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Islet Transplantation for Type 1 Diabetes

Primary Purpose

Diabetes Mellitus, Insulin-Dependent

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Islet Transplantation
Sirolimus
Tacrolimus
Daclizumab
Sulfamethoxazole
Ganciclovir
Trimethoprim
Pentamidine
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Insulin-Dependent

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Patients may be eligible for this study if they: Have had Type 1 diabetes mellitus for more than 5 years, and are exhibiting 1 of the following, despite intensive insulin management efforts: a) hypoglycemic unawareness, as defined by inability to sense hypoglycemia until the blood glucose falls to less than 54 mg/dL; b) metabolic instability, with 2 or more episodes of severe hypoglycemia (defined as an event with symptoms consistent with hypoglycemia in which the patient requires the assistance of another person and which is associated with a blood glucose below 54 mg/dL) or 2 or more hospital visits for diabetic ketoacidosis over the last year; or c) despite efforts at optimal glucose control, progressive secondary complications of diabetes as defined by retinopathy, nephropathy, or neuropathy. Are 18 to 65 years of age. Exclusion Criteria Patients will not be eligible for this study if they: Have had severe cardiac disease as defined by: a) recent myocardial infarction within the past 6 months; b) angiographic evidence of non-correctable coronary artery disease; or c) evidence of ischemia on a functional cardiac exam. Actively abuse alcohol or substances, including cigarette smoking (must not have smoked within the last 6 months). Have psychiatric problems that prevent them from being a suitable candidate for transplantation (such as schizophrenia, bipolar disorder, or major depression that is not controlled or stable on current medication). Have a history of not following prescribed regimens. Have active infection including hepatitis C virus, hepatitis B virus, human immunodeficiency virus (HIV), or Tuberculosis (TB) (or under treatment for suspected TB). Have a history of malignancy, except squamous or basal skin cancer. Weigh more than 70 kilograms or have a Body Mass Index (BMI) greater than 26 kg/m^2 at time of screening. Have a C-peptide value of 0.3 ng/ml or more following a 5.0 gram intravenous arginine infusion challenge. Are unable to provide informed consent. Have gallstones or hemangioma in liver. Have untreated proliferative retinopathy. Are breast-feeding or pregnant, or intend to try and become pregnant (females) or to father a child (males), or fail to follow birth control methods. Have had a previous transplant, or evidence of anti-human leukocyte antigen (HLA) antibody. Have an insulin requirement of more that 0.7 International Units (IU)/kilograms/day. Have a blood glycosylated hemoglobin (HbA1c) higher than 12 percent. Are unable to reach the hospital for transplantation within 2 hours of notification. Have untreated or treated hyperlipidemia. Have a medical condition requiring chronic use of steroids. Use coumadin or other anticoagulants (aspirin is allowed). Have Addison's disease. Have a negative screen for Epstein-Barr virus (EBV).

Sites / Locations

  • University of Miami
  • Massachusetts General Hospital
  • University of Minnesota
  • Washington University
  • Benaroya Research Institute at Virginia Mason Research Center
  • University of Alberta
  • Justus-Leibig University
  • University of Milan
  • University of Geneva

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Islet Transplantation

Arm Description

All study participants

Outcomes

Primary Outcome Measures

Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation.
Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1.) a blood glycosylated hemoglobin (HbA1c) level < 6.5% (Normal:<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: <140mg/dL if <=50 years of age, <150 mg/dL for ages 50-60 years and <160 mg/dL for ages 60+)

Secondary Outcome Measures

Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation.
Partial islet function definition: a fasting basal C-peptide level >= 0.3 ng/mL and a continuing need for insulin or suboptimal glycemic control (Note: C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making). Adequate glycemic control is defined by: 1) a blood HbA1c level <6.5%, 2) a blood glucose level after an overnight fast not exceeding 140 mg/dL more than three times in any week and, 3) a 2-hour postprandial blood glucose level not exceeding 180 mg/dL more than four times per week
Percent of Participants That Achieved Insulin Independence From First Transplant
Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1) a blood glycosylated hemoglobin (HbA1c) level < 6.5% (Normal:<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: <140mg/dL if <=50 years of age, <150 mg/dL for ages 50-60 years and <160 mg/dL for ages 60+)
Percent of Participants With Detectable Fasting Basal C-Peptide Levels
C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making. C-peptide secretion is used to measure the function of transplanted islets. Higher levels indicate better islet function. Detectable fasting basal levels of C-peptide secretion are >=0.3 ng/ml.

