<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02997878</url>
  </required_header>
  <id_info>
    <org_study_id>RG-13-124</org_study_id>
    <nct_id>NCT02997878</nct_id>
  </id_info>
  <brief_title>Selected Mesenchymal Stromal Cells to Reduce Inflammation in Patients With PSC and AIH</brief_title>
  <acronym>Merlin</acronym>
  <official_title>An Adaptive, Multicentre, Phase IIa, Multi-disease Trial Investigating the Safety &amp; Activity of a Single Infusion of Selected Mesenchymal Stromal Cells in the Treatment of Patients With Primary Sclerosing Cholangitis &amp; Autoimmune Hepatitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>NHS Blood and Transplant</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Birmingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      MERLIN is an adaptive, single arm, multi-centre, phase IIa multi-disease clinical trial. It&#xD;
      is designed to:&#xD;
&#xD;
      i) Determine dose safety of ORBCEL-C™ (selected Mesenchymal stromal cells derived from human&#xD;
      umbilical cord) ii) Evaluate treatment activity through assessment of biomarkers (for&#xD;
      patients treated at the highest safe dose only (HSD))&#xD;
&#xD;
      This trial will determine the Highest Safe Dose (HSD) that can be administered by observing&#xD;
      for occurrence of dose limiting toxicity (DLT).&#xD;
&#xD;
      Upon completion of this trial we hope to be able to justify and conduct separate, larger&#xD;
      scale trials using ORBCEL-C™.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      MERLIN is an adaptive, single arm, multi-centre, phase IIa multi-disease clinical trial. It&#xD;
      is designed to:&#xD;
&#xD;
      i) Determine dose safety of ORBCEL-C™ (selected Mesenchymal stromal cells derived from human&#xD;
      umbilical cord) ii) Evaluate treatment activity through assessment of biomarkers&#xD;
&#xD;
      This trial will determine the HSD* that can be administered by observing for occurrence of&#xD;
      dose limiting toxicity (DLT).&#xD;
&#xD;
      * An investigated dose level is determined to be safe if we see 0 DLTs in 3 patients or ((in&#xD;
      the instance where a cohort is expanded to 6 patients due to occurrence of a DLT in the first&#xD;
      3 patients treated at a cohort) &lt; 2 DLTs in 6 patients. The HSD is the highest such dose&#xD;
      which fulfils these criteria and will be ascertained via dose-escalation using 3+3&#xD;
      methodology.&#xD;
&#xD;
      Further safety and activity outcomes will be determined on patients treated at the HSD only.&#xD;
      Upon completion of this trial we hope to be able to justify and conduct separate, larger&#xD;
      scale trials using ORBCEL-C™.&#xD;
&#xD;
      OBJECTIVES&#xD;
&#xD;
      For Both Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AIH) patients:&#xD;
&#xD;
      The primary objective for all patients is:&#xD;
&#xD;
      • To determine the highest safe single intravenous infusion dose of ORBCEL-C™ over a 14 day&#xD;
      (Visit 3 to Visit 5) reporting period.&#xD;
&#xD;
      For patients treated at HSD only, there is an additional co-primary objective:&#xD;
&#xD;
      • To investigate whether a single intravenous infusion of ORBCEL-C™ in patients with PSC and&#xD;
      AIH treated at the HSD is safe and tolerated over the period of trial follow-up (up to Visit&#xD;
      8)&#xD;
&#xD;
      For PSC patients only:&#xD;
&#xD;
      • Reduces serum alkaline phosphatase (ALP) in patients with PSC. This is a non- invasive&#xD;
      biochemical surrogate of clinical outcomes in PSC&#xD;
&#xD;
      For AIH patients only:&#xD;
&#xD;
      • Reduces serum alanine aminotransferase (ALT) in patients with AIH. This is a non- invasive&#xD;
      biochemical surrogate marker of hepatic inflammatory activity and outcomes in AIH.&#xD;
&#xD;
      The secondary objectives are to investigate whether a single intravenous infusion of&#xD;
      ORBCEL-C™ elicits a change over the duration of the trial after treatment in all patients&#xD;
      with PSC and AIH on:&#xD;
&#xD;
        -  Circulating inflammatory cells profile as measured by flow cytometry (key secondary&#xD;
           outcome)&#xD;
&#xD;
        -  Liver biochemistry and function, immunoglobulin G concentrations (in AIH patients) and&#xD;
           composite risk scores&#xD;
&#xD;
        -  Non-invasive clinical markers of fibrosis&#xD;
&#xD;
        -  Patient Quality of Life (QoL)&#xD;
&#xD;
        -  Severity of co-existent Inflammatory Bowel Disease (IBD) in patients with PSC&#xD;
&#xD;
      Further exploratory research objectives of the trial determine whether MSC infusion modulates&#xD;
      the immune response by measuring whether treatment elicits a change in all patients with PSC&#xD;
      and AIH:&#xD;
&#xD;
        -  Markers of immune activation including immunoglobulin values and C-reactive protein&#xD;
           (CRP) concentration&#xD;
&#xD;
        -  Markers of biliary injury including total bile acid levels&#xD;
