Hepatocyte Microbeads for Acute Liver Failure

NCT05491135 | Not Yet Recruiting Phase 1 DMC

• 2 other identifiers: 35712019-000316-29
• Study Type: interventional
• Target: 17
• Locations: 0 countries
• Sites: N/A

Brief Summary

Acute Liver Failure in children is associated with high mortality without liver transplantation. In addition, donor organ shortage makes it difficult to provide this treatment to every potential patient. Liver transplantation is life-saving but it carries the risk of major surgery and complications from lifelong anti-rejection drugs to suppress the immune system. If bridged across the immediate crisis following acute liver failure, the immense regenerative potential of the liver means that the patient's own liver may 're-grow'. This period is very time sensitive. Unfortunately, if the vital synthetic and detoxification function of the liver is not provided, the patient will often die before the liver can re-grow. Transplantation of liver cells (hepatocytes) can provide this 'bridge' with considerable advantages over whole organ transplantation. Firstly, hepatocytes are derived from donor livers which are otherwise unsuitable for transplantation. Secondly, unlike whole organs, they can be frozen and stored, thus act as an 'off the shelf' treatment. Thirdly, the technique of hepatocyte transplantation within microbeads coated with alginate (a gel originating from seaweed) and infused into the abdominal cavity is much less invasive than liver transplantation. Finally, the alginate protects the cells against the body's immune system, avoiding the need for immunosuppressive drugs and the associated major risks. Furthermore, preclinical work in King's College Hospital has shown that the addition of support cells called mesenchymal stromal cells (MSCs), can significantly improve the ability of hepatocytes to survive and function within the alginate microbead. The HELP trial is a Phase 1/2 safety and tolerability study of infusion of HMB002 (an optimal combination of hepatocytes and mesenchymal stromal cells put together in peptide-alginate microbeads) into paediatric patients with acute liver failure. This novel cellular therapy may act as a bridge treatment to liver transplant or lead to regeneration of the native liver.

Conditions

Acute Liver Failure

Keywords

Cell therapy; Paediatric Liver transplant

Outcome Measures

Primary Outcomes (3)

• Safety: Moderate to severe (including life threatening and death) adverse event occurrences due to product in 1st 52 weeks post procedure

  As above

  Baseline to 52 weeks

• Tolerability: assessed by the proportion of initiated infusion where >80% of the infusion is received by the patient.

  Tolerability: assessed by the proportion of initiated infusion defined by \>80% of the IMP infusion is received by the patient on Day 0.

  1 Day

• Biological activity: Survival with native liver at 24 weeks post treatment.

  As above

  baseline to 24 weeks

Secondary Outcomes (4)

• Change in blood marker levels including haematological, biochemical and coagulation baseline to 52 weeks post treatment.

  Baseline to 52 weeks

• Change in Quality of life measures from baseline to week 52

  Baseline and 52 weeks

• Patient survival with native liver at 52 weeks post treatment

  Baseline to 52 weeks

• Patient survival with transplanted or native liver at 24 and 52 weeks post treatment.

  Baseline to 24weeks and then 52 weeks

Other Outcomes (2)

• To compare the ratios of specific SNP combinations in proteins between patients and donor cells by targeted mass spectrometry to distinguish the patient and recepient derived proteins

  Baseline to 52 weeks

• To analyse viability using fluorescent stains and function through the measurement of albumin of hepatocytes in microbeads which are retrieved from the intraperitoneal cavity either at laparoscopy or transplant for phenotype ex vivo.

  Anytime within the 52 week period following investigational ,medicinal product infusiomn

Study Arms (1)

HMB002

EXPERIMENTAL

All patients will receive HMB002 infusion into the peritoneal cavity.

Biological: HMB002

Interventions

HMB002 BIOLOGICAL

The solution containing microbeads will be infused manually into the peritoneal cavity under ultrasound guidance, 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

Eligibility Criteria

• Age: Up to 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Infant or child (male or female) under the age of 16 years at recruitment.
• Written informed consent obtained from a parent / legal guardian
• Presence of ALF defined as a multisystemic disorder in which severe impairment of liver function with or without encephalopathy occurs in association with hepatocellular necrosis reflected as synthetic liver failure in a child with no recognised underlying chronic liver disease. Children must fit one of the ALF categories as described in Appendix 1b(study protocol);
• Willing and able to comply with the study visit schedule.

You may not qualify if:

• Severe ascites causing high intra-abdominal pressure and / or respiratory compromise;
• Intra-abdominal sepsis suspected or proven;
• Clinical condition too unstable to tolerate procedure without compromise;
• Proven pre-existing allergy or intolerance to alginate on medical history;
• Proven pre-existing allergy to gentamicin on medical history;
• Intraperitoneal or intra-abdominal malignancy;
• Adhesions or fistulae to anterior abdominal wall;
• Children who weigh in excess of 33kg
• Pregnant or lactating patients (positive pregnancy test for females of child bearing potential at screening).
• Female patients of childbearing potential who are not willing to use highly effective methods of contraception to prevent pregnancy or abstain from heterosexual activity for 52 weeks post treatment.
• \*Females of child bearing potential are females who have experienced menarche and are not surgically sterilised (e.g. by tubal occlusion, hysterectomy, bilateral salpingectomy) or post-menopausal (defined as at least 1 year since last regular menstrual period).
• \*\* Highly effective methods of birth control are those with a failure rate of \< 1% per year when employed consistently and correctly. Highly effective methods of contraception as per HMA / CTFG working group are combined (Estrogen and Progestogen containing) hormonal contraception associated with inhibition of ovulation, the preparation may be oral, intravaginal or transdermal; progesterone-only hormonal contraception associated with inhibition of ovulation which may be oral, injectable or implantable; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence for 52 weeks post study treatment;
• \*\*\* Sexual abstinence is considered to be highly effective method only if defined as refraining from heterosexual activity from the date of consent until the week 52 visit post study treatment. The reliability of this method should be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
• Male patients who are not willing to use an effective method of contraception (condom, vasectomy, sexual abstinence) for 52 weeks post study treatment, when engaging in sexual activity with a female of childbearing potential;
• Participation in concurrent therapeutic trial for ALF;

Sponsors & Collaborators

• King's College Hospital NHS Trust: lead
• Medical Research Council: collaborator

MeSH Terms

Conditions

Liver Failure, Acute

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases

Study Officials

• Anil Dhawan, Professor

  King's College Hospital NHS Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anil Dhawan, Professor

CONTACT

0203 2994408; anil.dhawan@kcl.ac.uk

Barath Jagadisan, Dr

CONTACT

barath.jagadisan@nhs.net

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: ATIMP

Study Record Dates

• First Submitted: July 27, 2022
• First Posted: August 8, 2022
• Study Start: September 1, 2022
• Primary Completion: November 1, 2025
• Study Completion: May 1, 2026
• Last Updated: August 8, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share