NASH is characterized by steatosis, inflammation and cytological ballooning with varying amounts of fibrosis. Patients with NASH are at risk of cardiovascular morbidity and mortality. In chronic liver disease, changes in inflammatory components of the liver are not limited to the sole organ, but has a systemic influence. Disease evolution is characterized by increasing fibrosis and cirrhosis in a subset of patients, and a degree of fibrosis linked with increased risk of mortality. MedDRA versio
Conditions
Interventions
Product Name: HepaStem
Product Code: HHALPC
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: Heterologous Human Adult Liver-derived Progenitor Cells
Current Sponsor code: HepaStem
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Sponsors
Promethera Biosciences
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria: 1. Able and willing to provide written informed consent and comply with the requirements of this study protocol 2. Age 18 to 70-years old, inclusive 3. Proven diagnosis of NASH based on histological evidence from biopsy performed within 6 months for F3 patients and within 2 years for F4 patients prior to Screening If no biopsy is available within these time windows, a biopsy should be performed at Screening NB: For F4 patients for whom the biopsy cannot confirm the diagnosis of NASH, any other causes of underlying liver diseases should be excluded Infusion eligibility criteria 1. Fibrinogen > 80 mg/dL 2. And Platelets > 40.000/mm3 3. Absence thrombosis of the portal vein 4. No clinically significant reaction during previous infusions of IMP that, according to investigator, preclude the administration of HepaStem Inclusion criteria for sub-study 1. Able and willing to provide written informed consent for the sub-study and comply the inclusion/exclusion of the study. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 4
Exclusion criteria
Exclusion criteria: Exclusion criteria: 1. Alanine aminotransferase (ALT) = 8 x upper limit of normal (ULN) 2. Alcoholic liver disease or alcohol consumption exceeding the daily intake of 140g/w (two doses) for women and of 210g/w (three doses) for men 3. Other causes of liver disease including, but not limited to, alcoholic liver disease, active hepatitis B (HbsAg+), hepatitis C (PCR positive), autoimmune disorders, drug-induced hepatotoxicity, Wilson disease, hemochromatosis, and alpha-1-antitryspin deficiency based on medical history and/ or clinical and biological assessment 4. Recent recurrent or ongoing thrombotic or bleeding events within 3 months prior the screening 5. Patients considered at persistent risk of thrombosis or bleeding at the time of screening 6. Patients with high risk of Gastro intestinal bleeding at time of the screening. Patients with liver stiffness = 21 kPa at the time of thescreening must have endoscopic assessment of variceal bleeding risk; presence of grade III or IV varices is an exclusion criterion, unless treated with primary prophylaxis 7. Heart failure (grade III and IV of New York Heart Association (NYHA) classification) 8. Major invasive procedure within 4 weeks prior to screening. The proper healing of the puncture site should be verified by the investigator 9. Cerebrovascular, myocardial, or limb arterial thrombotic event within 12 months prior to the screening and/or not considered stabilized by the investigator 10. Bariatric surgery within 1 year prior to the screening 11. Coagulation disturbances defined as (Drolz et al. 2016, Nadim et al. 2016, Stravitz et al. 2018, Green et al. 2018): fibrinogen at 2) 13. Acute Decompensation of cirrhosis with Chronic Liver Failure Consortium Acute Decompensation (CLIF-C AD) score > 60 14. Acute on Chronic liver failure (ACLF) grade 1, 2 ,3 15. MELD score > 20 16. Child Pugh score = C 17. Septic shock or serious – non-controlled bacterial or systemic fungal infection defined as persistent or recent ( 9.5 %) or/and known diabetic proliferative retinopathy 22. Seropositive to Human Immunodeficiency Virus (HIV) 23. Previous organ transplantation 24. Patients receiving immunosuppressive drugs 25. Malignancies, other than cured skin cancer, or cancer treated unless a complete remission over last 5 years is documented, or cancer considered as definitive cured by the investigator 26. Current or a history of hepatocellular carcinoma or serum alphafetoprotein > 200 ng/mL (Bruix, Sherman and Practice Guidelines Committee 2005, Omata et al. 2010) 27. Previous treatment with mesenchymal stem cells (MSCs) or other cell therapies beside
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this trial is to determine the safety and tolerability of ascending single and repeated doses of HepaStem up to Day 28 administered to patients with cirrhotic and pre cirrhotic NASH.;Secondary Objective: 1. Secondary safety objective: - To assess the appearance of anti-HLA Antigen antibodies and identification of donor HLA specificity following infusion of HepaStem - To assess changes in levels of coagulation-related factors and coagulation efficiency up to 24 hours post-infusion - To determine the safety and tolerability of HepaStem up to 6 months post-infusion 2. Preliminary efficacy objectives: - To assess changes composite scores for disease stage: MELD, Child-Pugh scores and CLIF-C AD (for F4 decompensated) - To assess changes in liver function tests - To assess changes in metabolic biomarkers and clinical signs - To assess changes in hepatic fibrosis by non-invasive methods 3. Exploratory objectives: - To assess the effect of HepaStem on cellular immune response - To assess changes in inflammatory, apoptosis, and NASH biomarkers -To assess changes in non-invasive markers of portal hypertension - To assess the evolution to acute decompensation of cirrhosis;Primary end point(s): Primary endpoint: dose-finding and safety - AEs reported up to Day 28 assessed for seriousness, severity, relationship to the investigational medicinal product (IMP) and/or IMP administration procedure. This includes but is not limited to clinically changes in clinical examinations, vital signs, laboratory tests and imaging.;Timepoint(s) of evaluation of this end point: Primary endpoint: dose-finding and safety up to Day 28. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: - Secondary safety endpoints: up to Month 6 - Preliminary efficacy endpoints: up to Month 6 - Exploratory endpoints: - Quantitative assessment of inflammatory, apoptosis, and NASH biomarkers from baseline to up to 6 months after last infusion - AES up to day 28 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure. This includes inflammation scores evaluated on Liver histology prior and 6 months post infusion - Sub-study endpoints: - Quantitative assessment of HPVG prior and 6 months post infusion;Secondary end point(s): Secondary safety endpoints: - Presence of anti-HLA Abs and identification for donor HLA specificity - Coagulation tests - AEs reported up to Month 6 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure. This includes but is not limited to clinically changes in clinical examinations, vital signs, laboratory tests and imaging Preliminary efficacy endpoints: - Composite score for disease stage: MELD, Child-Pugh scores and CLIF-CAD (for F4 decompensated) - Quantitative assessment of liver and metabolic function - Quantitative assessment of Liver fibrosis biomarkers - Quantitative assessment of Liver stiffness Exploratory endpoints: - Number of new/new onset of acute decompensation events - In vitro proliferative and cytokine secretion function of PBMC in response to TetT, PPD, and PHA - In vitro T cell response to HepaStem - Quantitative assessment of inflammatory, apoptosis, and NASH biomarkers from baseline to up to 6 months after last infusion - Quantitative assessment of Portal hypertension biomarkers - Day 28 assessed for seriousness, severity, relationship to the IMP and/or IMP administration procedure. This includes inflammation scores evaluated on Liver histology prior and 6 months post infusion Sub-study endpoints: - Quantitative assessment of HPVG prior and 6 months post infusion - Quantitative assessment of NA | — |
Countries
Belgium, Bulgaria, France, Poland, Spain, Switzerland
Contacts
Public ContactWelcome desk
Promethera Biosciences
Outcome results
None listed