Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders

Open, Prospective, Uncontrolled, Multicentre Study to Evaluate The Safety and Efficacy of Multiple Applications of Liver Cell Suspension Into The Portal Vein in Children With Urea Cycle Disorders (UCDs)

Urea cycle disorders are rare inherited diseases that generally have a poor outcome. In this study, neonates and infants with UCD will be included within the first 3 months of life and will be treated by repetitive application of human liver cells to reduce the risk of neurological deterioration while awaiting OLT.

Study Overview

• Status: Completed
• Conditions: Ornithine Transcarbamylase Deficiency; Urea Cycle Disorders; Citrullinemia; Carbamoylphosphate Synthetase I Deficiency
• Intervention / Treatment: Biological: Human Heterologous Liver Cells

Detailed Description

Urea cycle disorders are rare inherited diseases that generally have a poor outcome, especially with onset of the disease in the neonatal period. UCDs are caused by a deficiency of one of six enzymes responsible for removing ammonia from the bloodstream. Instead of being converted into urea which is removed from the body with the urine, ammonia accumulates in UCD patients leading to brain damage or death. In the light of a mortality rate of > 50% at the age of 10 years the current pharmacological and dietary therapy is of modest success. Furthermore, mental retardation, cerebral palsy and other neurological sequelae are common among surviving patients.

In the last years, orthotopic liver transplantation (OLT) has become the best therapeutic option for UCD with long-term survival rates of about 90%. However, in the first weeks of life OLT still is technically demanding and prone to complications. With larger size of the recipient, the technical problems with OLT decrease considerably. The increased body weight usually achieved at the age of more than 8 weeks is related to a major reduction in transplantation related morbidity. Stabilization of metabolism until the patient can undergo OLT is essential.

In this study, neonates and infants with UCD will be included within the first 3 months of life and will be treated by repetitive application of human liver cells. In the last consequence, the aim of this new therapy option is to supply a sufficient amount of healthy liver cells to compensate for the metabolic defect and to reduce the risk of neurological deterioration while awaiting OLT.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany, 40225
    • University Children's Hospital, Heinrich-Heine University
  • Heidelberg, Germany, D-69120
    • University Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Neonates and infants up to the age of ≤ 3 months with prenatally or postnatally confirmed urea cycle disorder and

• Children aged > 3 months up to ≤ 5 years of age with unstable metabolism and confirmed urea cycle disorder of either:

  • Carbamylphosphate synthetase I [CPSD] or
  • Ornithine transcarbamylase [OTCD] or
  • Argininosuccinate synthetase [Citrullinaemia]

• A DNA analysis will further confirm diagnosis prior to or after inclusion according to the protocol.

  • Accessibility of the portal vein
  • Plasma ammonia level ≤ 250 μmol/l
  • Written informed consent

Exclusion Criteria

• Structural liver disease (cirrhosis, portal hypertension), or venoocclusive diseases
• Portal vein thrombosis
• Body Weight ≤3.5 kg
• Carrier of the human immuno-deficiency virus (HIV)
• Any other contraindication for immunosuppression
• Presence of acute infection at the time of inclusion
• Participation in other clinical trials or received experimental medication within the last 30 days
• Live vaccination planned during the course of the study
• Live vaccination within 4 weeks prior to beginning of study
• Allergic disposition against contrast medium used in study and/or antibiotics used in the manufacturing process
• Required valproate therapy
• Severe coagulopathy or thrombocytopenia
• Known diagnosis of hereditary thrombophilia (e.g. Factor V Leiden, Prothrombin 20210A variant) or parental history of hereditary thrombophilia and absense of thrombophilia testing in subject
• Cancer, severe systemic or chronic disease other than study indication (urea cycle deficiency)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HHLivC Therapy Group	Biological: Human Heterologous Liver Cells; Multiple applications of liver cell suspension for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety of the application of liver cells, safety of the placement of an application catheter to the portal vein.	7 - 15 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Changes in 13C urea formation. Changes in the respective enzyme activity in liver biopsies from the explanted organ compared to the enzyme activity in the liver before cell application.	7-15 weeks

Collaborators and Investigators

• Sponsor: Cytonet GmbH & Co. KG
• Investigators: Principal Investigator: Georg Hoffmann, Prof., University Children's Hospital

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: July 16, 2008
• First Submitted That Met QC Criteria: July 17, 2008
• First Posted (Estimate): July 18, 2008

Study Record Updates

• Last Update Posted (Estimate): February 8, 2016
• Last Update Submitted That Met QC Criteria: February 5, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: infants; newborns; Citrullinemia; Urea cycle Disorders; Carbamoylphosphate synthetase I deficiency; Ornithine transcarbamoylase deficiency; Argininosuccinate synthase deficiency; liver cell transplantation; liver cell infusion
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Mitochondrial Diseases; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Disease; Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn; Carbamoyl-Phosphate Synthase I Deficiency Disease; Citrullinemia
• Other Study ID Numbers: CCD02 (Other Identifier: cytonet); 2006-000136-27 (EudraCT Number)