Safety Study of Multipotent Progenitor Cells for Immunomodulation Therapy After Liver Transplantation

Study Overview
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Brief Summary
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MultiStem ® is a new biological product, manufactured from human stem cells obtained from adult bone marrow. Factors expressed by MultiStem cells are believed to regulate immune system function and augment tissue repair. Standard of care pharmacological immunosuppression after liver transplantation can achieve reasonable survival of liver grafts and patients. The side effects of this treatment, however, are clinically significant and diminish the overall success of organ transplantation as a curative therapy. It is therefore the objective of this study to implement cellular immunomodulation therapy with MultiStem as an adjunct to standard pharmacological immunosuppression with the ultimate goal of significantly reducing drug-based immunosuppression. As this is the first study with MultiStem in this subject population it has been designed as a safety and feasibility trial. However, first evidence of a potential benefit for this patient population will be explored cautiously.

Official Title
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Safety and Feasibility of Multipotent Adult Progenitor Cells for Immunomodulation Therapy After Liver Transplantation: A Phase I Study of the MiSOT Study Consortium

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: MultiStem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥18 years of age undergoing allogeneic liver transplantation Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Written informed consent prior to any study procedures Exclusion Criteria: Known allergies to bovine or porcine products or any other ingredients of the product Patients older than 65 years of age Patients listed in a high-urgency status that would not allow proper preparation of the study interventions Patients receiving a secondary liver graft (Re-Transplantation) Double organ transplant recipients Pre-existing renal failure that requires or has required hemodialysis within the last year Pulmonary function: FEV1, FVC, DLCO ≤50% predicted Cardiac function: left ventricular ejection fraction ≤50% HIV seropositive, varicella virus active infection or any other clinically relevant infection History of any malignancy (including lymphoproliferative disease and hepatocellular carcinoma) except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence Unstable myocardium (evolving myocardial infarction), cardiogenic shock Females of childbearing potential (hormonal status and gynecological consultation required) Patients with portal vein thrombosis Patients with a history of pulmonary embolism

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MultiStem<br>Dose escalation Cohort 1 Drug: MultiStem, Dose 1 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) Cohort 2 Drug: MultiStem, Dose 2 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) Cohort 3 Drug: MultiStem, Dose 3 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) Cohort 4 Drug: MultiStem, Dose 4 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) | Drug: MultiStem<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infusional and Acute Toxicity, Using Toxicity Scoring Mechanism | For the description of intraportal toxicity a doppler ultrasound examination will be performed to assess various parameters that describe velocity of flow and flow pattern. For pulmonary toxicity the assessment begins with an arterial blood gas. If this reveals pathological findings, a chest X-ray is required for clinical reasons independent of the study enrolment. In addition, clinical data describing the need for postoperative re-intubation will be recorded and the patient is assessed for the occurrence of a pulmonary embolism according to clinical guidelines. For systemic toxicity, the occurrence of anaphylactic shock due to standard clinical guidelines is recorded. | up to day 30 (+10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Biopsy-proven Acute Rejection | Per protocol biopsies will be performed on days 1, 4, 10. Additional biopsies will be taken whenever clinically necessary. | up to day 90 (+/-30) | 
| Evidence Confirming That MultiStem Does Not Promote Malignant Transformation or Tumor Growth | Four additional outpatient visits are planned to further evaluate the study patients (including screening for malignancies). | up to day 365 (+/-30) | 
| Evaluation of Data From Routine Examinations Following Last Study Visit for Evidence of Long Term Safety From MultiStem Administration | The results of routine examinations, which are necessary for all transplant patients, will be used once a year and analyzed retrospectively. | up to six years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, Allogeneic liver transplantation, Solid organ transplantation