Full Information

First Posted
April 13, 2001
Last Updated
February 6, 2017
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Immune Tolerance Network (ITN)
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1. Study Identification

Unique Protocol Identification Number
NCT00014911
Brief Title
Islet Transplantation for Type 1 Diabetes
Official Title
Islet Transplantation for Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression (ITN005CT)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
April 2001 (undefined)
Primary Completion Date
June 2005 (Actual)
Study Completion Date
August 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Immune Tolerance Network (ITN)

4. Oversight

5. Study Description

Brief Summary
The purpose of this study is to test whether the islet cell transplantation procedures and results from a previous study in Edmonton, Canada, can be repeated. The study also is designed to learn more about diabetes control using islet cell transplantation. This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression.
Detailed Description
This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression. Eligible patients were randomly selected from the total pool of people who applied through the Immune Tolerance Network. Patients will receive at least 10,000 "islet equivalents" per kilogram (2.2 pounds) of body weight. This likely will require 2 separate islet infusions from 2 separate donors. Immediately before the first transplant, patients will be given anti-rejection (immune suppressing) drugs, including tacrolimus and sirolimus (orally) and daclizumab (intravenously). The islets will be infused into the liver through a tube placed in the portal vein. Heparin (a medication to prevent blood clots) will be administered with the islet infusion. A longer-acting form of heparin will also be given by daily injections during the next week after each transplant. After surgery, patients will receive insulin intravenously for 24 hours. Patients will have an abdominal ultrasound and blood tests to determine liver function. If fewer than 10,000 islets were transplanted, patients will continue insulin treatment, with the dosages adjusted if necessary to account for the transplanted islets. They will take daclizumab every 2 weeks for 8 weeks and tacrolimus and sirolimus daily. Patients will be given antibiotics to prevent infections. Blood tests to determine how much immunosuppressant drug is in the blood will be performed until the drug is at a stable level. Periodically there will be tests to see if the islet cells are functioning. Blood will be drawn to check drug levels and for other tests routinely. Daily insulin requirements will be checked, and these will be recorded monthly. Patients will be followed for at least 1 year post last islet transplantation. Additional follow-up may be provided at least annually for up to 9 years post first transplantation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Insulin-Dependent

