Hepatocytes Co-Encapsulated With Mesenchymal Stromal Cells in Alginate Microbeads for the Treatment of Acute Liver Failure in Paediatric Patients (HELP)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 17
- 主要终点
- Safety: Moderate to severe (including life threatening and death) adverse event occurrences due to product in 1st 52 weeks post procedure
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 16 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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;
- •Imminent liver transplantation expected within 12 hours of infusion;
- •Total hepatectomy;
- •Dependent on Extracorporeal Membrane Oxygenation (ECMO);
- •Previous liver transplant
结局指标
主要结局
Safety: Moderate to severe (including life threatening and death) adverse event occurrences due to product in 1st 52 weeks post procedure
时间窗: Baseline to 52 weeks
As above
Tolerability: assessed by the proportion of initiated infusion where >80% of the infusion is received by the patient.
时间窗: 1 Day
Tolerability: assessed by the proportion of initiated infusion defined by \>80% of the IMP infusion is received by the patient on Day 0.
Biological activity: Survival with native liver at 24 weeks post treatment.
时间窗: baseline to 24 weeks
As above
次要结局
- 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)