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Mobilization of Mesenchymal Stem Cells During Liver Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02557724
Recruitment Status : Completed
First Posted : September 23, 2015
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
Yuriy Gubenko, MD, Rutgers, The State University of New Jersey

Tracking Information
First Submitted Date September 18, 2015
First Posted Date September 23, 2015
Last Update Posted Date October 16, 2018
Study Start Date September 2015
Actual Primary Completion Date July 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 22, 2015)
post operative liver injury [ Time Frame: 0-7 post operative days ]
. Primary endpoint is defined by postoperative liver injury assessed by peak serum value of aspartate aminotransferase (AST) or alanine aminotransferase (ALT).
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: October 18, 2016)
  • Total Bilirubin level [ Time Frame: post operative day 7 ]
    bilirubin greater than or equal to 10mg/dl on day 7
  • (INR) International Normalized Ratio [ Time Frame: post operative day 7 ]
    INR> or = to 1.6
  • (ALT) Alanine Aminotransferase [ Time Frame: post operative day 7 ]
    ALT> 2000 IU/L
  • (AST) Aspartate Aminotransferase [ Time Frame: post operative day 7 ]
    AST> 2000 IU/L
Original Secondary Outcome Measures
 (submitted: September 22, 2015)
  • Total Bilirubin level [ Time Frame: post operative day 7 ]
    bilirubin greater than or equal to 10mg/dl on day 7
  • INR [ Time Frame: post operative day 7 ]
    INR> or = to 1.6
  • ALT (SGOT) [ Time Frame: post opeartive day 7 ]
    ALT> 2000 IU/L
  • AST (SGPT) [ Time Frame: post operative day 7 ]
    AST> 2000 IU/L
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Mobilization of Mesenchymal Stem Cells During Liver Transplantation
Official Title Mobilization of Mesenchymal Stem Cells During Liver Transplantation
Brief Summary To study if the administration of corticoid hinder or enhance the mobilization of Mesenchymal Stem Cells (MSCs) in the peripheral blood during liver transplantation and whether this affects the outcome with respect to graft versus host response.
Detailed Description

Mesenchymal stem cells (MSCs) are a known immune modulator with significant immunosuppressive effects. MSCs have emerged as a promising frontier in human clinical trials. MSCs have been shown to be non-immunogenic making them capable of transplantation across allogeneic barrier. These qualities make MSCs an ideal candidate to study if they are involved in reducing the rejection of the graft, in this case, liver transplant. If so, the information would be highly significant as it would lead to significant reduction in use of immunosuppressants with the replacement of MSCs. This will serve dual purposes: reduced clinical problems associated with pharmacological immunosuppression (discussed in the next paragraph); additional help in the protection of the transplanted liver by the MSCs.

The use of immunosuppressants in particular is vital in organ transplantation including liver transplant patients. However, their use is accompanied by numerous drawbacks such as reactivation of viral hepatitis, opportunistic infections and other complications. If MSCs can be used to decrease the use of immunosuppressive agents in liver transplant patients it can lead to a significant decrease in morbidity and mortality as a consequence of liver transplantation.

Hepatic macrophages, ie Kupffer cells, have a known function of recruiting monocytes into the liver. They have been shown to have a proinflammatory effect by attracting monocytes into the liver. They also interact with hepatic stellate cells (HSCs) which have pro-fibrogenic functions. However, they have been shown to have anti-inflammatory effects as well, implicating a role in fibrosis regression. Hepatic macrophages are an interesting new target for therapeutic intervention and the effect of steroids on kupffer cells as well as their interaction with MSCs have not been fully explored.

Patient will be attached to standard American Society of Anesthesiologists (ASA) monitors including pulse oximetry, electrocardiogram, noninvasive blood pressure monitoring temperature and capnometry. Patients will be placed under general anesthesia with endotracheal intubation and controlled ventilation. As is customary for all liver surgeries, an arterial line will be inserted for blood pressure monitoring and for repeat blood samples. If indicated, a pulmonary artery catheter will be inserted.