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Islet Transplantation
Arm Type
Experimental
Arm Description
All study participants
Intervention Type
Procedure
Intervention Name(s)
Islet Transplantation
Intervention Description
Participants will receive portal vein islet infusions (up to 3), e.g., islet transplantations, with a targeted total of exceeding 10,000 islet equivalents per kilogram of body weight (IE/kg) per infusion. Up to three transplants are possible depending on individual results.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Intervention Description
Administered at a dose of 0.2 mg/kg by mouth once pre-transplantation then 0.1 mg/kg daily post-transplantation. Dosing will be adjusted to achieve a trough peripheral blood level of 12-15 ng/mL x3 months after transplantation and 7-12 ng/mL for the remainder of the study.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Intervention Description
Administered at a dose of 1 mg by mouth once pre-transplantation followed by 1 mg twice daily post transplantation. Levels will be adjusted to achieve a peripheral blood trough level of 3-6 ng/mL for maintenance immunosuppression.
Intervention Type
Drug
Intervention Name(s)
Daclizumab
Intervention Description
Administered at a dose of 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation, totaling 5 doses(over 8 weeks). Further daclizumab dosing may be necessary based on individual results and islet transplantation needs.
Intervention Type
Drug
Intervention Name(s)
Sulfamethoxazole
Intervention Description
An antibacterial used to prevent opportunistic infections
Intervention Type
Drug
Intervention Name(s)
Ganciclovir
Intervention Description
An antiviral used to kill viruses and stop viral replication
Intervention Type
Drug
Intervention Name(s)
Trimethoprim
Intervention Description
An antibacterial used to prevent opportunistic infections
Intervention Type
Drug
Intervention Name(s)
Pentamidine
Intervention Description
An antiprotozoal used to prevent disease
Primary Outcome Measure Information:
Title
Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation.
Description
Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1.) a blood glycosylated hemoglobin (HbA1c) level < 6.5% (Normal:<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: <140mg/dL if <=50 years of age, <150 mg/dL for ages 50-60 years and <160 mg/dL for ages 60+)
Time Frame
One year status post participant receipt of final islet transplantation
Secondary Outcome Measure Information:
Title
Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation.
Description
Partial islet function definition: a fasting basal C-peptide level >= 0.3 ng/mL and a continuing need for insulin or suboptimal glycemic control (Note: C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making). Adequate glycemic control is defined by: 1) a blood HbA1c level <6.5%, 2) a blood glucose level after an overnight fast not exceeding 140 mg/dL more than three times in any week and, 3) a 2-hour postprandial blood glucose level not exceeding 180 mg/dL more than four times per week
Time Frame
One year post receipt of final islet transplantation
Title
Percent of Participants That Achieved Insulin Independence From First Transplant
Description
Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1) a blood glycosylated hemoglobin (HbA1c) level < 6.5% (Normal:<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: <140mg/dL if <=50 years of age, <150 mg/dL for ages 50-60 years and <160 mg/dL for ages 60+)
Time Frame
First transplantation until end of study (up to six years post final transplantation)
Title
Percent of Participants With Detectable Fasting Basal C-Peptide Levels
Description
C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making. C-peptide secretion is used to measure the function of transplanted islets. Higher levels indicate better islet function. Detectable fasting basal levels of C-peptide secretion are >=0.3 ng/ml.
Time Frame
Two years post first transplantation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Patients may be eligible for this study if they: Have had Type 1 diabetes mellitus for more than 5 years, and are exhibiting 1 of the following, despite intensive insulin management efforts: a) hypoglycemic unawareness, as defined by inability to sense hypoglycemia until the blood glucose falls to less than 54 mg/dL; b) metabolic instability, with 2 or more episodes of severe hypoglycemia (defined as an event with symptoms consistent with hypoglycemia in which the patient requires the assistance of another person and which is associated with a blood glucose below 54 mg/dL) or 2 or more hospital visits for diabetic ketoacidosis over the last year; or c) despite efforts at optimal glucose control, progressive secondary complications of diabetes as defined by retinopathy, nephropathy, or neuropathy. Are 18 to 65 years of age. Exclusion Criteria Patients will not be eligible for this study if they: Have had severe cardiac disease as defined by: a) recent myocardial infarction within the past 6 months; b) angiographic evidence of non-correctable coronary artery disease; or c) evidence of ischemia on a functional cardiac exam. Actively abuse alcohol or substances, including cigarette smoking (must not have smoked within the last 6 months). Have psychiatric problems that prevent them from being a suitable candidate for transplantation (such as schizophrenia, bipolar disorder, or major depression that is not controlled or stable on current medication). Have a history of not following prescribed regimens. Have active infection including hepatitis C virus, hepatitis B virus, human immunodeficiency virus (HIV), or Tuberculosis (TB) (or under treatment for suspected TB). Have a history of malignancy, except squamous or basal skin cancer. Weigh more than 70 kilograms or have a Body Mass Index (BMI) greater than 26 kg/m^2 at time of screening. Have a C-peptide value of 0.3 ng/ml or more following a 5.0 gram intravenous arginine infusion challenge. Are unable to provide informed consent. Have gallstones or hemangioma in liver. Have untreated proliferative retinopathy. Are breast-feeding or pregnant, or intend to try and become pregnant (females) or to father a child (males), or fail to follow birth control methods. Have had a previous transplant, or evidence of anti-human leukocyte antigen (HLA) antibody. Have an insulin requirement of more that 0.7 International Units (IU)/kilograms/day. Have a blood glycosylated hemoglobin (HbA1c) higher than 12 percent. Are unable to reach the hospital for transplantation within 2 hours of notification. Have untreated or treated hyperlipidemia. Have a medical condition requiring chronic use of steroids. Use coumadin or other anticoagulants (aspirin is allowed). Have Addison's disease. Have a negative screen for Epstein-Barr virus (EBV).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James Shapiro, MD, PhD
Organizational Affiliation
University of Alberta
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Washington University
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Benaroya Research Institute at Virginia Mason Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
Country
Canada
Facility Name
Justus-Leibig University
City
Giessen
ZIP/Postal Code
35385
Country
Germany
Facility Name
University of Milan
City
Milan
Country
Italy
Facility Name
University of Geneva
City
Geneva
Country
Switzerland

