Peritransplant Deoxyspergualin in Islet Transplantation in Type 1 Diabetes

Phase 2

Completed

Conditions: Diabetes Mellitus, Type 1

Interventions: Biological: Allogeneic Pancreatic Islet Cells
Drug: Deoxyspergualin
Biological: Antithymocyte globulin
Biological: Daclizumab or basiliximab
Drug: Sirolimus
Drug: Tacrolimus
Biological: Etanercept

Registration Number: NCT00434850

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed, resulting in poor blood sugar control. The purpose of this study is to assess the safety and efficacy of deoxyspergualin (DSG), an immunosuppressant drug, on post-transplant islet function in people with type 1 diabetes who have not responded to intensive insulin therapy.

Detailed Description: Type 1 diabetes, also known as insulin-dependent diabetes, is a chronic disease in which the pancreas produces insufficient insulin to properly regulate blood sugar levels. Hypoglycemia, low blood sugar, and hyperglycemia, high blood sugar, can lead to significant complications in people with type 1 diabetes. Intensive insulin therapy has been shown to reduce the risk of chronic complications in people who achieve near normalization of glycemia. However, this therapy is labor intensive, difficult to implement, and associated with an increased frequency of severe hypoglycemia. Transplantation of islets from a healthy pancreas has been successful in restoring normal blood sugar levels and has led to initial insulin independence in people with type 1 diabetes. Rejection of these islets by the recipient's immune system, however, makes the treatment ineffective within a couple of years. Immunosuppressant drugs may be an effective way to maintain islet function post-transplant. The purpose of this study is to assess the safety and efficacy of an immunosuppressive regimen that includes DSG on post-transplant islet function in people with type 1 diabetes who have not responded to intensive insulin therapy. The study will also seek to improve the understanding of determinants of success and failure of islet transplants for type 1 diabetes.

Following screening procedures and 2 days prior to islet transplant, participants will be randomly assigned to either this Phase 2 trial or a multicenter Phase 3 trial. Participants in this study will receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.

Transplantations will involve an inpatient hospital stay and infusion of islets into a branch of the portal vein. Participants who do not achieve or maintain insulin independence by Day 75 post-transplant will be considered for a second islet transplant. Participants who remain dependent on insulin for longer than 1 month after the second transplant and who show partial graft function will be considered for a third transplant. Daclizumab or basiliximab will be used in place of ATG for the second and third transplants, if they are necessary. Participants who do not meet the criteria for a subsequent transplant and do not have a functioning graft will enter a reduced follow-up period.

There will be up to 21 study visits following each transplant. A physical exam, review of adverse events, blood collection, urine tests, and measures of immunosuppression levels will occur at most visits. An abdominal ultrasound and glomerular filtration rate testing will occur at some study visits. Participants will also self-test their glucose levels at least five times per day throughout the study. A 12-month follow-up period will take place after the participant's last transplant.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Mentally stable and able to comply with study procedures
Clinical history compatible with type 1 diabetes, with onset of disease at less than 40 years of age; insulin dependence for at least 5 years at study entry; AND sum of age and insulin-dependent diabetes duration of at least 28
Absent stimulated C-peptide (less than 0.3 ng/ml) 60 and 90 minutes post mixed-meal tolerance test
Involvement of intensive diabetes management, defined as:
1. Self monitoring of glucose values no less than a mean of three times each day, averaged over each week
2. Administration of three or more insulin injections each day or insulin pump therapy
3. Under the direction of an endocrinologist, diabetologist, or diabetes specialist, with at least three clinical evaluations during the past 12 months prior to study enrollment
At least one episode of severe hypoglycemia, defined as an event with one of the following symptoms: memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, in which the participant was unable to treat him/herself and which was associated with either a blood glucose level less than 54 mg/dl or prompt recovery after an oral carbohydrate, intravenous glucose, or glucagon administration in the 12 months prior to study enrollment.
Reduced awareness of hypoglycemia. More information about this criterion, including the specific definition of hypoglycemia unawareness, is in the protocol.

Exclusion Criteria

Body mass index (BMI) greater than 30 kg/m2 or weight less than or equal to 50 kg
Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/day
HbA1c greater than 10%
Untreated proliferative diabetic retinopathy
Systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than 100 mmHg
Measured glomerular filtration rate using iohexol of less than 80 ml/min/1.73m2. More information about this criterion is in the protocol.
Presence or history of macroalbuminuria (greater than 300 mg/g creatinine)
Presence or history of panel-reactive anti-HLA antibody levels greater than background by flow cytometry. More information about this criterion is in the protocol.
Pregnant, breastfeeding, or unwilling to use effective contraception throughout the study and for 4 months after study completion
Active infection, including hepatitis B virus, hepatitis C virus, HIV, or tuberculosis. More information about this criterion is in the protocol.
Negative for Epstein-Barr virus by IgG determination
Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection in the past year
History of malignancy except for completely resected squamous or basal cell carcinoma of the skin
Known active alcohol or substance abuse
Baseline Hgb below the lower limits of normal, lymphopenia, neutropenia, or thrombocytopenia
History of Factor V deficiency
Any coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or individuals with an INR greater than 1.5
Severe coexisting cardiac disease, characterized by any one of the following conditions:
1. Heart attack within the last 6 months
2. Evidence of ischemia on functional heart exam within the year prior to study entry
3. Left ventricular ejection fraction less than 30%
Persistent elevation of liver function tests at the time of study entry
Symptomatic cholecystolithiasis
Acute or chronic pancreatitis
Symptomatic peptic ulcer disease
Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with the ability to absorb oral medications
Hyperlipidemia despite medical therapy, defined as fasting LDL cholesterol greater than 130 mg/dl (treated or untreated) and/or fasting triglycerides greater than 200 mg/dl
Currently receiving treatment for a medical condition that requires chronic use of systemic steroids except for the use of less than or equal to 5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only
Treatment with any anti-diabetic medication other than insulin within 4 weeks prior to study entry
Use of any study medications within the past 4 weeks
Received a live attenuated vaccine within the past 2 months
Any medical condition that, in the opinion of the investigator, might interfere with safe participation in the trial
Treatment with any immunosuppressive regimen at the time of enrollment.
A previous islet transplant.
A previous pancreas transplant, unless the graft failed within the first week due to thrombosis, followed by pancreatectomy and the transplant occurred more than 6 months prior to enrollment