&#xD;
        -  Endothelial cell activation markers such as VAP-1 and ICAM1&#xD;
&#xD;
        -  Serum cytokine, chemokine, ribonucleic acid (RNA) and micro-RNA expression profiles&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 7, 2018</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">March 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose finding and incidence of treatment emergent adverse events (safety and tolerability) in all PSC and AIH Patients</measure>
    <time_frame>Visit 3 to Visit 5 -14 days</time_frame>
    <description>Occurrence of Dose Limiting Toxicity (DLT) over 14 day (Visit 3 to Visit 5) reporting period after ORBCEL-C infusion</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of treatment emergent adverse events (safety and tolerability) for PSC and AIH patients treated at the Highest Safe Dose (HSD) only</measure>
    <time_frame>Visit 3 to Visit 8 - 56 days</time_frame>
    <description>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)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Activity and Safety at the Highest Safe Dose (HSD) of ORBCEL-C in PSC patients, by measure of change in Alkaline Phosphatase (ALP)</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Activity at the Highest Safe Dose (HSD) of ORBCEL-C in AIH patients, by measure of change in Alanine Aminotransferase (ALT)</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 1</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 2</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 3</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 4</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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®)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 5</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 1</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 2</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 3</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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®)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 4</measure>
    <time_frame>Baseline to Visit 8 - Approximately 80 days</time_frame>
    <description>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</description>
  </secondary_outcome>
  <other_outcome>
    <measure>All patients with PSC and AIH - Exploratory Research Outcome 1</measure>
    <time_frame>Up to Visit 8 (56 days)</time_frame>
    <description>Change throughout the trial period up to Visit 8 of the following measured parameters:&#xD;
Markers of immune activation including immunoglobulin values and C-reactive protein concentration</description>
  </other_outcome>
  <other_outcome>
    <measure>All patients with PSC and AIH - Exploratory Research Outcome 2</measure>
    <time_frame>Up to Visit 8 (56 days)</time_frame>
    <description>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)</description>
  </other_outcome>
  <other_outcome>
    <measure>All patients with PSC and AIH - Exploratory Research Outcome 3</measure>
    <time_frame>Up to Visit 8 (56 days)</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>All patients with PSC and AIH - Exploratory Research Outcome 4</measure>
    <time_frame>Up to Visit 8 (56 days)</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>All patients with PSC and AIH - Exploratory Research Outcome 5</measure>
    <time_frame>Up to Visit 8 (56 days)</time_frame>
    <description>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</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Cholangitis, Sclerosing</condition>
  <condition>Hepatitis, Autoimmune</condition>
  <arm_group>
    <arm_group_label>PSC patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AIH patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Orbcel-C</intervention_name>
    <description>Selected Mesenchymal Stromal Cells derived from human umbilical cord</description>
    <arm_group_label>AIH patients</arm_group_label>
    <arm_group_label>PSC patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria - Patients with Primary Sclerosing Cholangitis (PSC):&#xD;
&#xD;
          1. Age ≥ 18 at Visit 1&#xD;
&#xD;
          2. Diagnosis of PSC at Visit 1 as evidenced clinically by:&#xD;
&#xD;
               1. Chronic biochemical cholestasis (elevated serum alkaline phosphatase (ALP) above&#xD;
                  the upper limit of normal (ULN) and/or gamma-glutamyl transpeptidase (GGT) above&#xD;
                  the ULN) ≥6 months duration AND&#xD;
&#xD;
               2. Radiological AND/OR histological evidence of clinically documented PSC&#xD;
&#xD;
          3. Serum ALP ≥ 1.5 x ULN at Visit 1&#xD;
&#xD;
          4. Any serum ALP value change is &lt;40% using two sets of laboratory values obtained during&#xD;
             screening:&#xD;
&#xD;
             If a participant fails to confirm an ALP at Visit 2 that is within 40% of the ALP at&#xD;
