Clinical trial NCT00214786: Pancreatic Islet Cell Transplantation
Official title: Pancreatic Islet Cell Transplantation - A Novel Approach to Immunosuppression and Validation of Remote Site Islet Cell Processing, Islet Cell Culture and Two-Layer Preservation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 1 Diabetes
Keywords: Diabetes Mellitus
Hypoglycemia
Hyperglycemia
Lead sponsor: Baylor Research Institute
Sponsor class: OTHER
Collaborators: name: Baylor Health Care System
name: University of Miami
First posted: 2005-09-22
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. 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
3. 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.

1. Patient has previously received or is receiving an organ or bone marrow transplant
2. Patient has a known hypersensitivity to Tacrolimus, sirolimus, daclizumab, or CellCept
3. Patient is pregnant or lactating
4. Patient has participated in a blinded trial or participated in a trial involving a non-marketed (investigational) drug within 3 months of enrollment
5. Patient has participated in a trial involving a marketed drug or an infusion device within 30 days of the start of the trial
6. Glomerular filtration rate (GLOFIL) \< 60 mL/min
7. Serum Creatinine \> 1.6 mg/dL consistently
8. Body mass index \> 30
9. Autoimmune thyroiditis
10. Malignancy other than basal cell carcinoma or squamous cell carcinoma
11. Radiographic evidence of pulmonary infection
12. Evidence of liver disease
13. Portal hypertension
14. Active infections
15. Hypercoagulable states (history of recurrent venous thrombosis, defined thrombophilia)
16. Bleeding / coagulation disorders
17. Basal insulin C-Peptide \> 0.3 ng/dL
18. Insulin C-peptide \> 0.3 ng/dL during stimulation test
19. HbA1c \> 12%
20. Insulin requirement \> 1 IU/kg/day
21. Seropositivity for Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Human T-cell leukemia virus-1 (HTLV-1)
22. Abnormal Pap smear in the last two months, active gynecological infection
23. Positive exercise or chemical tolerance test
24. Steroid dependence
25. Substance/alcohol abuse
26. 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

Primary outcomes:
measure: Achievement of Insulin Independence at 12-month Post Transplant
timeFrame: 12 months post transplant
Secondary outcomes:
measure: Presence or Absence of Hypoglycemic Unawareness
timeFrame: 12 months after transplantation
measure: Incidence of Hypoglycemic Episodes
timeFrame: 12 months after transplantation
measure: Change of Insulin Requirements in Patients Who Did Not Become Insulin Independent
timeFrame: 12 months after transplantation
measure: Islet Cell Mass Obtained After Remote Site Processing
timeFrame: At transplantation
measure: The Number of Islet Cell Infusions Needed to Achieve Insulin Independence
timeFrame: 12 months after transplantation
measure: Renal Function
timeFrame: 12 months after transplantation
measure: Morbidity Related to the Immunosuppression Regimen
timeFrame: 12 months after transplantation
measure: Morbidity Related to the Islet Cell Infusion
timeFrame: 12months after transplantation
measure: The Quality of Life of the Recipients Measured With the RAND 36-item Short Form Health Survey
timeFrame: 12 months after transplantation
Other outcomes:
Locations:
city: Dallas
country: United States
facility: Baylor Regional Transplant Institute - Baylor University Medical Center
state: Texas
Study officials:
affiliation: Baylor Regional Transplant Institute
name: Marlon Levy, MD
role: PRINCIPAL_INVESTIGATOR
References: