Cholangitis, Sclerosing, Hepatitis, Autoimmune
Conditions
Keywords
Autoimmune, AIH, PSC, Liver disease, Cholangitis
Brief summary
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™.
Detailed description
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™. OBJECTIVES For Both Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AIH) patients: The primary objective for all patients is: • To determine the highest safe single intravenous infusion dose of ORBCEL-C™ over a 14 day (Visit 3 to Visit 5) reporting period. For patients treated at HSD only, there is an additional co-primary objective: • To investigate whether a single intravenous infusion of ORBCEL-C™ in patients with PSC and AIH treated at the HSD is safe and tolerated over the period of trial follow-up (up to Visit 8) For PSC patients only: • Reduces serum alkaline phosphatase (ALP) in patients with PSC. This is a non- invasive biochemical surrogate of clinical outcomes in PSC For AIH patients only: • Reduces serum alanine aminotransferase (ALT) in patients with AIH. This is a non- invasive biochemical surrogate marker of hepatic inflammatory activity and outcomes in AIH. The secondary objectives are to investigate whether a single intravenous infusion of ORBCEL-C™ elicits a change over the duration of the trial after treatment in all patients with PSC and AIH on: * Circulating inflammatory cells profile as measured by flow cytometry (key secondary outcome) * Liver biochemistry and function, immunoglobulin G concentrations (in AIH patients) and composite risk scores * Non-invasive clinical markers of fibrosis * Patient Quality of Life (QoL) * Severity of co-existent Inflammatory Bowel Disease (IBD) in patients with PSC Further exploratory research objectives of the trial determine whether MSC infusion modulates the immune response by measuring whether treatment elicits a change in all patients with PSC and AIH: * Markers of immune activation including immunoglobulin values and C-reactive protein (CRP) concentration * Markers of biliary injury including total bile acid levels * Endothelial cell activation markers such as VAP-1 and ICAM1 * Serum cytokine, chemokine, ribonucleic acid (RNA) and micro-RNA expression profiles
Interventions
BIOLOGICALOrbcel-C
Selected Mesenchymal Stromal Cells derived from human umbilical cord
Sponsors
NHS Blood and Transplant
University of Birmingham
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Patients with Primary Sclerosing Cholangitis (PSC): 1. Age ≥ 18 at Visit 1 2. Diagnosis of PSC at Visit 1 as evidenced clinically by: 1. 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 2. Radiological AND/OR histological evidence of clinically documented PSC 3. Serum ALP ≥ 1.5 x ULN at Visit 1 4. 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. 5. At Visit 2 (and Visit 2a if applicable), it should be confirmed that a patient does not meet any of the
Exclusion criteria
Inclusion Criteria - Patients with Autoimmune Hepatitis (AIH): 1. Age ≥ 18 at Visit 1 2. 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 3. Active AIH defined by ALT ≥ 1.1 x ULN 4. Serum ALT must be above ≥ 1.1 x ULN at both Visit 1 and Visit 2 5. At Visit 2, it should be confirmed that a patient does not meet any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Activity at the Highest Safe Dose (HSD) of ORBCEL-C in AIH patients, by measure of change in Alanine Aminotransferase (ALT) | 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. |
| Activity and Safety at the Highest Safe Dose (HSD) of ORBCEL-C in PSC patients, by measure of change in Alkaline Phosphatase (ALP) | 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) |
| Incidence of treatment emergent adverse events (safety and tolerability) for PSC and AIH patients treated at the Highest Safe Dose (HSD) only | 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) |
| Dose finding and incidence of treatment emergent adverse events (safety and tolerability) in all PSC and AIH Patients | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 3 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in marker of immune activation - immunoglobulin G concentrations |
| All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 5 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in QoL as measured by Pruritus Visual Analogue Scale, nine-point fatigue severity scale and SF-36v2 |
| All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 4 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in Non-invasive clinical markers of fibrosis - ELF and transient elastography (Fibroscan®) |
| All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 1 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in Phenotypic expression of TRegs as measured by flow cytometry (principal secondary outcome) |
| All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 2 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in Individual markers of liver biochemistry and function including AST, ALP, GGT, bilirubin, albumin, INR and composite risk score (MELD) |
| All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 1 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in Phenotypic expression of TRegs as measured by flow cytometry (principal secondary outcome) |
| All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 2 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in Individual markers of liver biochemistry and function including aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), bilirubin, albumin, international normalised ratio \[INR\] and composite risk scores (Mayo PSC risk score and Model for End Stage Liver Disease \[MELD\]) |
| All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 3 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in Non-invasive clinical markers of fibrosis: Enhanced Liver Fibrosis (ELF) and transient elastography (Fibroscan®) |
| All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 4 | Baseline to Visit 8 - Approximately 80 days | Change from baseline at Visit 7, Visit 8 and throughout the trial period (up to Visit 8) following ORBCEL-C™ infusion in QoL as measured by Pruritus Visual Analogue Scale, nine-point fatigue severity scale and SF-36v2 Severity of IBD as measured by the non-endoscopic aspects of the Mayo IBD score - stool frequency, rectal bleeding, and physician's global assessment |
Other
| Measure | Time frame | Description |
|---|---|---|
| All patients with PSC and AIH - Exploratory Research Outcome 2 | Up to Visit 8 (56 days) | Change throughout the trial period up to Visit 8 of the following measured parameters: Markers of biliary injury including total bile acid levels (these will only be measured prior to infusion at Visit 3 and Visit 7) |
| All patients with PSC and AIH - Exploratory Research Outcome 1 | Up to Visit 8 (56 days) | Change throughout the trial period up to Visit 8 of the following measured parameters: Markers of immune activation including immunoglobulin values and C-reactive protein concentration |
| All patients with PSC and AIH - Exploratory Research Outcome 5 | Up to Visit 8 (56 days) | Change throughout the trial period up to Visit 8 of the following measured parameters: RNA and micro-RNA profiles in circulating cells as measured by quantitative polymerase chain reaction (qPCR) or equivalent technology |
| All patients with PSC and AIH - Exploratory Research Outcome 4 | Up to Visit 8 (56 days) | Change throughout the trial period up to Visit 8 of the following measured parameters: Serum cytokine and chemokine profiles as measured by cytokine array analysis |
| All patients with PSC and AIH - Exploratory Research Outcome 3 | Up to Visit 8 (56 days) | Change throughout the trial period up to Visit 8 of the following measured parameters: Circulating inflammatory cells profile as measured by flow cytometry Endothelial cell activation markers such as VAP-1 and ICAM1 |
Countries
United Kingdom
Outcome results
None listed