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Islet Transplantation in Type 1 Diabetes

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00434811
First received: February 9, 2007
Last updated: June 10, 2014
Last verified: June 2014

February 9, 2007
June 10, 2014
October 2006
September 2012   (final data collection date for primary outcome measure)
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 ]
Proportion of participants with an HbA1c less than 6.5% and free of severe hypoglycemic events (from Days 28 to 365) at 1 year after the first islet transplant
Complete list of historical versions of study NCT00434811 on ClinicalTrials.gov Archive Site
  • 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: 365 days following the first islet transplant ] [ Designated as safety issue: Yes ]
  • 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 transplant [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
  • Proportion of participants receiving a third islet transplant [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
  • Incidence and severity of adverse events related to the islet transplant procedure [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  • Incidence and severity of adverse events related to the immunosuppression therapy [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  • Incidence of a change in the immunosuppression drug regimen [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  • Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation [ Time Frame: 75 days following each transplant and 365 days following the first and final islet transplant ] [ Designated as safety issue: Yes ]
  • Proportion of insulin-independent participants [ Time Frame: 75 days following first and subsequent islet transplant ] [ Designated as safety issue: No ]
  • Acute insulin response to glucose insulin sensitivity, and disposition index derived from the FSIGT test [ Time Frame: 365 days following the first and final islet transplant ] [ Designated as safety issue: No ]
  • Measured 75 days after the first and final islet transplants: Acute insulin response to glucose, insulin sensitivity, and disposition index derived from insulin-modified frequently sampled intravenous glucose test
  • glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system
  • Measured 365 days after the first and/or final islet transplants: Proportion of insulin-dependent participants
  • Clarke score
  • proportion of participants receiving a second islet infusion
  • proportion of participants receiving a third islet infusion
  • incidence of worsening retinopathy as assessed by change in retinal photography from pre-transplant to Day 365
  • Measured 75 and 365 days after the first and final islet infusions: Percent reduction in insulin requirements
  • HbA1c
  • mean amplitude of glycemic excursions (MAGE)
  • glycemic lability index
  • ryan hypoglycemia severity (HYPO) score
  • basal (fasting) and 90-minute glucose and C-peptide derived from mixed-meal tolerance test (MTT)
  • β-score
  • C-peptide:glucose creatinine ratio
  • quality of life measures
  • incidence and severity of adverse events related to islet infusion procedure
  • incidence and severity of adverse events related to immunosuppression
  • incidence of a change in immunosuppression drug regimen
  • incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation
Not Provided
Not Provided
 
Islet Transplantation in Type 1 Diabetes
Islet Transplantation in Type 1 Diabetes

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.

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.

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. 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 19 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 24-month follow-up period will take place after the participant's last transplant.

Interventional
Phase 3
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Type 1 Diabetes Mellitus
  • Biological: Allogeneic Pancreatic Islet Cells
    200 ml suspension of allogenic human purified islets
  • Biological: Antithymocyte Globulin
    Participants will begin receiving ATG 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant.
  • Drug: Sirolimus
    Participants will begin receiving sirolimus 2 days prior to the first islet transplant and will be given for the duration of the study.
    Other Name: Rapamycin
  • Drug: Tacrolimus
    On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study.
    Other Names:
    • FK-506
    • Fujimycin
  • Biological: Etanercept
    Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.
  • Procedure: Islet Transplantation
    Transplantation of pancreatic islet cell
  • Biological: Basiliximab
    Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary.
    Other Names:
    • chimeric mouse-human antiCD25
    • Ig gamma-1 chain C region
Experimental: Islet Transplantation
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.
Interventions:
  • Biological: Allogeneic Pancreatic Islet Cells
  • Biological: Antithymocyte Globulin
  • Drug: Sirolimus
  • Drug: Tacrolimus
  • Biological: Etanercept
  • Procedure: Islet Transplantation
  • Biological: Basiliximab
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
48
May 2014
September 2012   (final data collection date for primary outcome measure)

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 in the 12 months prior to study enrollment
  • 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
  • Presence or history of active infection, including hepatitis B, hepatitis C, HIV, or tuberculosis.
  • 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.
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada
 
NCT00434811
DAIT CIT-07
Yes
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Chair: Bernhard Hering, MD University of Minnesota - Clinical and Translational Science Institute
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
Study Chair: Andrew Posselt, MD, PhD University of California, San Francisco
Study Chair: Nicole Turgeon, MD Emory University
Study Chair: Xunrong Luo, MD, PhD Northwestern Univerity
National Institute of Allergy and Infectious Diseases (NIAID)
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP