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A Single-arm,Phase IIa,Safety and Efficacy Trial of Selected MSCs in the Treatment of Patients With PSC & AiH (Merlin)

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ClinicalTrials.gov Identifier: NCT02997878
Recruitment Status : Not yet recruiting
First Posted : December 20, 2016
Last Update Posted : June 5, 2018
Sponsor:
Collaborator:
European Union
Information provided by (Responsible Party):
University of Birmingham

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

This trial has two main stages:

  • Stage 1 will determine the maximum tolerated dose that can be administered by observing for occurrence of dose limiting toxicity (DLT).
  • Stage 2 will use the maximum tolerated dose found in stage 1 to and further determine safety and activity outcomes of ORBCEL-C.

Upon completion of this trial we hope to be able to justify and conduct separate, larger scale trials using ORBCEL-C.


Condition or disease Intervention/treatment Phase
Cholangitis, Sclerosing Hepatitis, Autoimmune Biological: Orbcel-C Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: 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.
Biological: Orbcel-C
Selected Mesenchymal Stromal Cells derived from human ubmical cord

Experimental: 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.
Biological: Orbcel-C
Selected Mesenchymal Stromal Cells derived from human ubmical cord




Primary Outcome Measures :
  1. Stage 1- Dose finding and Incidence of treatment emergent adverse events (safety and tolerability) PSC and AiH Patients [ Time Frame: 14 days ]
    Occurrence of Dose Limiting Toxicity over 14 day reporting period after ORBCEL-C infusion

  2. Stage 2: Incidence of treatment emergent adverse events (safety and tolerability) - Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AiH) patients [ Time Frame: 56 days ]
    Determine safety and tolerability by occurrence of Dose Limiting Toxicity (Day 0-14 only), Serious Adverse Events (SAE) and adverse events (AE) throughout trial period (up to day 56)

  3. Stage 2: Activity: change in Alkaline Phosphatase (ALP) value : ( absolute % change /duration of change between baseline and day 56) - PSC [ Time Frame: 56 days ]
    change in Alkaline phosphatase after ORBCEL-C infusion

  4. Stage 2: Activity: change in Alanine transaminase ( absolute % change /duration of change between baseline and day 56) - Autoimmune Hepatitits [ Time Frame: 56 days ]
    Change in Alanine Aminotransferase (ALT) trend after ORBCEL-C infusion


Secondary Outcome Measures :
  1. Autoimmune Hepatitis secondary outcomes 1 [ Time Frame: 56 days ]
    Non-invasive clinical markers of fibrosis - Enhanced Liver Fibrosis (ELF) and transient elastography (Fibroscan®)

  2. Autoimmune Hepatitis secondary outcomes 2 [ Time Frame: 56 days ]
    QoL as measured by Pruritus Visual Analogue Scale, nine-point fatigue severity scale and SF-36v2

  3. AIH secondary outcomes 3 [ Time Frame: 56 days ]

    Marker of immune activation - immunoglobulin G concentrations Non-invasive clinical markers of fibrosis - Enhanced Liver Fibrosis (ELF) and transient elastography (Fibroscan®)

    • QoL as measured by Pruritus Visual Analogue Scale, nine-point fatigue severity scale and SF-36v2


  4. AIH secondary outcomes 4 [ Time Frame: 56 days ]
    change in Individual markers of liver biochemistry and function including aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), bilirubin, albumin, international normalised ratio (INR) and composite risk score (Model for End Stage Liver Disease (MELD))

  5. PSC secondary outcomes 1 [ Time Frame: 56 days ]
    Individual markers of liver biochemistry and function including aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyltranspeptidase (GGT), bilirubin, albumin, international normalised ratio (INR) and composite risk scores (Mayo PSC risk score and Model for End Stage Liver Disease (MELD))

  6. PSC secondary outcomes 2 [ Time Frame: 56 days ]
    QoL as measured by Pruritus Visual Analogue Scale, nine-point fatigue severity scale and SF-36v2

  7. PSC secondary outcomes 3 [ Time Frame: 56 days ]
    Severity of IBD as measured by the non-endoscopic aspects of the Mayo IBD score - stool frequency, rectal bleeding, and physician's global assessment



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

PSC patients - Inclusion

  1. Age ≥ 18 , ≤70 years old at visit 1 (screening)
  2. Diagnosis of PSC at visit 1 (screening) 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 ULN at visit 1 (screening) Serum ALP value at Visit 2 within +/- 25% of ALP value at visit 1

