A Safety and Efficacy Study of Infusions of HepaStem in Urea Cycle Disorders Pediatric Patients

Study Overview
=================
Brief Summary
-----------------
This is a phase2, prospective, open label study designed to investigate the safety and efficacy of several infusions of HepaStem. This study will include 5 pediatric Urea Cycle Disorder (UCD) patients under 12 years old. Its assessment includes all safety parameters and an efficacy assessment based on 13C tracer tests, ammonia, medication and diet changes. HepaStem will be administered in addition to the conventional UCD treatments.

Detailed Description
-----------------
Patient eligibility will be assessed during the Screening visit. The investigator should ensure that the chronic metabolic treatment (i.e. balance between low protein diet, supplements in amino acid mix, nitrogen scavenger and supplements in arginine and/or citrulline) of the patient is optimized for his/her metabolic condition. During the baseline period, 3 study visits will take place at 6 weeks interval for assessing the metabolic condition and the chronic metabolic treatment of the patient. A calculated dose based on patient's body weight will be administered via Permanent mesenteric Portal Access and Catheter for four times or a Transient Percutaneous Transhepatic Catheter for three times. The follow-up period will start approximately 12 weeks after the first HepaStem infusion day. This period will last approximately 9 months. Study visits will take place every 1.5month, FU visit 1 to FU visit 7. Primary Objective: To demonstrate the functional efficacy of HepaStem at 6 months after initiation of infusion in terms of ureagenesis improvement based on a functional test (13C tracer method) To evaluate the safety of Hepastem up to one year after initiation the Hepastem infusion Secondary Objective: 1. To evaluate the efficacy of Hepastem in terms of functional, clinical, and biochemical parameters up to one year after initiation of the infusion.

Official Title
-----------------
A Prospective, Open Label, Safety and Efficacy Study of Infusions of HepaStem in Urea Cycle Disorders Pediatric Patients

Conditions
-----------------
Urea Cycle Disorder

Intervention / Treatment
-----------------
* Biological: HepaStem Infusion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient is a pediatric patient <12 years The patients presents with one of the following UCDs. (CPS1D, OTCD, ASSD, ASLD, ARGD) The patient has severe disease with impaired protein tolerance defined as: chronic protein restricted diet AND chronic treatment with at lease one nitrogen scavenger. The patient shows patency of the portal vein and its branches including mesenteric veins, with normal flow velocity as confirmed by Doppler US and accessibility of the portal vein and/or affluents. The patient (if capable of signing) and parents or legal representative have signed a written informed consent form. Exclusion Criteria: The patient presents acute liver failure. The patient presents clinical or radiological evidence of liver cirrhosis. The patient presents or has a history of hepatic or extrahepatic malignancy. The patient has a known clinically significant cardiac malformation. The patient has a personal history of venous thrombosis, or has a clinically significant abnormal value for protein S, protein C, anti-thrombin III, and/or activated Protein C Resistance (aPCR) at screening. In case of known family history, a complete coagulation work-up should be performed. in all above described cases, results need to be discussed with sponsor before enrolling the patient in the study. Patient currently receiving other unapproved investigational drug or device. The patient underwent previous mature liver cell or stem cell transplantation or received an organ liver transplant or received HepaStem infusion. The patient has a contraindication to methylprednisolone, tacrolimus. The patient has a known hypersensitivity or allergy to heparin. The patient has a known hypersensitivity or allergy to the antibiotics preventing post-operative infections that are prescribed according to institutional guidelines, and no alternative prophylaxis can be found. The patient had or has a renal insufficiency treated by dialysis. The patient requires valproate therapy. The patient has a known hypersensitivity or allergy to contrast agents (if applicable) that cannot be treated adequately. The patient has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow. The patient has a porto systemic shunt or fistula assessed by Doppler US or an Arantius channel or protal hypertension. The site where the catheter is intended to be placed has previously suffered from venous thrombosis or vascular surgical procedures. The patient has an ongoing infection or suffered from an infection in the last 2 weeks (including active EBV infection at screening). The patient may be enrolled after resolution of the infection. There is any significant condition or disability that, in the investigator's opinion, may interfere with the patient's participation in the study.

