Pancreatic Islet Cell Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to assess a novel approach to immunosuppression in allogenic pancreatic islet cell transplant recipients. In addition, the study aims to assess remote site islet processing with culture for pancreatic islet cell transplantation in human subjects.

Detailed Description
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The purpose of this study is to assess a novel approach to immunosuppression in allogenic pancreatic islet cell transplant recipients. In addition, the study aims to assess remote site islet processing with culture for pancreatic islet cell transplantation in human subjects. Detailed Description: Diabetes mellitus (DM) type I is a disease that has significant social and economical impact. The prevalence of the disease in the United States is about 120,000 in individuals aged 19 or less and 300,000 to 500,000 at all ages and 150 million worldwide. So far there are no mechanical devices able to effectively adjust the dose of insulin injected according to the serum glucose in patients with DM. This leads to less than perfect sugar control, with episodes of hypoglycemia. Successful pancreas transplantation averts the need of insulin administration. The emerging alternative to whole organ pancreas transplantation is pancreatic islet cell transplantation (ICT). The process is based on the enzymatic isolation of the pancreatic islets from an organ procured from a cadaver donor. The islets obtained are injected into the liver in the recipient via percutaneous catheterization of the portal venous system. This procedure allows the selective transplantation of the insulin-producing cell population avoiding open surgery as well as the transplantation of the duodenum and the exocrine pancreas and their related morbidity. The initial efforts with ICT had only modest results. The immunosuppression regimen was similar to the one used in solid organ transplantation, based on high dose steroids and calcineurin inhibitors - both agents with diabetogenic effects. The results improved markedly with the changes in the manipulations of the islets, and the change in immunosuppression thus avoiding the higher doses of steroids and using sirolimus, tacrolimus and daclizumab initiated by the investigators group at the University of Alberta in Edmonton, Canada. Their protocol requires in general two islet cell infusions in order to attain the critical cell mass necessary to achieve insulin-independency. The changes in treatment were adopted as the Edmonton Protocol, which is used in several transplant centers, worldwide. A novel approach to organ preservation uses the two-layer preservation technique. This allows for longer travel time for the eventual shipment of the pancreas to an islet cell processing facility remotely located from the donor procurement site. The isolation of the islets from the donor pancreas will be performed at the Diabetes Research Institute in Miami, Florida, according to the standard currently used by that institution. The Diabetes Research Institute is a well-established center with a state-of-the-art islet cell isolation facility for the purpose of transplantation in humans, accredited and monitored by the FDA according to FDA standards. The focus of the research in the ICT is centered on the development of a safe and effective procedure that will eventually replace surgical pancreas transplantation together with an ideal immunosuppressive regimen that provides safe and effective prevention against rejection, while minimizing the adverse events associated that negatively impact transplant recipient's quality of life. This study is being conducted as a validation of the Edmonton protocol for ICT at our institution. Our aim is to test the efficacy of the use of the two-layer preservation technique for transport of the donor pancreas to the off-site processing facility and the use of islet cell culture in the off-site processing facility before the islet isolate is shipped to our center.

Official Title
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Pancreatic Islet Cell Transplantation - A Novel Approach to Immunosuppression and Validation of Remote Site Islet Cell Processing, Islet Cell Culture and Two-Layer Preservation

