had a cerebrovascular, myocardial, limb arterial thrombotic event, or history for both thrombotic and hemorrhagic cerebrovascular events within 12 months prior to the Screening and not considered stabilized by the investigator.
11. 11. Have an inability to maintain mean blood pressure (BP) > 60 mmHg despite use of vasopressors.
12. 12. Have severe pulmonary arterial hypertension defined as mean pulmonary arterial pressure (MPAP) ≥ 45 mmHg (or right ventricular systolic pressure ≥ 50 mmHg) by echocardiography.
13. 13. Have hepatopulmonary syndrome.
14. 14. Are receiving mechanical ventilation due to respiratory failure.
15. 15. Have known or suspected hypersensitivity or allergy to any of the components of the HepaStem diluent, dimethyl sulfoxide (DMSO), or bovine serum albumin.
16. 16. Have a history of severe allergies to drugs and/or a history of severe anaphylactic reactions.
17. 17. Have undergone a major invasive procedure within 2 weeks of randomization. These are open surgeries (the proper healing of the scar should be verified by the investigator). Liver biopsy (transjugular or percutaneous), paracentesis, and transjugular intrahepatic portosystemic shunt (TIPS) are not considered as major invasive procedures.
18. 18. Had a previous organ transplantation and or treatment with cell-based therapy.
19. 19. Are accepted as High Urgency status patient by the organ allocation system.
20. 20. Have active primary or recurrent malignant disease (including hepatocellular carcinoma) or have been in remission from clinically significant malignancy for < 5 years. o Patients with cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease for at least 3 years may participate in the study. o Patients with basal cell or squamous epithelial skin cancers that have been completely resected with no evidence of recurrence for at least 3 years may participate in the study.
21. 21. Are receiving immunosuppressive drugs, except glucocorticoids. Patients receiving glucocorticoids administered for treatment of severe alcoholic hepatitis may participate in the study.
22. 22. Have a contraindication to or are unwilling to take glucocorticoids to prevent infusion-like reaction.
23. 23. Have persistently positive blood cultures despite 48 hours of antibiotic therapy that indicates uncontrolled bacterial infection.
24. 24. Have diagnosis of invasive aspergillosis.
25. 25. Have known infection with human immunodeficiency virus (HIV).
26. 26. Have a history of hepatitis D virus infection.
27. 28. Are women of childbearing potential who decline to use highly effective (authorized) methods of contraception during the study.
28. 27. Are women who have been using hormonal oral contraception within 8 weeks of study entry.
29. 29. Are pregnant (i.e., positive blood or urine b-hCG test) or nursing/breastfeeding.
30. 30. Have participated in any other interventional study within 4 weeks of study entry, or participation and/or under follow-up in another interventional clinical trial.
31. 31. Have any significant medical or social condition or disability that, in the investigator’s opinion, may interfere with the patient’s optimal participation or compliance with the study procedures.
32. 32. Are persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical trials, and persons, who due to their age, disability or state of health are reliant on care and for that reason accommodated in residential care institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such assistance, are in a situation of subordination or factual dependency and therefore may require specific protective measures.
33. 33. Are employees of the Sponsor or investigator, or otherwise dependent on them.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Survival at Day 90: Whether the patients are still alive will be recorded up to Day 90. Time and reason of death will be recorded.

Secondary endpoints 10

1. Liver transplant-free survival (TFS) at Day 90.
2. TFS at Day 90 while free of ACLF.
3. TFS at Day 90 with MELD-Na score below 15.
4. Duration of overall hospitalization and hospitalization in ICU and non- ICU during the index hospitalization up to Day 90.
5. Number, nature, severity, seriousness and relationship of AEs during the whole study. This includes but is not limited to clinically changes in clinical examinations, vital signs, laboratory tests, and imaging.
6. Occurrence of systemic infection (sepsis shock, bacteremia, invasive fungal infection).
7. Presence of anti-HLA Abs and donor-specific Abs (DSA) (thresholds more 1500 mean fluorescence intensity [MFI] and more than 5000 MFI).
8. Quantitative measurement of coagulation parameters: PT, INR, aPTT, fibrinogen, platelets, D-dimer.
9. Any change in laboratory data at all visits, including data on serology, hematology, biochemistry. Abnormal laboratory results will only constitute an AE, and will be reported as such, if they are considered abnormal within the pathology of this study population.
10. Physical examination and vital signs at all visits.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cellaïon SA

Sponsor organisation

Cellaïon SA

Address

Rue Granbonpre 11

City

Mont-Saint-Guibert

Postcode

1435

Country

Belgium

Scientific contact point

Organisation

Cellaïon SA

Contact name

Regulatory Affairs

Public contact point

Organisation

Cellaïon SA

Contact name

Regulatory Affairs

Third parties 3

Locations

0 EU/EEA countries · 0 investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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