An Adaptive, Multicentre, Phase IIa, Multi-disease Trial Investigating the Safety & Activity of a Single Infusion of Selected Mesenchymal Stromal Cells in the Treatment of Patients With Primary Sclerosing Cholangitis & Autoimmune Hepatitis
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Activity and Safety at the Highest Safe Dose (HSD) of ORBCEL-C in PSC patients, by measure of change in Alkaline Phosphatase (ALP)
研究概览
简要总结
MERLIN is an adaptive, single arm, multi-centre, phase IIa multi-disease clinical trial. It is designed to:
i) Determine dose safety of ORBCEL-C™ (selected Mesenchymal stromal cells derived from human umbilical cord) ii) Evaluate treatment activity through assessment of biomarkers (for patients treated at the highest safe dose only (HSD))
This trial will determine the Highest Safe Dose (HSD) that can be administered by observing for occurrence of dose limiting toxicity (DLT).
Upon completion of this trial we hope to be able to justify and conduct separate, larger scale trials using ORBCEL-C™.
详细描述
MERLIN is an adaptive, single arm, multi-centre, phase IIa multi-disease clinical trial. It is designed to:
i) Determine dose safety of ORBCEL-C™ (selected Mesenchymal stromal cells derived from human umbilical cord) ii) Evaluate treatment activity through assessment of biomarkers
This trial will determine the HSD* that can be administered by observing for occurrence of dose limiting toxicity (DLT).
* An investigated dose level is determined to be safe if we see 0 DLTs in 3 patients or ((in the instance where a cohort is expanded to 6 patients due to occurrence of a DLT in the first 3 patients treated at a cohort) < 2 DLTs in 6 patients. The HSD is the highest such dose which fulfils these criteria and will be ascertained via dose-escalation using 3+3 methodology.
Further safety and activity outcomes will be determined on patients treated at the HSD only. Upon completion of this trial we hope to be able to justify and conduct separate, larger scale trials using ORBCEL-C™.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with Primary Sclerosing Cholangitis (PSC):
- •Age ≥ 18 at Visit 1
- •Diagnosis of PSC at Visit 1 as evidenced clinically by:
- •Chronic biochemical cholestasis (elevated serum alkaline phosphatase (ALP) above the upper limit of normal (ULN) and/or gamma-glutamyl transpeptidase (GGT) above the ULN) ≥6 months duration AND
- •Radiological AND/OR histological evidence of clinically documented PSC
- •Serum ALP ≥ 1.5 x ULN at Visit 1
- •Any serum ALP value change is <40% using two sets of laboratory values obtained during screening:
- •If a participant fails to confirm an ALP at Visit 2 that is within 40% of the ALP at Visit 1, a further screening ALP (Visit 2a) can be arranged, so long as the variation in ALP was <50%, and the Principal Investigator has no other clinical reason to suggest the participant is clinically unstable. If the ALP is within 40% variance at Visit 2a as compared to visit 1, Trial registration is permitted.
- •At Visit 2 (and Visit 2a if applicable), it should be confirmed that a patient does not meet any of the
排除标准
- •Inclusion Criteria - Patients with Autoimmune Hepatitis (AIH):
- •Age ≥ 18 at Visit 1
- •Established pre-existing clinical diagnosis of AIH confirmed by clinical expert review consistent with the simplified IAIHG criteria (http://www.mdcalc.com/simplified-scoring-autoimmune-hepatitis-aih/) and must include history of a liver biopsy reported compatible with AIH
- •Active AIH defined by ALT ≥ 1.1 x ULN
- •Serum ALT must be above ≥ 1.1 x ULN at both Visit 1 and Visit 2
- •At Visit 2, it should be confirmed that a patient does not meet any of the exclusion criteria
- •Patients must be on standard-of-care AIH treatment for ≥ 24 weeks -this includes any AIH therapy except biologics
- •Stable doses of immunosuppression for a minimum period of 4 weeks (28 days) at the time of Visit
- •Exclusion Criteria - Patients with PSC and AIH:
- •Patients who meet any of the following exclusion criteria are excluded from participating in the MERLIN trial
- •Refusal or lacks capacity to give informed consent to participate in trial
- •Patient who is unable to participate in follow-up assessment
- •Participation actively, or within 5 half-lives, of another interventional clinical trial
- •Known hypersensitivity to the investigational product or any of its formulation excipients
- •Evidence of active malignancy (within 3 years of Visit 1), other than non-melanomatous skin cancer and cervical dysplasia in situ
- •Major surgical procedure within 30 days at Visit 1
- •Prior organ transplantation
- •Active harmful alcohol consumption as evaluated and documented by the Investigator
- •Poor venous access, therefore unable to support a 22G needle for infusion
- •Creatinine > 133 μmol/L or being treated with renal replacement therapy at the time of Visit 1
- •AST or ALT > 10 x ULN
- •ALP > 10 x ULN
- •Platelets < 50 x 10^9/L
- •Total Bilirubin > 2 x ULN
- •INR > 1.3 (in the absence of concomitant use of Warfarin or equivalent anti-coagulant therapy)
- •Albumin < 35 g/L
- •Haemoglobin < 10 g/dL
- •Past or present evidence of decompensated chronic liver disease:
- •Radiological or clinical evidence of ascites
- •Hepatic encephalopathy
- •Endoscopic evidence for portal hypertensive bleeding
- •Any active treatment with biologic therapy (monoclonal antibodies)
- •Clinically severe cardiovascular disease as evaluated by the Investigator
- •Pregnancy or breast-feeding
- •Women of child bearing potential who are unwilling to practice effective contraception (i.e. barrier, oral contraceptive pill, implanted contraception, or previous hysterectomy, bilateral oophorectomy) for the duration of the trial up to 90 days after the trial drug is administered. If using hormonal agents the same method must have been used for at least 1 month before trial dosing and patients must use a barrier method during that time period
- •Non-vasectomised men, sexually active with women of child bearing potential, who are not willing to practice effective contraception (condom with spermicide) for the duration of the trial up to 90 days after the trial drug is administered
- •Patients with a history of hepatitis C (present or past infection), known positivity for antibody to HIV or any evidence of current or past hepatitis B infection
- •Presence of an acute/chronic infection or illness that, at the discretion of the Investigator, might compromise the patient's health and safety in the trial
- •Any symptoms indicative of Covid-19; including fever, chronic/persistent cough, or loss of sense of taste or smell in the preceding two weeks.
