Hepatocyte Microbeads for Acute Liver Failure

This is an open label, single centre study first in man study. The study will be conducted using the Simon two stage design. Nine patients will be recruited during stage 1 of the study. Once 9 patients have completed their 24 weeks visit, the study will stop for futility if only 2 or fewer patients have survived with the native liver. Otherwise, the study will progress to Stage 2 of recruitment, where the trial will continue to enroll a further 8 patients. A total of 17 patients will be recruited into the study (at the end of stages 1 and 2). At the end of the second stage, 7 or more patients out of the 17 enrolled should have survived with the native liver at 24 weeks post HMB002 treatment, to show evidence of efficacy of this novel hepatocyte transplantation that would support a larger randomised controlled trial.

Following signed informed consent from parent/legal guardian, the following screening tests and procedures will be undertaken to ensure patient is eligible to take part in the study (some of these may be part of routine care).

• Medical and Medication History
• Physical examination
• Height and weight monitoring
• Vital signs (body temperature, blood pressure, Pulse rate and Oxygen saturation)
• Urine or serum pregnancy test in females of childbearing potential
• Clinical blood tests and additional research bloods
• Recording of neurological parameters
• Ultrasound of the abdomen
• Quality of Life - Parent and where appropriate patient questionnaires (optional)

Enrolled participants will have pre-infusion checks and monitoring in the paediatric high dependency unit (HDU) or Paediatric intensive care unit (PICU). Children with acute liver failure generally require this degree of monitoring in any case. The child may be intubated and ventilated as part of routine care. This involves ventilation using a machine to help move air into and out of the lungs. If a suitable donor liver becomes available within 12 hours of planned study treatment, patient will go onto receive a liver transplant.

Following successful pre-infusion checks, the solution containing beads will be infused manually into the peritoneal cavity with usually a 50ml syringe, as a single infusion or several infusions, to achieve in excess of 25 million hepatocytes per kilogram of the body weight. HMB002 infusion will be done under ultrasound guidance.

• Participants will be continuously monitored before and for at least 24 hours after infusion in PICU/HDU. Some of these tests outlined below will be as per HDU and PICU standard of care. Once clinical condition permits and after 24 hours post infusion, the child may be stepped down to the paediatric wards.
• Physical and neurological examination
• Intra-abdominal pressure will be measured using urinary catheter where possible, at regular intervals both before and after infusion.
• Regular review of the IMP infusion site
• regular Vital signs (body temperature, blood pressure, Pulse rate and Oxygen saturation) • Clinical bloods at regular intervals both pre and post infusion.
• Additional research bloods
• Recording of ventilator settings and additional supportive therapy given as part of standard of care • Ultrasound of the abdomen
• Recording of side effects
• Recording of change in medications
• Participants will undergo daily examination until Day 7 while still an inpatient, and then be followed up at weeks 2, 4, 8, 12, 16, 24 and 52. Participants will be discharged following a liver organ transplant or upon recovery of their native liver. Therefore some of the follow up visits will be done in the outpatient clinics at King's College Hospital. Patients will have some or all of the assessments below at each follow up visit. Some of these visits will be part of standard routine care.
• Physical and neurological examination
• Height and weight monitoring,
• Monitoring of Vital signs (body temperature, blood pressure, Pulse rate and Oxygen saturation)
• Clinical Blood tests and additional bloods for research (at some visits; optional)
• Recording of level of ventilator settings and supportive treatment as given with routine care.
• Recording of side effects
• Recording of changes to Medication
• Parent and where appropriate patient questionnaires at final visit (optional parents/legal guardian consent
• Ultrasound of the abdomen at specified time points in the protocol.

Microbeads will ideally be removed within 4 weeks of infusion. This will be done at the time of liver transplant or upon recovery of the native liver prior to discharge (using laparoscopy, a small key hole surgery of the abdomen).

Participants will also be followed up for another 9 years after HMB0002 infusion for monitoring of long term safety. This will be aligned with routine care and will be conducted annually as a minimum but may be more frequent depending on the clinical condition of the child or young person. Clinical blood tests and abdominal ultrasound data will be collected annually during the long term follow up period (years 2 to 5 as per routine care). SAEs (with exceptions) will be collected for the duration of the follow up period as outlined in the study protocol.