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data access is provided to the public in : 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts that also provides data analysis tools available to researchers; and 2.) TrialShare, the Immune Tolerance Network (ITN) portal.
Citations:
PubMed Identifier
17005949
Citation
Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone J, Lakey JR. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006 Sep 28;355(13):1318-30. doi: 10.1056/NEJMoa061267.
Results Reference
result
PubMed Identifier
15257060
Citation
Brennan DC, Shannon MB, Koch MJ, Polonsky KS, Desai N, Shapiro J. Portal vein thrombosis complicating islet transplantation in a recipient with the Factor V Leiden mutation. Transplantation. 2004 Jul 15;78(1):172-3. doi: 10.1097/01.tp.0000128332.71657.ea. No abstract available.
Results Reference
result
PubMed Identifier
29654388
Citation
Benedini S, Ermetici F, Briganti S, Codella R, Terruzzi I, Maffi P, Caldara R, Secchi A, Nano R, Piemonti L, Alejandro R, Ricordi C, Luzi L. Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation. Acta Diabetol. 2018 Jul;55(7):715-722. doi: 10.1007/s00592-018-1141-z. Epub 2018 Apr 13.
Results Reference
derived
PubMed Identifier
23438305
Citation
Gala-Lopez B, Kin T, O'Gorman D, Pepper AR, Senior P, Humar A, Shapiro AM. Microbial contamination of clinical islet transplant preparations is associated with very low risk of infection. Diabetes Technol Ther. 2013 Apr;15(4):323-7. doi: 10.1089/dia.2012.0297. Epub 2013 Feb 25.
Results Reference
derived
Links:
URL
https://www.niaid.nih.gov/
Description
National Institute of Allergy and Infectious Diseases (NIAID) website
URL
https://www.niaid.nih.gov/about/dait
Description
Division of Allergy, Immunology, and Transplantation (DAIT) website
URL
http://www.immunetolerance.org
Description
Immune Tolerance Network (ITN) website
Available IPD and Supporting Information:
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
http://www.immport.org/immport-open/public/study/study/displayStudyDetail/SDY567
Available IPD/Information Identifier
SDY567
Available IPD/Information Comments
ImmPort study identifier is SDY567. ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts and is available to the Public.
Available IPD/Information Type
Study summary, -schematic, -design, -adverse event(s),-medications,-demographics, - lab tests, -study files
Available IPD/Information URL
http://www.immport.org/immport-open/public/study/study/displayStudyDetail/SDY567
Available IPD/Information Identifier
SDY567
Available IPD/Information Comments
ImmPort study identifier is SDY567. ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts and is available to the Public.
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
http://www.itntrialshare.org/project/Studies/ITN005CTPUBLIC/Study%20Data/begin.view?
Available IPD/Information Identifier
ITN005CT
Available IPD/Information Comments
TrialShare is the Immune Tolerance Network (ITN) portal that makes data from the consortium's clinical trials publicly available without charge. Creating an account for ITN TrialShare is free and allows for searching studies of interest.
Available IPD/Information Type
Study overview & protocol synopsis, -navigator, -schedule of assessments, -data&reports, -specimens, etc.
Available IPD/Information URL
http://www.itntrialshare.org/project/Studies/ITN005CTPUBLIC/Study%20Data/begin.view?
Available IPD/Information Identifier
ITN005CT
Available IPD/Information Comments
TrialShare is a clinical trials research portal developed by the Immune Tolerance Network (ITN) that makes data from the consortium's clinical trials publicly available without charge.

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Islet Transplantation for Type 1 Diabetes

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