The primary objective is:to demonstrate the efficacy of 2 infusions (intravenous [i.v.]) of HepaStem at 1.0 million of cells/kg body weight (BW) (7 days apart) on the overall survival proportion at 90 days post first infusion.The secondary…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
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 outcome
The secondary efficacy endpoints include:
• Liver transplant-free survival (TFS) at Day 90.
• TFS at Day 90 while free of ACLF.
• TFS at Day 90 with MELD-Na score < 15.
• Duration of overall hospitalization and hospitalization in ICU and non-ICU
during the index
hospitalization up to Day 90.
The secondary safety endpoints include:
• 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.
• Occurrence of systemic infection (sepsis/shock, bacteremia, invasive fungal
infection).
• Presence of anti-HLA Abs and donor-specific Abs (DSA) (thresholds > 1500 mean
fluorescence intensity [MFI] and > 5000 MFI).
• Quantitative measurement of coagulation parameters: PT, INR, aPTT,
fibrinogen, platelets, Ddimer.
• 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.
• Physical examination and vital signs at all visits.
Background summary
Acute on Chronic Liver Failure (ACLF) encompasses an acute deterioration of
liver function in patients with cirrhosis, which is usually associated with a
precipitating event and results in the failure of one or more organs and high
short-term mortality. Medical management of ACLF consists of early recognition,
treatment of the precipitating event and supportive care. Most of ACLF
management is focused on supportive care. At present, there is no specific
treatment for ACLF that improves survival. Liver transplantation (LT)
represents the only definitive therapeutic option for patients with ACLF.
Dysregulation of liver inflammation is a hallmark of chronic infection,
autoimmunity and malignancy, which is mediated by multiple overlapping pathways
in different liver diseases. While homeostatic inflammation and liver fibrosis
are aspects of the healthy adult liver, a lack of resolution or chronic liver
injury leads to progressive liver fibrosis and permanent liver damage. In these
situations, pathological inflammation promotes the progression of liver
fibrosis to cirrhosis and establishes a dysregulated balance between
inflammation and immunosuppression within the liver (Robinson, Harmon, and
O'Farrelly 2016).
In fibro-inflammatory chronic progressive liver diseases, it is expected that
HepaStem will have immunomodulatory effects by direct cell-to-cell interactions
with immune cells of the patient, and by paracrine effects through the various
cytokines, chemokines, matrix metalloproteinases, and growth factors they may
secrete. By these combined effects, it is expected that HepaStem will play a
favourable role in restoring the immunological disturbances observed in
patients with fibro-inflammatory liver diseases such as ACLF and Non-alcoholic
steatohepatitis (NASH), and ultimately will be able to restore liver
homeostasis.
Study objective
The primary objective is:
to demonstrate the efficacy of 2 infusions (intravenous [i.v.]) of HepaStem at
1.0 million of cells/kg body weight (BW) (7 days apart) on the overall survival
proportion at 90 days post first infusion.
The secondary objectives are :
• To assess the safety of 2 infusions (i.v.) of HepaStem at 1.0 million of
cells/kg BW
(7 days apart) through 90 days post first infusion
• To assess the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million of
cells/kg BW
(7 days apart):
o on the percentage of patients alive and free of liver transplantation (LT) at
90 days post first infusion
o on the percentage of patients alive, free of LT and free of ACLF at 90 days
post
first infusion
o 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
o on the number of intensive care unit (ICU)-free days during the index
hospitalization up to 90 days post first infusion
o on the number of hospital-free days during the index hospitalization up to
90 days post first infusion
Study design
This is an interventional, double blind, randomized (2:1), and
placebo-controlled study of 2 infusions of a 1 dose regimen of HepaStem in
patients recently diagnosed (<= 1 week) with ACLF grade 1 or 2 on top of
standard of care (SoC), and for whom the diagnosis is not resolved on the
day of infusion.
Intervention
During the study each patient will be administered 2 intra-venous infusions
which last 10-20 minutes each. The infusions contain HepaStem with 1.0 million
cells/kg body weight (in de active arm) or placebo. Between the infusions there
is a 7 days interval (+/-2 days).
Study burden and risks
The patients who will participate will be associated with the following burden
and risks:
- a total of 9 visits in 3 months
- at each visit there will be a blood draw (with in total 405 ml). With
permission 4x20 ml for genetic research and 2x 6 ml for biomarker research
- at all visits there will be a physical examination (including vital signs)
- at 4 visits the patient will be requested to complete questionnaires
- there will be one ECG taken.
- at 3 visits there will be Doppler measurements.
It must be taken into consideration that the patients will have 12 visits, but
a significant part of these visits will take place while the patients are
hospitalized. These hospitalizations can last up to 2 months.
Concerning adverse events we know that there are risks for:
Short-term:
• Thrombosis and bleeding). There will be close control of the blood clotting
parameters throughout the study.
• Respiratory (no cases so far) - since Hepastem is going through the lungs
before attending the liver, respiratory difficulties may occur.
• Hypersensitivity reaction or reaction to the infusion - this occurs when the
body's immune system overreacts to something like medication. Hypersensitivity
reactions may include: skin irritation, redness, itching, swelling, fluid
discharge, crusting, skin rash, eruptions, coughing or shortness of breath,
hoarse voice, headache, clogged or runny nose, sneezing, red (bloodshot) eyes,
stomach pain, nausea, vomiting, diarrhea, fatigue, sore throat, dizziness.