      - AIH patients - Inclusion

      • Age ≥ 18, ≤70 years old at visit 1 (screening)
      • 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 ≥ 1.5 ULN.
      • Serum ALT must be above ≥ 1.5 ULN at both screening (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 at the time of screening, and no planned change in immunosuppression for the course of the trial
      • Generic exclusion criteria that apply to both patients with PSC and AIH
      • 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 (screening)), other than non-melanomatous skin cancer and cervical dysplasia in situ
      • Major surgical procedure within 30 days at visit 1 (screening)
      • Prior organ transplantation
      • Active harmful alcohol consumption as evaluated and documented by the investigator
      • Creatinine >133 μmol/L or being treated with renal replacement therapy at the time of Visit 1 (screening)
      • AST or ALT > 10 x ULN
      • ALP > 10 x ULN
      • Platelets < 50 x 109/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/litre
      • 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 childbearing age 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 study dosing and subjects must use a barrier method during that time period
      • Non-vasectomised men, sexually active with women of child-bearing age, 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
      • Receipt of live vaccination within six weeks prior to visit 1 (screening)

Exclusion criteria specific to patients with PSC

  1. Documented alternative aetiology for sclerosing cholangitis (i.e. secondary sclerosing cholangitis)
  2. A dominant (as determined by Investigator) alternative chronic or active liver injury other than PSC at the time of visit 1 (screening); Patients with possible overlap syndrome with AIH are excluded from the PSC cohort if the Investigator considers AIH as the dominant liver injury
  3. UDCA use within 8 weeks of the first screening visit (if a patient was taking UDCA a washout period of at least 8 weeks prior to the first screening is required)
  4. ALP > 10 x ULN
  5. Evidence of cholangitis within 90 days of visit 1 (screening)

    - Documented evidence of cholangitis by physician

    - Need for any antibiotics for presumed cholangitis

  6. Any patient taking prophylactic antibiotics to combat recurrent cholangitis
  7. Presence of percutaneous biliary drain, or internal biliary stent
  8. Diagnosed hepatocellular carcinoma or cholangiocarcinoma or high clinical suspicion thereof
  9. Dominant stricture clinically suspicious of cholangiocarcinoma (as determined by Investigator) For those with IBD

1. Unstable disease as evidenced by:

  • Documented clinically significant flare within 90 days of enrolment requiring any marked intensification of therapy from baseline maintenance (maintenance therapy = thiopurines, 5-aminosalicylates, or oral prednisolone <10mg/day; biologics therapy is an exclusion criteria; see section 5.2
  • Requirement for daily prednisolone >10mg
  • Mayo Clinic Score ≥ 2 (see Appendix 11 for details) AND clinician assessment of active disease requiring up-titration of treatment; last colonoscopy within last year used for endoscopic component [1].

    2. Any colonoscopic evidence of clinically significant dysplasia at last colonoscopy 3. Patients who have not had their routine colonoscopy within 24 months prior to planned MSC infusion and are unable to have their screening colonoscopy examination as per standard care prior to study visit 3 (treatment) Exclusion criteria specific to patients with AIH

    1. A dominant (as determined by Investigator) alternative chronic or active liver injury other than AIH at the time of visit 1 (screening); Patients with possible overlap syndrome with PSC are excluded from the AIH cohort if the Investigator considers PSC as the dominant liver injury
    2. AST or ALT > 10 x ULN
    3. Patients on a prednisolone dose of > 20 mg at the time of screening
    4. Treatment with biologic therapy within 24 weeks of the time of screening
    5. Patients with a history of poor compliance with medication
    6. Diagnosed hepatocellular carcinoma or cholangiocarcinoma or high clinical suspicion thereof

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02997878


Contacts
Contact: Rebecca Storey, MBA +44(0)1213718109 r.storey@bham.ac.uk
Contact: Darren Barton, BSc +44(0)1213718027 d.barton@bham.ac.uk

Sponsors and Collaborators
University of Birmingham
European Union
Investigators
Principal Investigator: Gideon Hirschfield, MD University of Birmingham

Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT02997878     History of Changes
Other Study ID Numbers: RG-13-124
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: June 5, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Birmingham:
autoimmune
AiH
PSC
liver disease
cholangitis

Additional relevant MeSH terms:
Hepatitis
Cholangitis
Cholangitis, Sclerosing
Hepatitis, Autoimmune
Liver Diseases
Digestive System Diseases
Bile Duct Diseases
Biliary Tract Diseases
Hepatitis, Chronic
Autoimmune Diseases
Immune System Diseases