HepaStem Long-Term Safety Registry – Registry for Patients who have been administered HepaStem

The primary objective of this study is to assess the **long-term safety** of HepaStem therapy in patients who have previously received at least one infusion of HepaStem during an interventional clinical study conducted by Promethera Therapeutics. This evaluation is clinically relevant as it aims to ensure the sustained safety profile of HepaStem, a cell suspension for injection, in managing conditions such as urea cycle disorders, Crigler-Najjar syndrome, and fibroinflammatory liver diseases. The study will include all patients who have been administered HepaStem, focusing on monitoring any long-term adverse effects or complications associated with the therapy.

The clinical trial involves a **study population** comprising both male and female participants who have previously received at least one infusion of the Investigational Medicinal Product (IMP) HepaStem HALPC in earlier interventional studies conducted by Promethera Biosciences or Promethera Therapeutics. The participants include individuals suffering from urea cycle disorders (UCD), Crigler-Najjar syndrome, and fibroinflammatory liver diseases. The age range of the participants spans from children to adults, indicating a diverse age group. The trial includes a vulnerable population, as it involves individuals who may be legally incapable of providing informed consent due to conditions such as brain disease or hepatic encephalopathy. The total number of participants is not specified. Participants were selected based on their previous involvement in studies where they received HepaStem, and they must be able to understand and provide written informed consent, or have consent provided by a legal representative if necessary. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to assess the long-term safety of **HepaStem** therapy in patients who have previously received at least one infusion of this investigational medicinal product during an interventional clinical study conducted by Promethera Therapeutics. The study targets patients with conditions such as urea cycle disorders, Crigler-Najjar syndrome, and fibroinflammatory liver diseases. This is a Phase 4 trial, which is not categorized as low intervention, and it aims to document adverse events of special interest, including fatal outcomes, organ transplantation, malignancy development, and disease transmission linked to the therapy.

The trial follows a non-randomized, open-label design, focusing on patients who have already been treated with HepaStem. The estimated duration of the trial extends from December 2017 to July 2028, with the primary objective being the documentation of long-term safety outcomes. Participants are expected to be involved for the entire duration of the study unless specific conditions necessitate early termination, such as the completion of a concurrent double-blinded controlled study or the unblinding of treatment, which would result in the termination of control-recipients' participation.

Study visits are structured to include an initial inclusion (screening) visit, where eligibility is confirmed based on prior receipt of HepaStem and the ability to provide informed consent. Follow-up visits are scheduled to monitor the occurrence of adverse events and assess the long-term safety of the therapy. The end-of-study visit will conclude the participant's involvement, summarizing the safety data collected throughout the trial. The trial's design ensures that all participants, including minors and those with incapacitating conditions, are adequately informed and consented, with legal representatives involved as necessary.

The clinical trial involves the administration of **HepaStem**, an advanced therapy investigational medicinal product developed by Promethera Biosciences. HepaStem is formulated as a **cell suspension for injection** and is intended for **intravenous use**. The active substance in HepaStem is **HHALPC**, a structurally diverse substance utilized in cell therapy. The maximum daily dose of HepaStem is 4000 million organisms, with a total maximum dose of 4000 million organisms over the treatment period. The maximum treatment period is set at 8 weeks. This product is not a pediatric formulation and has been designated as an orphan drug under the designation number EU/3/13/1161.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on assessing the long-term safety of HepaStem therapy in patients who have previously received at least one dose of HepaStem in an earlier interventional clinical study conducted by Promethera Therapeutics. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial involving HepaStem will be assessed primarily through the documentation of adverse events of special interest (AESIs). These AESIs include events with fatal outcomes, organ transplantation and its outcomes, development of malignancy or unwanted tissue formation in different organs, diseases linked to the transmission of adventitious agents or reactivation of latent pathogens, and any adverse event judged to have a plausible causal relationship to HepaStem. The trial is designed to evaluate the long-term safety of HepaStem therapy in patients who have previously received at least one infusion of the product in an interventional clinical study conducted by Promethera Therapeutics. The trial is categorized as a Phase 4 study, focusing on the long-term safety follow-up of the investigational medicinal product.