Anesthesia will be maintained using a volatile agent. Paralysis will be provided using a non-depolarizing neuromuscular blocking agent of the anesthesiologist's choice.

As is standard practice hourly blood samples will be taken from the arterial line to analyze Protime(PT)/International Normalized Ratio (INR)/Complete Blood Count/electrolytes. Red Blood Cells, Fresh Frozen Plasma and platelets will be transfused as necessary.

As is customary liver transplant recipients will be given the customary dose of methylprednisolone for immune suppression in the anhepatic phase.

Intraoperatively, patients undergoing transplant will have three blood samples collected from the arterial line for study purposes. Each sample will contain 3cc of blood.

The time points for blood samples are as follows:

  • Immediately after arterial line placement as a baseline
  • In the anhepatic stage prior to steroid injection
  • Two hours after administration of steroids Post-operatively, two additional 3 mL blood samples will be taken by a member of the study team. The first will be on postoperative day 1 prior to the administration of immunosuppressive drugs and the second sample on postoperative day five. Thus for liver transplant patients a total of 15 milliliters (mL) of blood over a period of 5 days will be collected for the study.

The administration of immunosuppression drugs and or dosage will not be altered as a component of the research study.

A tissue sample of the liver donor organ will also be taken to culture MCSs (exempt informed consent).

Control group patients will undergo liver resection. They will not receive the dose of methylprednisolone. Intra-operatively blood samples will be collected at these time points:

  • immediately after arterial line placement
  • two hours after liver resection. Postoperatively two additional 3-mL blood samples will be taken. The first will be taken on postoperative day one and the second on postoperative day five or on the day of discharge whichever comes sooner. These samples will be collected by a study team member. A total of 12mL of blood over a period of 5 days will be collected from the liver resection patients for study purposes.

All blood samples will be immediately delivered to Dr. Rameswhar's lab, located in MSB, E579. The relative frequency of MSCs present in the blood of the two groups will be assessed by flow cytometry. The data will be presented as the percentage of MSCs/106 mononuclear cells. Statistical analyses will be performed to determine if there are differences between the two groups of subjects.

In addition to the above studies with the donor liver, we will also treat liver cells with glucocorticoids and then examine the liver for changes in aquaporin. The reason for this modification is to determine if aquaporin increases the ability to accumulate water. This additional study will not change the samples since only a small (<1mg) of tissue will be sufficient.

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Probability Sample
Study Population Patients undergoing liver transplant or liver resection
Condition
  • Liver Failure
  • Liver Neoplasm
Intervention
  • Procedure: blood samples
    liver transplant patients will have (5) 3cc blood samples drawn at specific time points.
  • Procedure: blood samples
    liver resection patients will have (3) 3cc. blood samples drawn at specific time points
Study Groups/Cohorts
  • liver transplant patients
    5 blood samples at time points as described in protocol
    Intervention: Procedure: blood samples
  • Liver resection patients
    3 blood samples at time points described in protocol
    Intervention: Procedure: blood samples
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: October 15, 2018)
35
Original Estimated Enrollment
 (submitted: September 22, 2015)
150
Actual Study Completion Date July 2017
Actual Primary Completion Date July 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • • Patients 21-80 capable of providing informed consent

    • ASA rating between 1-4
    • Patients undergoing liver transplant or liver surgery for the first time.

Exclusion Criteria:

  • • Patient less than 21 years of age

    • Patients unwilling to consent
    • If donor liver was obtained after cardiac death
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT02557724
Other Study ID Numbers 20140000266
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Yuriy Gubenko, MD, Rutgers, The State University of New Jersey
Study Sponsor Rutgers, The State University of New Jersey
Collaborators Not Provided
Investigators
Principal Investigator: Yuriy Gubenko, MD Rutrgers/SUNJ
PRS Account Rutgers, The State University of New Jersey
Verification Date October 2018