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

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

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.

Study Overview

• Status: Terminated
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: MultiStem

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Department of Surgery, University Hospital Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: MultiStem; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Prof. Dr. Marc-H. Dahlke, Ph. D.
• Collaborators: University Hospital Regensburg; Athersys, Inc

Publications and helpful links

General Publications

• Popp FC, Fillenberg B, Eggenhofer E, Renner P, Dillmann J, Benseler V, Schnitzbauer AA, Hutchinson J, Deans R, Ladenheim D, Graveen CA, Zeman F, Koller M, Hoogduijn MJ, Geissler EK, Schlitt HJ, Dahlke MH. Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I). J Transl Med. 2011 Jul 28;9:124. doi: 10.1186/1479-5876-9-124.
• Dillmann J, Popp FC, Fillenberg B, Zeman F, Eggenhofer E, Farkas S, Scherer MN, Koller M, Geissler EK, Deans R, Ladenheim D, Loss M, Schlitt HJ, Dahlke MH. Treatment-emergent adverse events after infusion of adherent stem cells: the MiSOT-I score for solid organ transplantation. Trials. 2012 Nov 15;13:211. doi: 10.1186/1745-6215-13-211.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2013
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: April 19, 2013
• First Submitted That Met QC Criteria: April 23, 2013
• First Posted (Estimate): April 26, 2013

Study Record Updates

• Last Update Posted (Actual): August 17, 2018
• Last Update Submitted That Met QC Criteria: December 9, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: Liver transplantation; Solid organ transplantation; Allogeneic liver transplantation
• Other Study ID Numbers: MISOT-I; 2009-017795-25 (EudraCT Number)