             Visit 1, a further screening ALP (Visit 2a) can be arranged, so long as the variation&#xD;
             in ALP was &lt;50%, and the Principal Investigator has no other clinical reason to&#xD;
             suggest the participant is clinically unstable. If the ALP is within 40% variance at&#xD;
             Visit 2a as compared to visit 1, Trial registration is permitted.&#xD;
&#xD;
          5. At Visit 2 (and Visit 2a if applicable), it should be confirmed that a patient does&#xD;
             not meet any of the exclusion criteria&#xD;
&#xD;
        Inclusion Criteria - Patients with Autoimmune Hepatitis (AIH):&#xD;
&#xD;
          1. Age ≥ 18 at Visit 1&#xD;
&#xD;
          2. Established pre-existing clinical diagnosis of AIH confirmed by clinical expert review&#xD;
             consistent with the simplified IAIHG criteria&#xD;
             (http://www.mdcalc.com/simplified-scoring-autoimmune-hepatitis-aih/) and must include&#xD;
             history of a liver biopsy reported compatible with AIH&#xD;
&#xD;
          3. Active AIH defined by ALT ≥ 1.5 x ULN&#xD;
&#xD;
          4. Serum ALT must be above ≥ 1.5 x ULN at both Visit 1 and Visit 2&#xD;
&#xD;
          5. At Visit 2, it should be confirmed that a patient does not meet any of the exclusion&#xD;
             criteria&#xD;
&#xD;
          6. Patients must be on standard-of-care AIH treatment for ≥ 24 weeks -this includes any&#xD;
             AIH therapy except biologics&#xD;
&#xD;
          7. Stable doses of immunosuppression for a minimum period of 4 weeks (28 days) at the&#xD;
             time of Visit 1.&#xD;
&#xD;
        Exclusion Criteria - Patients with PSC and AIH:&#xD;
&#xD;
        Patients who meet any of the following exclusion criteria are excluded from participating&#xD;
        in the MERLIN trial&#xD;
&#xD;
          1. Refusal or lacks capacity to give informed consent to participate in trial&#xD;
&#xD;
          2. Patient who is unable to participate in follow-up assessment&#xD;
&#xD;
          3. Participation actively, or within 5 half-lives, of another interventional clinical&#xD;
             trial&#xD;
&#xD;
          4. Known hypersensitivity to the investigational product or any of its formulation&#xD;
             excipients&#xD;
&#xD;
          5. Evidence of active malignancy (within 3 years of Visit 1), other than non-melanomatous&#xD;
             skin cancer and cervical dysplasia in situ&#xD;
&#xD;
          6. Major surgical procedure within 30 days at Visit 1&#xD;
&#xD;
          7. Prior organ transplantation&#xD;
&#xD;
          8. Active harmful alcohol consumption as evaluated and documented by the Investigator&#xD;
&#xD;
          9. Poor venous access, therefore unable to support a 22G needle for infusion&#xD;
&#xD;
         10. Creatinine &gt; 133 μmol/L or being treated with renal replacement therapy at the time of&#xD;
             Visit 1&#xD;
&#xD;
         11. AST or ALT &gt; 10 x ULN&#xD;
&#xD;
         12. ALP &gt; 10 x ULN&#xD;
&#xD;
         13. Platelets &lt; 50 x 10^9/L&#xD;
&#xD;
         14. Total Bilirubin &gt; 2 x ULN&#xD;
&#xD;
         15. INR &gt; 1.3 (in the absence of concomitant use of Warfarin or equivalent anti-coagulant&#xD;
             therapy)&#xD;
&#xD;
         16. Albumin &lt; 35 g/L&#xD;
&#xD;
         17. Haemoglobin &lt; 10 g/dL&#xD;
&#xD;
         18. Past or present evidence of decompensated chronic liver disease:&#xD;
&#xD;
               1. Radiological or clinical evidence of ascites&#xD;
&#xD;
               2. Hepatic encephalopathy&#xD;
&#xD;
               3. Endoscopic evidence for portal hypertensive bleeding&#xD;
&#xD;
         19. Any active treatment with biologic therapy (monoclonal antibodies)&#xD;
&#xD;
         20. Clinically severe cardiovascular disease as evaluated by the Investigator&#xD;
&#xD;
         21. Pregnancy or breast-feeding&#xD;
&#xD;
         22. Women of child bearing potential who are unwilling to practice effective contraception&#xD;
             (i.e. barrier, oral contraceptive pill, implanted contraception, or previous&#xD;
             hysterectomy, bilateral oophorectomy) for the duration of the trial up to 90 days&#xD;
             after the trial drug is administered. If using hormonal agents the same method must&#xD;
             have been used for at least 1 month before trial dosing and patients must use a&#xD;
             barrier method during that time period&#xD;
&#xD;
         23. Non-vasectomised men, sexually active with women of child bearing potential, who are&#xD;
             not willing to practice effective contraception (condom with spermicide) for the&#xD;
             duration of the trial up to 90 days after the trial drug is administered&#xD;
&#xD;
         24. Patients with a history of hepatitis C (present or past infection), known positivity&#xD;
             for antibody to HIV or any evidence of current or past hepatitis B infection&#xD;
&#xD;
         25. Presence of an acute/chronic infection or illness that, at the discretion of the&#xD;