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Allogeneic Pancreatic Islet Cells	Allogeneic Pancreatic Islet Cells	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.
Allogeneic Pancreatic Islet Cells	Daclizumab or basiliximab	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.
Allogeneic Pancreatic Islet Cells	Antithymocyte globulin	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.
Allogeneic Pancreatic Islet Cells	Etanercept	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.
Allogeneic Pancreatic Islet Cells	Tacrolimus	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.
Allogeneic Pancreatic Islet Cells	Sirolimus	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.
Allogeneic Pancreatic Islet Cells	Deoxyspergualin	Participants in this study can receive up to three separate islet transplants. They will begin receiving antithymocyte globulin (ATG) and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. Participants will continue taking sirolimus for the duration of the study. On the day of transplant, participants will receive DSG and etanercept, in addition to ATG and sirolimus. The DSG infusion will be administered over 3 hours and will immediately precede the islet transplant. Participants will continue receiving daily 3-hour infusions of DSG through Day 6 post-transplant. Etanercept will also be administered on Days 3, 7, and 10 post-transplant. Tacrolimus will be administered on Day 1 post-transplant and continued throughout the study.

Primary Outcome Measures

Name	Time	Method
Proportion of Insulin-independent Subjects	75 days following the first islet transplant

Secondary Outcome Measures

Name	Time	Method
Glycemic Lability Index (LI)	365 days following the first and final islet transplant
Quality of Life (QOL) Measure	75 days following the first and subsequent islet transplant
Ryan Hypoglycemia Severity Score (HYPO)	75 days following the first and subsequent islet transplant
Percent Reduction in Insulin Requirements	365 days following the first and final islet transplant
Quality of life (QOL) Measure	365 days following the first and final islet transplant
Basal (fasting) and 90-minute Glucose and C-peptide Results	75 days following the first and subsequent islet transplant	Derived from Mixed Meal Tolerance Test (MMTT)
C-peptide: Glucose Creatinine Ratio	365 days following the first and final islet transplant
Beta-score	365 days following the first and final islet transplant	Assesses beta-cell function after islet transplantation
Incidence of Worsening Retinopathy	365 days following the first islet transplant
Basal (fasting) and 90-minute Glucose and C-peptide	365 days following the first and final islet transplant	Derived from Mixed Meal Tolerance Test (MMTT)
Glucose Variability and Hypoglycemia Duration	75 days following the first and subsequent islet transplant	Derived from the continuous glucose monitoring system (CGMS)
Hemoglobin A1c (HbA1c)	365 days following the first and final islet transplant
Acute Insulin Response to Glucose, Insulin Sensitivity, and Disposition Index	75 days following the first and subsequent islet transplant	Derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test
Proportion of Insulin-independent Subjects	365 days following the first and final islet transplant
Clarke Score	365 days following the first and final islet transplant	A hypoglycemia score
HYPO Score	365 days following the first and final islet transplant	A hypoglycemia score
Proportion of Subjects Receiving a Second Islet Cell Transplant	365 days following the first islet transplant
Proportion of Subjects Receiving a Third Islet Cell Transplant	365 days following the first and final islet transplant
Incidence and Severity of Adverse Events Related to the Immunosuppression Therapy	75 days and 365 days following the first and final islet transplant
Incidence of a Change in the Immunosuppression Drug Regimen	75 days and 365 days following the first and final islet cell transplant
Mean Amplitude of Glycemic Excursions (MAGE)	365 days following the first and final islet transplant
Incidence and Severity of Adverse Events Related to the Islet Cell Transplant Procedure	75 days and 365 days following the first and final islet cell infusion
Incidence of Immune Sensitization	75 days and 365 days following the first and final islet transplant	Defined by detecting anti-HLA antibodies not present prior to transplantation
Acute Insulin Response to Glucose, Insulin Sensitivity, and Disposition Index (DI)	365 day following the first and final islet transplant	Derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test

Trial Locations

Locations (3): University of Californinia, San Francisco
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San Francisco, California, United States
Northwestern University
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Chicago, Illinois, United States
University of Minnesota
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Minneapolis, Minnesota, United States