Protocol version 2.3 (dated April 16, 2009) was amended and replaced by protocol version 2.4 (dated January 20, 2010), 4 patients enrolled • Changed first inclusion criterion from “biochemically proven urea cycle disorder” to “prenatally or postnatally confirmed urea cycle disorder” and changed inclusion criterion “Serum ammonia level ≤250 μmol/l” to “Plasma ammonia level ≤250 μmol/l”. • Updated the description of the surgical procedure for catheter placement, closure of the Ductus Venosus Arantii and catheter removal. • Changed the tolerable limit of portal vein pressure. • Added allowance for administration of intravenous methylprednisolone, CNIs as immunosuppressants and basically anticoagulants when discontinued before and during surgical interventions in accordance with the standard of care. Deleted “Experimental drugs”. • Added Megalotect (Cytotect®) or the site’s standard of care for prophylaxis of EBV-infection. • Added the respective SmPC in its current version as reference document for co-medications. • Deleted regularly flushing of the catheter with a solution containing heparin and that heparin was added to the cell suspension. • Added that cell suspension containing >15 million cells/ml may be diluted with Composol PS® to a maximum volume of 15 ml/kg body weight. • Changed the biometric examinations scheduled for every visit to twice weekly, deleted the urine status parameter urine nitrogen, clarified the time of the second blood draw and changed tacrolimus (or cyclosporin) trough level measurement to from V-1 to V1. • Added additional stopping rules for safety reasons. • Updated Chapter 9 “Safety Reporting”. • Minor changes

Protocol version 2.4 (dated January 20, 2010) was amended and replaced by protocol version 3.0 (dated August 07, 2010), 2 patients enrolled • Added a 13C ureagenesis assay using Sodium 13C acetate as new diagnostic method, as an advanced protocol for the direct determination of the capacity of the urea cycle based on the determination of 13C urea in patient’s blood, added 13C assay as additional efficacy outcome measure and expanded study duration due to the test implementation. • Added a subgroup of 3 evaluable older children in the age of 15 months up to ≤5 years and changed the inclusion criteria and exclusion criteria (added that the body weight should not be ≤3.5 kg) accordingly as well as cell dosage adjustment for older children. • Discontinued sequential enrolment process, as the results of the Interim Analysis have not indicated any safety concerns. • Changed SAE reporting procedure and regular updating. • Changed time period for OLT listing stretching the definite moment for OLT listing at V23 in Week 8 to a time period from V23 in Week 8 to V31 (FV) in Week 16 (‘listing period’) due to differences in age and developmental progress of the patients. • Changed concomitant medication for safety reasons to allow exchange of methylprednisolone by prednisone, to consider detoxification as best medical care, to add valproate to exclusion criteria, to reduce the trough level of tacrolimus and to evaluate immunosuppression trough level during follow-up visits. • Extended enrolment options to encourage referrals of patients to study centres from other hospitals, also from abroad, due to the rareness of UCD patient. • Changed study title due to the addition of a sub-group to the existing patient population.

Protocol version 3.0 (dated August 07, 2010) was amended and replaced by protocol version 3.1 (dated March 09, 2011), 3 patients enrolled • Implemented additional time points to 13C assay based on first test results in 1 Patient.

Protocol version 3.1 (dated March 09, 2011) was amended and replaced by protocol version 4.0 (dated May 23, 2012), 1 patient enrolled, 3 patients continued • Extended the range for age at enrolment to include patients between >3¬<15 months of age to make the age range consistent to the US study CCD05. • Added allowance for peripheral lines to be used at physicians discretion as for older patients a central line may not always be needed. • Specified handling of portal vein catheter dislocation. • Included assessment of initial disease diagnosis by requesting confirmation of diagnosis by mutational analyses into the revised study protocol. • Allowed the documentation of additional parameters to be consistent to the US study CCD05. • Introduced time windows for study visits due to patients coming from abroad and not staying at the study sites for the complete study duration. • Added administrative corrections in protocol including the flowchart for consistency reasons. • Clarified the different modalities for performing the 13C assay scheduled at Final Visit if OLT takes place prior to 4 months of study participation. • Changed Patient Information and the Informed Consent Form to collect and evaluate data by ongoing routine procedures/visits to cover additional information on the influence of HHLivC therapy. • Clarified definition of SAE reporting period. • Changed dosing of cefuroxim or any other prophylactic antibiotic treatment according to different sites’ standard of care. • Added HLA-assessments to comply with regulatory requirements. • Adapted time points and volumes in 13C assay according to the experience with kinetics of the 13C-urea formation in paediatric UCD patients. • Omitted V15-17, V19 and V31 since no safety concerns occurred after liver cell application in the first 10 patients and V31 caused a discrepancy with the whole study duration described in the study protocol. • An additional amendment, protocol version 3.2, was pla

Protocol version 4.0 (dated May 23, 2012) was amended and replaced by protocol version 5.0 (June 12, 2013), no patients enrolled under protocol version 5.0 • Extended the exclusion criteria for thrombocytopenia and hereditary thrombophilia according to the Pediatric Investigation Plan (PIP). • Extended primary safety variable of placement of an application catheter to the portal vein to consider all safety issues after liver cell infusion. • Adapted the secondary efficacy variables according to the PIP. • Removed haemodynamic and respiratory monitoring from the secondary efficacy variable vital signs, as assessments for respiratory monitoring are not part of the protocol and blood oxygen saturation is a primary safety variable. • Adapted the number of trial sites to reflect the current status. • Adapted the Justification of Study Design. Dosage and Application Schedule section to reflect the current trial status. • Changed continuous recording of concomitant medication to be documented from V-4 until OLT and only for subjects not undergoing OLT to last FU visit, as documentation of medication during and after OLT has no direct benefit for trial evaluation. • Adapted the End of Study and Patient Population description to include all available data into the analysis of the results, as some patients included in the trial were not able to be fully documented due to various reasons. • Added a second Interim Analysis after treatment of 11 patients for submission process to the European Medicines Agency. • Extended the trial duration and schedule to include the follow-up phase. • Corrected mistakes in the Visit Schedule and modified text to limit the documentation of immunosuppression to the phase before the OLT. • Clarified the description of documentation of AEs and of concomitant medication in the Visit Schedule. • Specified determination and documentation of the tacrolimus blood levels during the Follow-up phase of the trial until OLT. • Specified determi

Amendment to protocol version 5.0 (June 12, 2013) dated September 21, 2015 • Administrative change of responsibilities for pharmacovigilance and QPPV • Reduction of sample size from 13 patients planned to 12 patients. • Change in wording of the third primary safety endpoint due to the fact that adverse events collected after the liver cell transplantation do not provide meaningful safety information on catheter placement. • Change in definition of age groups for paediatric sub-group Analysis