- •Receipt of live vaccination within six weeks prior to Visit 1
- •Exclusion Criteria Specific to Patients with PSC:
- •Documented alternative aetiology for sclerosing cholangitis (i.e. secondary sclerosing cholangitis)
- •A dominant (as determined by Investigator) alternative chronic or active liver injury other than PSC at the time of Visit 1; Patients with possible overlap syndrome with AIH are excluded from the PSC cohort if the Investigator considers AIH as the dominant liver injury
- •UDCA dose modification within the last 90 days
- •ALP > 10 x ULN
- •Evidence of cholangitis within 90 days of Visit 1
- •Documented evidence of cholangitis by physician
- •Need for any antibiotics for presumed cholangitis
- •Any patient taking prophylactic antibiotics to combat recurrent cholangitis
- •Presence of percutaneous biliary drain, or internal biliary stent
- 另有 17 项未显示
研究组 & 干预措施
AIH patients
Selected Mesenchymal Stromal Cells (dose selection and efficacy) - Orbcel-C. dose selection, combination of 0.5, 1.0,2.5 million cells/kg (3 dose levels). IV single-infusion.
干预措施: Orbcel-C (Biological)
PSC patients
Selected Mesenchymal Stromal Cells (dose selection and efficacy) - Orbcel-C. dose selection, combination of 0.5, 1.0,2.5 million cells/kg (3 dose levels). IV single-infusion.
干预措施: Orbcel-C (Biological)
结局指标
主要结局
Activity and Safety at the Highest Safe Dose (HSD) of ORBCEL-C in PSC patients, by measure of change in Alkaline Phosphatase (ALP)
时间窗: Baseline to Visit 8 - Approximately 80 days
Change in Alkaline Phosphatase (ALP) after ORBCEL-C infusion - Examination of change in ALP at Day 28 from Baseline and changes over multiple time-points before and after infusion (Visit 1 to Visit 8)
Dose finding and incidence of treatment emergent adverse events (safety and tolerability) in all PSC and AIH Patients
时间窗: Visit 3 to Visit 5 -14 days
Occurrence of Dose Limiting Toxicity (DLT) over 14 day (Visit 3 to Visit 5) reporting period after ORBCEL-C infusion
Incidence of treatment emergent adverse events (safety and tolerability) for PSC and AIH patients treated at the Highest Safe Dose (HSD) only
时间窗: Visit 3 to Visit 8 - 56 days
Determine safety and tolerability by occurrence of Dose Limiting Toxicity (DLT) (Visit 3 to Visit 5 only), Serious Adverse Events (SAEs) and Adverse Events (AEs) throughout trial period (up to Visit 8)
Activity at the Highest Safe Dose (HSD) of ORBCEL-C in AIH patients, by measure of change in Alanine Aminotransferase (ALT)
时间窗: Baseline to Visit 8 - Approximately 80 days
Change in Alanine Aminotransferase (ALT) trend after ORBCEL-C infusion. Measurements of ALT will be taken at multiple time points from Visit 1 to Visit 8.
次要结局
- All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 3(Baseline to Visit 8 - Approximately 80 days)
- All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 2(Baseline to Visit 8 - Approximately 80 days)
- All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 4(Baseline to Visit 8 - Approximately 80 days)
- All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 5(Baseline to Visit 8 - Approximately 80 days)
- All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 1(Baseline to Visit 8 - Approximately 80 days)
- All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 1(Baseline to Visit 8 - Approximately 80 days)
- All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 3(Baseline to Visit 8 - Approximately 80 days)
- All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 2(Baseline to Visit 8 - Approximately 80 days)
- All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 4(Baseline to Visit 8 - Approximately 80 days)