Islet Transplantation in Type 1 Diabetes - Full Text View

Sponsors and Collaborators:	National Institute of Allergy and Infectious Diseases (NIAID) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00434811

Purpose

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 determine the safety and effectiveness of islet transplantation, combined with immunosuppressive medications, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes.

Condition	Intervention	Phase
Type 1 Diabetes Mellitus	Procedure: Islet transplant	Phase III

MedlinePlus related topics: Diabetes Diabetes Type 1 Hypoglycemia Islet Cell Transplantation

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Islet Transplantation in Type 1 Diabetes

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Proportion of participants with an HbA1c less than 7.0% and free of severe hypoglycemic events [ Time Frame: From Days 28 to 365 (inclusive) after the first islet transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Percent reduction in insulin requirements [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
HbA1c [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Mean amplitude of glycemic excursions (MAGE) [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Glycemic liability index (LI) [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Ryan hypoglycemia severity score (HYPO) [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Basal (fasting) and 90-minute glucose and C-peptide derived from mixed meal tolerance test (MMTT) [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
β-score [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
C-peptide:glucose creatinine ratio [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system (CGMS) [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Quality of life [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Incidence of worsening retinopathy [ Time Frame: 75 days following the first and subsequent islet transplant ] [ Designated as safety issue: No ]
Proportion of insulin-independent subjects [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
Percent reduction in insulin requirements [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
HbA1c [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
MAGE [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
LI [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
Clarke score [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
HYPO score [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
Basal (fasting) and 90-minute glucose and C-peptide (MTT) [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
β-score [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
C-peptide: glucose creatinine ratio [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
Quality of life [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
Proportion of participants receiving a second islet cell infusion [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
Proportion of participants receiving a third islet cell infusion [ Time Frame: 365 days following the first islet cell infusion ] [ Designated as safety issue: No ]
Incidence and severity of adverse events related to the islet infusion procedure [ Time Frame: 75 days and 365 days following the first islet cell infusion ] [ Designated as safety issue: Yes ]
Incidence and severity of adverse events related to the immunosuppression therapy [ Time Frame: 75 days and 365 days following the first islet cell infusion ] [ Designated as safety issue: Yes ]
Incidence of a change in the immunosuppression drug regimen [ Time Frame: 75 days and 365 days following the first islet cell transplant ] [ Designated as safety issue: No ]
Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation [ Time Frame: 75 days and 365 days following the first islet cell transplant ] [ Designated as safety issue: No ]

Estimated Enrollment:	48
Study Start Date:	October 2006
Estimated Study Completion Date:	January 2011
Estimated Primary Completion Date:	May 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Participants will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus. They will begin receiving ATG and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant, and sirolimus will be given for the duration of the study. On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study. Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.	Procedure: Islet transplant 200 ml suspension of allogenic human purified islets

Arms

Assigned Interventions

1: Experimental

Participants will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus. They will begin receiving ATG and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant, and sirolimus will be given for the duration of the study. On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study. Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.

Procedure: Islet transplant

200 ml suspension of allogenic human purified islets

Detailed Description:

Type 1 diabetes is commonly treated with the administration of insulin, either by multiple insulin injections or by a continuous supply of insulin through a wearable pump. Insulin therapy allows long-term survival in individuals with type 1 diabetes; however, it does not guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic survivors often develop vascular complications, such as diabetic retinopathy, an eye disease that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that can lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia unawareness, a life-threatening condition that is not easily treatable with medication and is characterized by reduced or absent warning signals for hypoglycemia. For such individuals, transplantation of pancreatic islets is a possible treatment option. Unfortunately, insulin independence among islet transplant recipients tends to decline over time. New strategies aimed at promoting engraftment of transplanted islets are needed to improve the clinical outcomes associated with this procedure. The purpose of this study is determine the safety and efficacy of islet transplantation, when combined with an immunosuppressive medication regimen, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes. This study will also seek to improve the understanding of determinants of success and failure of islet transplants for type 1 diabetes.

Eligible participants will be randomly assigned to this study or a site-specific Phase 2 islet transplantation study. Participants in this study will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus. They will begin receiving ATG and sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant, and sirolimus will be given for the duration of the study. On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study. Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.

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 islet 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 15 study visits following each transplant. A physical exam, review of adverse events, and blood collection will occur at most visits. A chest x-ray, abdominal ultrasound, electrocardiogram, quality of life questionnaires, urine collection, and glomerular filtrating rate (GFR) testing will occur at some visits. Participants will also test their own blood 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.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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 a 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 in the past 12 months, 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, compatible with hypoglycemia in which the individual required assistance of another subject was unable to treat him/herself person and which was associated with either a blood glucose level less than 54 mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration
Reduced awareness of hypoglycemia. More information about this criterion, including 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/1.73mm2. 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 4 months after study completion
Active infection, including hepatitis B, hepatitis C, 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 5 mg or less of prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only
Treatment with any antidiabetic medication other than insulin within the past 4 weeks
Use of any study medications within the past 4 weeks
Received a live attenuated vaccine(s) 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00434811

Locations

United States, California
University of Callifornia, San Francisco	Not yet recruiting
San Francisco, California, United States, 94143
Contact: Debbie Ramos, RN, BSN 415-353-8615 debbie.ramos@ucsfmedctr.org
Principal Investigator: Peter Stock, MD, PhD
United States, Florida
University of Miami	Recruiting
Miami, Florida, United States, 33136
Contact: Eva Herrada, RN, BSN 305-243-6070 eherrada@med.miami.edu
Principal Investigator: Camillo Ricordi, MD
United States, Georgia
Emory University	Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Marti Sears, RN, BSN 404-712-2004 islets@emoryhealthcare.org
Principal Investigator: Chris Larsen, MD, D.Phil
United States, Illinois
Northwestern University	Recruiting
Chicago, Illinois, United States, 60611
Contact: Elyse Stuart, RN, CCRC 312-503-1060 e-stuart@northwestern.edu
Principal Investigator: Dixon Kaufman, MD, PhD
University of Illinois, Chicago	Recruiting
Chicago, Illinois, United States, 60612
Contact: Joan Martelloto, RN, PhD 312-996-6087 jmartell@uic.edu
Principal Investigator: Jose Oberholzer, MD
United States, Minnesota
University of Minnesota	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Jayne Pederson 612-624-8402 peder059@umn.edu
Principal Investigator: Bernhard Hering, MD
United States, Pennsylvania
University of Pennsylvania	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eileen Markmann, RN, BSN 215-662-4449 Eileen.Markmann@uphs.upenn.edu
Contact: Maral Palanjian, RN 215-615-3727 maral.palanjian@uphs.upenn.edu
Principal Investigator: Ali Naji, MD, PhD
Canada, Alberta
University of Alberta	Recruiting
Edmonton, Alberta, Canada, T6G028
Contact: Parastoo Dinyari, BSc, CCRP 780-407-3904 Parastoo@islet.ca
Principal Investigator: James Shapiro, MD, PhD

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

Study Chair:	Bernhard Hering, MD	University of Minnesota
Study Chair:	Olle Korsgren, PhD	Uppsala University Hospital
Study Chair:	Ali Naji, PhD	University of Pennsylvania
Study Chair:	Camillo Ricordi, MD	University of Miami
Study Chair:	James Shapiro, MD, PhD	University of Alberta

More Information

Additional Information:

Click here for the Clinical Islet Transplantation Consortium Web site This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	DIAT/NIAID ( Associate Director, Clinical Research Program )
Study ID Numbers:	DAIT CIT-07
Study First Received:	February 9, 2007
Last Updated:	November 10, 2008
ClinicalTrials.gov Identifier:	NCT00434811
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Insulin dependence
Hypoglycemia
Hypoglycemia unawareness

Study placed in the following topic categories:

Autoimmune Diseases
Metabolic Diseases
Diabetes Mellitus, Type 1
Diabetes mellitus type 1
Diabetes Mellitus
Endocrine System Diseases

Endocrinopathy
Metabolic disorder
Glucose Metabolism Disorders
Hypoglycemia
Insulin

Additional relevant MeSH terms:

Immune System Diseases

ClinicalTrials.gov processed this record on February 12, 2009