These reactions may be painful, uncomfortable or in some cases fatal (in the
case of anaphylaxis). This is a very serious allergic reaction.
Medium or Long Term:
• The distribution of the cells in different organs may promote tumor
development. Although such events have been rarely reported with immune
response of cell therapy, as HepaStem is made of cells from another person
which may eventually lead to cell rejection.
• HepaStem is an allogeneic (from another person) cell product. Immune response
following HepaStem infusion cannot be excluded and if it develops could induce
symptoms including, chills, nausea, ill feeling, fever or impact efficacy. This
could lead to consequences in case of a future transplantation with a possible
rejection. Anti-HLA antibodies and Donor Specific antibodies (DSA) will be
measured in order to document the patient*s potential allogenic response and
assess the potential risk of rejection for a future liver transplantation.
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Listed location countries
Age
Inclusion criteria
Patients must fulfill all of the following criteria in order to be eligible for
trial enrollment:
1. Are adults aged between 18 and 70 years old.
2. Have an initial diagnosis of ACLF at the investigational site.
3. Have ACLF grade 1 or 2 according to the EASL-CLIF Consortium definition.
4. Have a total bilirubin >= 5 mg/dL.
5. Are able to read, understand and give written informed consent.
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. In case of hepatic encephalopathy (HE), the ICF must be signed by
the patient after
encephalopathy improvement, if possible.
Enrollment criteria
Patients must fulfill all of the following criteria in order to be enrolled in
the trial at the end of the
Screening period:
1. Have completed all the procedures required at Screening.
2. Are still meeting all inclusion criteria and no exclusion criteria.
Infusion criteria
On the day of randomization and infusion, patients must fulfill all of the
following criteria in order
to be infused with the IMP (HepaStem or the Placebo):
1. Have ACLF grade 1 or 2 (before first infusion).
2. Have been diagnosed with ACLF at the investigational site according to the
EASL-CLIF
Consortium definition, no earlier than 8 days before randomization.
3. Have fibrinogen >= 80 mg/dL (as measured earlier on the same day before
infusion).
4. Have platelets >= 50 x 10³/mm³ (as measured earlier on the same day before
infusion).
5. Have no bleeding at a non-compressible site or no uncontrolled bleeding at a
compressible site as deemed by the investigator.
6. Is expected to remain hospitalized for at least 24 hours post infusion.
7. Have not experienced an adverse event (AE) considered related to the IMP and
associated
with an outcome defining an SAE (before the second infusion)
If the patient does not meet the infusion criteria prior to the first infusion,
the patient will be
considered as a screening failure.
If the patient does not meet the infusion criteria prior to the second
infusion, or the infusion
cannot be performed within the Day 8 Visit timeframe (±2 days), the infusion
will not be
performed but the Day 8 Visit and further visits should be performed according
to the protocol.
The missing infusion will not be replaced.
Exclusion criteria
Patients presenting with any of the following criteria will not be included in
the study:
1. Have a MELD-Na score > 35.
2. Have underlying cirrhosis due to biliary disease.
3. Have underlying cirrhosis due to autoimmune hepatitis.
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.
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.
6. Have a complete portal vein thrombosis.
7. Have coagulation disturbances defined as:
- fibrinogen < 80 mg/dL
- platelets < 50 x 10³/mm³
8. Are requiring chronic dialysis therapy.
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.
10. Have a previous history of myocardial infarction and/or cardiac failure,
with an ejection
fraction rate (EFR) <= 40%.
11. Have an inability to maintain mean blood pressure (BP) > 60 mmHg despite
use of
vasopressors.
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. Have hepatopulmonary syndrome.
14. Are receiving mechanical ventilation due to respiratory failure.
15. Have known or suspected hypersensitivity or allergy to any of the
components of theHepaStem diluent, dimethyl sulfoxide (DMSO), or bovine serum
albumin.
16. Have a history of severe allergies to drugs and/or a history of severe
anaphylactic
reactions.
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. Had a previous organ transplantation and/or treatment with cell-based
therapy.
19. Are accepted as High Urgency status patient by the organ allocation system.
20. Have active primary or recurrent malignant disease (including
hepatocellular carcinoma)
or have been in remission from clinically significant malignancy for < 5 years.
- 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.
- 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. Are receiving immunosuppressive drugs, except glucocorticoids.
- Patients receiving glucocorticoids administered for treatment of severe
alcoholic
hepatitis may participate in the study.
22. Have a contraindication to or are unwilling to take glucocorticoids to
prevent infusion-like
reaction.
23. Have persistently positive blood cultures despite 48 hours of antibiotic
therapy that
indicates uncontrolled bacterial infection.
24. Have diagnosis of invasive aspergillosis.
25. Have known infection with human immunodeficiency virus (HIV).
26. Have a history of hepatitis D virus infection.
27. Are women of childbearing potential and decline to use highly effective
contraception
methods during the study.
28. Are women who have been using hormonal oral contraception within 8 weeks of
study
entry.
29. Are pregnant (i.e., positive blood or urine β-hCG test) or
nursing/breastfeeding.
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. 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. Are committed to an institution by virtue of an order issued either by the
judicial or the
administrative authorities.
33. Are employees of the Sponsor or investigator, or otherwise dependent on
them.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003051-11-NL |
| CCMO | NL71942.000.19 |