             Investigator, might compromise the patient's health and safety in the trial&#xD;
&#xD;
         26. Any symptoms indicative of Covid-19; including fever, chronic/persistent cough, or&#xD;
             loss of sense of taste or smell in the preceding two weeks.&#xD;
&#xD;
         27. Receipt of live vaccination within six weeks prior to Visit 1&#xD;
&#xD;
        Exclusion Criteria Specific to Patients with PSC:&#xD;
&#xD;
          1. Documented alternative aetiology for sclerosing cholangitis (i.e. secondary sclerosing&#xD;
             cholangitis)&#xD;
&#xD;
          2. A dominant (as determined by Investigator) alternative chronic or active liver injury&#xD;
             other than PSC at the time of Visit 1; Patients with possible overlap syndrome with&#xD;
             AIH are excluded from the PSC cohort if the Investigator considers AIH as the dominant&#xD;
             liver injury&#xD;
&#xD;
          3. UDCA dose modification within the last 90 days&#xD;
&#xD;
          4. ALP &gt; 10 x ULN&#xD;
&#xD;
          5. Evidence of cholangitis within 90 days of Visit 1&#xD;
&#xD;
               1. Documented evidence of cholangitis by physician&#xD;
&#xD;
               2. Need for any antibiotics for presumed cholangitis&#xD;
&#xD;
          6. Any patient taking prophylactic antibiotics to combat recurrent cholangitis&#xD;
&#xD;
          7. Presence of percutaneous biliary drain, or internal biliary stent&#xD;
&#xD;
          8. Diagnosed hepatocellular carcinoma or cholangiocarcinoma or high clinical suspicion&#xD;
             thereof&#xD;
&#xD;
          9. Dominant stricture clinically suspicious of cholangiocarcinoma (as determined by&#xD;
             Investigator)&#xD;
&#xD;
        Exclusion Criteria for PSC patients with IBD:&#xD;
&#xD;
          1. Unstable disease as evidenced by:&#xD;
&#xD;
               1. Documented clinically significant flare within 90 days of enrolment requiring any&#xD;
                  marked intensification of therapy from baseline maintenance (maintenance therapy&#xD;
                  = thiopurines, 5- aminosalicylates, or oral prednisolone &lt; 10mg/day; biologics&#xD;
                  therapy is an exclusion criteria&#xD;
&#xD;
               2. Requirement for daily prednisolone &gt; 10mg&#xD;
&#xD;
               3. Mayo Clinic Score ≥ 2 (see Appendix 1 for details) AND clinician assessment of&#xD;
                  active disease requiring up-titration of treatment; last colonoscopy within last&#xD;
                  year used for endoscopic component&#xD;
&#xD;
          2. Any colonoscopic evidence of clinically significant dysplasia at last colonoscopy&#xD;
&#xD;
          3. Patients who have not had their routine colonoscopy within 24 months prior to planned&#xD;
             MSC infusion and are unable to have their screening colonoscopy examination as per&#xD;
             standard care prior to Visit 3&#xD;
&#xD;
          4. A Mayo score/ Disease Activity Index for Ulcerative Colitis of ≥ 5&#xD;
             (https://www.mdcalc.com/mayo-score- disease-activity-index-dai-ulcerative-colitis)&#xD;
&#xD;
        Exclusion Criteria Specific to Patients with AIH:&#xD;
&#xD;
          1. A dominant (as determined by Investigator) alternative chronic or active liver injury&#xD;
             other than AIH at the time of Visit 1; Patients with possible overlap syndrome with&#xD;
             PSC are excluded from the AIH cohort if the Investigator considers PSC as the dominant&#xD;
             liver injury&#xD;
&#xD;
          2. AST or ALT &gt; 10 x ULN&#xD;
&#xD;
          3. Patients on a prednisolone dose of &gt; 20 mg at the time of screening&#xD;
&#xD;
          4. Treatment with biologic therapy within 24 weeks of the time of screening&#xD;
&#xD;
          5. Patients with a history of poor compliance with medication&#xD;
&#xD;
          6. Diagnosed hepatocellular carcinoma or cholangiocarcinoma or high clinical suspicion&#xD;
             thereof&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Phillip N Newsome, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Birmingham</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Senior Trial Coordinator</last_name>
    <phone>01213718198</phone>
    <email>merlin@trials.bham.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Trial Coordinator</last_name>
    <phone>01213718167</phone>
    <email>merlin@trials.bham.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital</name>
      <address>
        <city>Birmingham</city>
        <state>West Midlands</state>
        <zip>B15 2TT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>December 13, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>November 7, 2022</last_update_submitted>
  <last_update_submitted_qc>November 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Autoimmune</keyword>
  <keyword>AIH</keyword>
  <keyword>PSC</keyword>
  <keyword>Liver disease</keyword>