Ages Eligible for Study
-----------------
Maximum Age: 12 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single group, open label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HepaStem Infusion<br>A calculated dose based on patient's body weight will be administered via Permanent mesenteric Portal Access and Catheter for four times or a Transient Percutaneous Transhepatic Catheter for three times. | Biological: HepaStem Infusion<br>* HepaStem will be infused intravenously into the portal vein, either (1) via a permanent mesenteric PAC inserted surgically in an affluent of the portal vein; or (2) through a transient percutaneous transhepatic catheter inserted in to the portal vein under radio guidance.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of ureagenesis | Change of de novo ureagenesis at 6 months after the first infusion: absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at FU visit 3 compared with baseline evaluations. | at 6 months after the first infusion | 
| Hemodynamics (measurement of portal vein pressures) | Safety evaluation in terms of portal-vein hemodynamics | up to 12 months after the first infusion | 
| Number of subjects with anti-HLA antibody | Safety evaluation in terms of de novo detection of donor-specific circulating anti-HLA antibodies and/or other immune-related markers | up to 12 months after the first infusion | 
| Number of subjects with SAEs and AEs | Safety evaluations in terms of SAEs and clinically significant AEs related to study procedures | up to 12 months after the first infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of ureagenesis | Change of de novo ureagenesis at 3, 9 and 12 months after the first infusion: absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at FU visit 1, 5 and 7 compared with baseline evaluations. | at 3, 9 and 12 months after the first infusion | 
| Change of chronic protein intake | Chronic protein intake (total and natural protein, reported in mg/kg/day and reported as compared to WHO safe level for age) considering diet evaluations at study visits during baseline period and at scheduled study visits during the follow-up period. | Up to 12 months after the first infusion | 
| Change of chronic nitrogen scavenger dose | Chronic nitrogen scavenger dose (mg/kg/day) considering reported doses at scheduled study visits during baseline period and at scheduled study visits during the follow-up period. | Up to 12 months after the first infusion | 
| Change of the level of blood ammonia | Blood ammonia considering values measured at scheduled study visits during screening and baseline periods ant at scheduled study visits during the follow-up period. | Up to 12 months after the first infusion | 
| Change of relevant blood amino acids values | Relevant blood amino acids considering values measured at scheduled study visits during the screening and baseline periods and at scheduled study visits during the follow-up period. | Up to 12 months after the first infusion | 
| Number of subjects with Metabolic decompensations | Metabolic decompensations (hyperammonemia episodes with evocative symptomatology such as drowsiness, gastrointestinal symptoms and treated at hospital), considering all collected events during screening and baseline periods, during active treatment period, during follow-up period. | Up to 12 months after the first infusion | 
| Change of chronic single amino acid intake | Chronic single animo acid intake considering reported doses at study visits during baseline period and at study visits during the follow-up period. | Up to 12 months after the first infusion | 
| Evaluation of cognitive skill | Change of patient's cognitive skill score between the baseline period (at Baseline visit 1) and the follow-up period (at Follow up visit 7) will be evaluated by the Bayley Scales of Infant Development. (7 classes, from extremely low to very superior) | Up to 12 months after the first infusion | 
| Evaluation of Behavior indicator | Behavior indicator will be evaluated by the Child Behavior Checklist (CBCL) at Baseline visit 1, during follow-up period at 4.5 months, 7.5 months and 12 months post-first fusion (at Follow up visit 2, 4, 7) | Up to 12 months after the first infusion | 
| Evaluation of health-related Quality of Life (QoL) indicator | Health-related QoL indicator will be evaluated by the Pediatric Quality of Life Inventory at Baseline visit 1, during follow-up period at 4.5 months, 7.5 months and 12 months post-first fusion (at Follow up visit 2, 4, 7) | Up to 12 months after the first infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Urea Cycle Disorder, Hyperammonemia, Metabolic Decompensation