E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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. |
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E.1.1.1 | Medical condition in easily understood language |
NASH is a chronic liver disease and a major health issue in association with obesity and diabetes. NASH patients are at risks of cardiovascular events, cirrhosis, cancer and mortality. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10031743 |
E.1.2 | Term | Other chronic nonalcoholic liver disease |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019708 |
E.1.2 | Term | Hepatic steatosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10041970 |
E.1.2 | Term | Steatosis hepatic |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10019669 |
E.1.2 | Term | Hepatic fibrosis and cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019641 |
E.1.2 | Term | Hepatic cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009211 |
E.1.2 | Term | Cirrhosis liver |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024667 |
E.1.2 | Term | Liver cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009213 |
E.1.2 | Term | Cirrhosis of liver |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064704 |
E.1.2 | Term | Decompensated cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064844 |
E.1.2 | Term | Compensated cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10076331 |
E.1.2 | Term | Steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
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E.2.2 | Secondary objectives of the trial |
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
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Assessment of the changes in Histology and HVPG in pre-cirrhotic and Cirrhotic patients from HEP201 study, having received HepaStem
Sub study exploratory efficacy objectives: - To assess changes in hepatic venous pressure gradient (HPVG) at 6 months post-infusion - To assess changes on fibrosis at 6 months post-infusion using histology scores based on biopsy. |
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E.3 | Principal 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. |
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E.4 | Principal 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 the screening 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 < 80 mg/dL and/or platelets at < 40 x 10³/mm3 12. Severe hepatic encephalopathy (defined by West Haven grade > 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 (< 48hrs) clinical signs of infection despite adequate antibiotic therapy 18. Circulatory failure defined as treated with vasoconstrictors to maintain arterial pressure or inotropes to improve cardiac output 19. Respiratory disorders with pulse oximetry < 90% and related clinical signs 20. Receiving one of the following treatments at the time of Screening: a. Vitamin E, thiazolidinediones (TZD), glucagon-like peptide-1 (GLP1) antagonists, unless the dose is stable for 3 months prior to Screening b. Drugs with any influence on coagulation: antiplatelet agents, anticoagulants (vitamin K antagonists, direct and parenteral anticoagulants, dual antiplatelet therapy) Prophylaxis treatment with aspirin is authorized 21. Uncontrolled diabetes mellitus (HbA1c > 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 alpha-fetoprotein > 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 blood products 28. Known or suspected hypersensitivity or allergy to any of the components of the HepaStem diluent (human albumin, heparin sodium, sodium bicarbonate, dimethyl sulfoxide (DMSO)) or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction 29. Pregnancy, breastfeeding or women with childbearing potential who decline to use reliable contraceptive method during the entire duration of the study 30. Participation in any clinical study of an investigational agent at the time of screening 31. Any other significant medical or social condition or disability that, in the investigator’s opinion, may warrant a specific treatment, or may interfere with the patient’s optimal participation or compliance with the study procedures |
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E.5 End points |
E.5.1 | 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint: dose-finding and safety up to Day 28.
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E.5.2 | 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-C AD (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 NAS, SAF score, METAVIR scores |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Secondary safety endpoints, AEs reported 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 - 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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 12 |