Type 1 Diabetes
Conditions
Keywords
Diabetes Mellitus, Hypoglycemia, Hyperglycemia
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.
Interventions
BIOLOGICALIslet cell transplantation
Allogenic islet transplantation
Sponsors
Baylor Health Care System
University of Miami
Baylor Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Achievement of Insulin Independence at 12-month Post Transplant | 12 months post transplant | To assess the number of patients who achieve insulin independence at 12-month after islet cell transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Hypoglycemic Episodes | 12 months after transplantation | Blood glucose \<70 mg/dl, number of times reported per month |
| Change of Insulin Requirements in Patients Who Did Not Become Insulin Independent | 12 months after transplantation | 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. |
| Islet Cell Mass Obtained After Remote Site Processing | At transplantation | 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. |
| The Number of Islet Cell Infusions Needed to Achieve Insulin Independence | 12 months after transplantation | — |
| Presence or Absence of Hypoglycemic Unawareness | 12 months after transplantation | Number of patients who achieved absence of hypoglycemic unawareness |
| Morbidity Related to the Immunosuppression Regimen | 12 months after transplantation | Number of participants who experienced serious adverse events related to immunosuppression regimen |
| Morbidity Related to the Islet Cell Infusion | 12months after transplantation | Number of participants who experienced serious adverse events related to islet cell infusion |
| The Quality of Life of the Recipients Measured With the RAND 36-item Short Form Health Survey | 12 months after transplantation | 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. |
| Renal Function | 12 months after transplantation | Glomerular filtration rate measured by sodium iothalamate I-125 injection (GLOFIL) |
Countries
United States
Participant flow
Recruitment details
Recruitment period took place between April 2003 thru November 2005. Consent took place in the transplant clinic at Baylor University Medical Center (BUMC).
Pre-assignment details
Patients signed informed consent after a consultation visit with tyhe PI. Then they proceeded through the evaluation phase of the study. During this phase, some patients were excluded based off of clinical findings (i.e. lab reports or procedures that did not meet protocol standards).
Participants by arm
| Arm | Count |
|---|---|
| Islet Cell Patients with allogeneic islet cell transplantation | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Islet Cell |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 35.5 years STANDARD_DEVIATION 11.56143 |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 4 / 4 |
Outcome results
Primary
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
Time frame: 12 months post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Cell | Achievement of Insulin Independence at 12-month Post Transplant | 1 participant |
Secondary
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.
Time frame: 12 months after transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Islet Cell | Change of Insulin Requirements in Patients Who Did Not Become Insulin Independent | 34.3 Percent decrease compared to baseline | Standard Error 10.5 |
Secondary
Incidence of Hypoglycemic Episodes
Blood glucose \<70 mg/dl, number of times reported per month
Time frame: 12 months after transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Islet Cell | Incidence of Hypoglycemic Episodes | 7.3 episodes per month | Standard Error 2.5 |
Secondary
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.
Time frame: At transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Islet Cell | Islet Cell Mass Obtained After Remote Site Processing | 8717 Islet Equivalent per kilogram | Standard Error 2243 |
Secondary
Morbidity Related to the Immunosuppression Regimen
Number of participants who experienced serious adverse events related to immunosuppression regimen
Time frame: 12 months after transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Cell | Morbidity Related to the Immunosuppression Regimen | 2 participant |
Secondary
Morbidity Related to the Islet Cell Infusion
Number of participants who experienced serious adverse events related to islet cell infusion
Time frame: 12months after transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Cell | Morbidity Related to the Islet Cell Infusion | 3 participant |
Secondary
Presence or Absence of Hypoglycemic Unawareness
Number of patients who achieved absence of hypoglycemic unawareness
Time frame: 12 months after transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Cell | Presence or Absence of Hypoglycemic Unawareness | 3 participants |
Secondary
Renal Function
Glomerular filtration rate measured by sodium iothalamate I-125 injection (GLOFIL)
Time frame: 12 months after transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Islet Cell | Renal Function | 127.3 ml/min | Standard Error 7.9 |
Secondary
The Number of Islet Cell Infusions Needed to Achieve Insulin Independence
Time frame: 12 months after transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Islet Cell | The Number of Islet Cell Infusions Needed to Achieve Insulin Independence | 2 number of infusion | Standard Error 0 |
Secondary
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.
Time frame: 12 months after transplantation
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Islet Cell | The Quality of Life of the Recipients Measured With the RAND 36-item Short Form Health Survey | 79.6 Scores on a scale | Full Range 12.4 |