Allogenic Hepatocyte Transplantation Into Periduodenal Lymph Nodes

Study Overview
=================
Brief Summary
-----------------
This Phase 2a clinical trial is a dose escalation study of the safety, tolerability, and efficacy of hepatocyte transplantation into lymph nodes via endoscopic ultrasound among subjects with end-stage liver disease.

Detailed Description
-----------------
This safety, tolerability, and efficacy study includes an open-label dose-escalation phase for up to 12 subjects with end-stage liver disease (ESLD).

Official Title
-----------------
A Phase 2a, Open Label, Dose Escalation Study for Safety, Tolerability, and Efficacy of Hepatocyte Transplantation Into Periduodenal Lymph Nodes Among Subjects With End-Stage Liver Disease

Conditions
-----------------
End Stage Liver Disease

Intervention / Treatment
-----------------
* Biological: LYG-LIV0001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have read, understood, and signed the informed consent form (ICF). Adults of either gender and ages 18 to 70 years old with a diagnosis of ESLD due to alcohol, chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections, autoimmune hepatitis, primary sclerosis cholangitis, primary biliary cirrhosis (cholangitis), cirrhosis as the result of Wilson disease, hemochromatosis, sarcoidosis and alpha 1 antitrypsin deficiency, cryptogenic cirrhosis, and nonalcoholic steatohepatitis cirrhosis with a MELD-Na score >10 and <25 at screening. Subjects must have a body mass index (BMI) <35. Subjects with HCV associated ESLD must have been treated and demonstrate 24 weeks of negative HCV ribonucleic acid (RNA). Subjects with HBV must be on stable therapy for 6 months and have HBV deoxyribonucleic acid <500 c/mL. Women of childbearing potential (WOCBP) or sexual partners of male subjects who are WOCBP must be able and willing to use at least 1 highly effective method of contraception during the study and for 1 month after the last study visit. A female subject is considered to be a WOCBP after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy; HMA, 2014). For the definition and list of highly effective methods of contraception, see Appendix 1. Has stable control of portal hypertension and upper gastrointestinal bleeding with medical therapy and/or endoscopic therapy. If the subject has undergone a TIPS procedure for the clinical management of portal hypertension, they must be stable after the successful TIPS procedure, and not experiencing serious complications from the TIPS procedure itself (e.g., infection and intractable hepatic encephalopathy). Has blood urea nitrogen (BUN) <80 mg/dL. Has an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2. Agrees to avoid alcohol consumption during the study. Is willing and able to comply with all requirements of the study protocol. Exclusion Criteria: Has primary hepatic neoplasms (hepatocellular carcinoma and cholangiocarcinoma). Has active and/or uncontrolled severe infections requiring hospitalization and prolonged antimicrobial therapy. Has severe coagulopathy (international normalized ratio [INR] >2, and/or platelet count <50,000/μL). Has psychiatric and/or social issues that could lead to noncompliance. Has an extrahepatic neoplastic disease requiring active chemotherapy, immunotherapy, and/or surgical resection. Has previously treated neoplastic disease with less than a 2-year cancer free period. Pregnant and lactating women should not be in the study. Known hypersensitivity to human serum albumin. Subjects with uncontrolled hypertension (defined as a diastolic blood pressure of 110 mmHg or higher). Has recurrent/intractable ascites refractory to diuretics and requiring periodic large volume paracentesis. Has primary alcoholic liver disease and has not demonstrated abstinence for at least 24 weeks (6 months) prior to enrollment while attending mandatory rehab programs (e.g., Alcoholics Anonymous) and psychotherapy. Has grade 3 esophageal varices requiring the continuous use of propranolol and cannot afford to have this medication withheld and/or discontinued. Has a Child-Turcotte-Pugh (CTP) Class of C. Is receiving or plans to receive treatment with another investigational product or device.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Open-Label Dose Escalation of Three Increasing Dosages
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LYG-LIV0001<br>Open label group of subjects with end stage liver disease receiving increasing doses of the experimental therapy. | Biological: LYG-LIV0001<br>* Allogenic hepatocytes suspended in a buffered cell preservation solution with increasing number of lymph nodes being transplanted for the dose escalation. Subjects will also receive immune suppression, including tacrolimus capsules to follow the dose prescribed by the investigator as well as a short course of prednisone.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dosage Selection | The primary objective of the dose escalation is to confirm the optimal dose of transplanted hepatocytes to safely achieve adequate allogeneic hepatocyte (AH) engraftment | Week 12 | 
| Safety of Engraftment of Hepatocytes in to Lymph Nodes | The primary safety objective of the dose escalation is to determine whether AH engraftments into the periduodenal lymph nodes in subjects with end-stage liver disease is safe as determined by the number/severity of adverse events | Week 12 | 
| Efficacy of Engraftment of Hepatocytes in to Lymph Nodes | The primary efficacy objective of the dose escalation is to determine whether AH engraftments into the periduodenal lymph nodes in subjects with end-stage liver disease is efficacious in addressing some of the signs and symptoms of end-stage liver disease | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness of Selected Treatment to Modify the Liver Function Panel | Evaluate the effectiveness of hepatocyte transplants in modifying the liver function panel (total serum bilirubin, ammonia, prothrombin time, international normalized ratio, sodium, blood urea nitrogen, and creatinine) as measured through changes in laboratory biomarkers caused by end-stage liver disease | Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Allogeneic, Organogenesis, Hepatocyte, Transplantation, Liver Disease