  <keyword>Cholangitis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Cholangitis</mesh_term>
    <mesh_term>Cholangitis, Sclerosing</mesh_term>
    <mesh_term>Hepatitis, Autoimmune</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02997878
org study id: RG-13-124
nct id: NCT02997878
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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™.
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
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose finding and incidence of treatment emergent adverse events (safety and tolerability) in all PSC and AIH Patients
time frame: Visit 3 to Visit 5 -14 days
description: Occurrence of Dose Limiting Toxicity (DLT) over 14 day (Visit 3 to Visit 5) reporting period after ORBCEL-C infusion
measure: Incidence of treatment emergent adverse events (safety and tolerability) for PSC and AIH patients treated at the Highest Safe Dose (HSD) only
time frame: Visit 3 to Visit 8 - 56 days
description: 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)
measure: Activity and Safety at the Highest Safe Dose (HSD) of ORBCEL-C in PSC patients, by measure of change in Alkaline Phosphatase (ALP)
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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)
measure: Activity at the Highest Safe Dose (HSD) of ORBCEL-C in AIH patients, by measure of change in Alanine Aminotransferase (ALT)
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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.
measure: All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 1
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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)
measure: All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 2
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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)
measure: All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 3
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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
measure: All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 4
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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®)
measure: All patients with Autoimmune Hepatitis (AIH) - Secondary Outcome Measure 5
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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
measure: All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 1
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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)
measure: All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 2
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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])
measure: All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 3
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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®)
measure: All patients with Primary Sclerosing Cholangitis (PSC) - Secondary Outcome Measure 4
time frame: Baseline to Visit 8 - Approximately 80 days
description: 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
measure: All patients with PSC and AIH - Exploratory Research Outcome 1
time frame: Up to Visit 8 (56 days)
description: 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
measure: All patients with PSC and AIH - Exploratory Research Outcome 2
time frame: Up to Visit 8 (56 days)
description: 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)
measure: All patients with PSC and AIH - Exploratory Research Outcome 3
time frame: Up to Visit 8 (56 days)
description: 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
measure: All patients with PSC and AIH - Exploratory Research Outcome 4
time frame: Up to Visit 8 (56 days)
description: 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
measure: All patients with PSC and AIH - Exploratory Research Outcome 5
time frame: Up to Visit 8 (56 days)
description: 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
arm group label: PSC patients
arm group type: Experimental
description: 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.
arm group label: AIH patients
arm group type: Experimental
description: 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.
intervention type: Biological
intervention name: Orbcel-C
description: Selected Mesenchymal Stromal Cells derived from human umbilical cord
arm group label: AIH patients
arm group label: PSC patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Phillip N Newsome, Prof
role: Principal Investigator
affiliation: University of Birmingham
last name: Senior Trial Coordinator
phone: 01213718198
email: merlin@trials.bham.ac.uk
last name: Trial Coordinator
phone: 01213718167
email: merlin@trials.bham.ac.uk
facility: 
status: Recruiting
country: United Kingdom
responsible party type: Sponsor
mesh term: Hepatitis
mesh term: Cholangitis
mesh term: Cholangitis, Sclerosing
mesh term: Hepatitis, Autoimmune
sharing ipd: No