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Biological: Islet cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has been fully informed and has signed an Institutional Review Board (IRB) approved informed consent form and is willing and able to follow study procedures for the full 2 years Patient is expected to receive an islet cell transplant (up to 3 infusions) for type I diabetes mellitus Type I diabetes of more than 5 years duration Age between 18 and 65 Unstable diabetes mellitus control, as defined by glucose measurements above 200 mg/dL and/or below 80 mg/dL despite adequate medical care Hypoglycemia unawareness, as defined by episodes of loss of cognitive function Incapacitating signs and symptoms, as defined by the referring physician Poor control of HbA1c > 8% Psychogenically able to comply, in the opinion of the investigator Female patients of childbearing potential must have a negative urine or serum pregnancy test upon hospitalization or within 7 days prior to enrollment and have agreed to utilize effective birth control throughout the study as well as for 6 weeks following study completion. Exclusion Criteria: Patients meeting any of the following criteria will be excluded from study participation. Patient has previously received or is receiving an organ or bone marrow transplant Patient has a known hypersensitivity to Tacrolimus, sirolimus, daclizumab, or CellCept Patient is pregnant or lactating Patient has participated in a blinded trial or participated in a trial involving a non-marketed (investigational) drug within 3 months of enrollment Patient has participated in a trial involving a marketed drug or an infusion device within 30 days of the start of the trial Glomerular filtration rate (GLOFIL) < 60 mL/min Serum Creatinine > 1.6 mg/dL consistently Body mass index > 30 Autoimmune thyroiditis Malignancy other than basal cell carcinoma or squamous cell carcinoma Radiographic evidence of pulmonary infection Evidence of liver disease Portal hypertension Active infections Hypercoagulable states (history of recurrent venous thrombosis, defined thrombophilia) Bleeding / coagulation disorders Basal insulin C-Peptide > 0.3 ng/dL Insulin C-peptide > 0.3 ng/dL during stimulation test HbA1c > 12% Insulin requirement > 1 IU/kg/day Seropositivity for Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Human T-cell leukemia virus-1 (HTLV-1) Abnormal Pap smear in the last two months, active gynecological infection Positive exercise or chemical tolerance test Steroid dependence Substance/alcohol abuse Untreated proliferating diabetic retinopathy aa) Purified protein derivative (PPD) conversion or positive PPD without isonicotinic acid hydrazide (INH) bb) No Primary care physician or primary care physician less than 6 months cc) Smoking in the last 6 months dd) Abnormal Complete Blood Count (CBC) / Hemoglobin < 12 g/dL ee) Macroalbuminuria > 300 mg/24 hours ff) History of thyroid disease other than autoimmune disease gg) Untreated hyperlipidemia - Total Cholesterol (TC) > 240 mg/dL, Triglycerides (TGC) > 200 mg/dL, Low Density Lipoprotein (LDL) > 140 mg/dL hh) Untreated hyponatremia, hypokalemia, hypercalcemia, hypocalcemia ii) Iodine contrast allergy jj) Prostate Specific Antigen (PSA) > 4 kk) Panel Reactive Antibody (PRA) > 20% ll) Active peptic ulcer disease/gallstones/hemangioma mm) Abnormal mammogram

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: Islet Cell Transplantation<br>Allogenic islet cell transplantation | Biological: Islet cell transplantation<br>* Allogenic islet transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of Insulin Independence at 12-month Post Transplant | To assess the number of patients who achieve insulin independence at 12-month after islet cell transplantation | 12 months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence or Absence of Hypoglycemic Unawareness | Number of patients who achieved absence of hypoglycemic unawareness | 12 months after transplantation | 
| Incidence of Hypoglycemic Episodes | Blood glucose <70 mg/dl, number of times reported per month | 12 months after transplantation | 
| Change of Insulin Requirements in Patients Who Did Not Become Insulin Independent | Percentage of insulin requirement at month 12 against that at baseline in the patients who did not achieve insulin independence. The percentage less than 100% indicates that subjects reduced insulin requirements 12 months after islet transplantation when compared with those at pre-transplant, while the parentage more than 100% represents that patients needed higher amount of exogenous insulin 12 months after islet transplantation. | 12 months after transplantation | 
| Islet Cell Mass Obtained After Remote Site Processing | The sum of Islet mass obtained after transport using the two-layer preservation method, remote site processing and islet culture. Islet mass as defined by Islet Equivalent per kilogram recipient body weight. | At transplantation | 
| The Number of Islet Cell Infusions Needed to Achieve Insulin Independence |  | 12 months after transplantation | 
| Renal Function | Glomerular filtration rate measured by sodium iothalamate I-125 injection (GLOFIL) | 12 months after transplantation | 
| Morbidity Related to the Immunosuppression Regimen | Number of participants who experienced serious adverse events related to immunosuppression regimen | 12 months after transplantation | 
| Morbidity Related to the Islet Cell Infusion | Number of participants who experienced serious adverse events related to islet cell infusion | 12months after transplantation | 
| The Quality of Life of the Recipients Measured With the RAND 36-item Short Form Health Survey | Averaged score in subscales of 'physical functioning', 'Role limitations due to emotional problems', 'energy/fatigue', 'emotional well-being', 'social functioning', 'pain' and 'general health' in the RAND 36-item short form health survey (SF-36). Full scale range is 0-100 for all subscales with 100 as the best outcome and 0 as the worst outcome. | 12 months after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Hypoglycemia, Hyperglycemia