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Peritransplant Deoxyspergualin in Islet Transplantation in Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT00434850
Recruitment Status : Completed
First Posted : February 13, 2007
Last Update Posted : March 16, 2016
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE February 9, 2007
First Posted Date  ICMJE February 13, 2007
Last Update Posted Date March 16, 2016
Study Start Date  ICMJE October 2006
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 10, 2014)
Proportion of Insulin-independent Subjects [ Time Frame: 75 days following the first islet transplant ]
Original Primary Outcome Measures  ICMJE
 (submitted: February 9, 2007)
Proportion of insulin-independent participants 75 days following the first islet cell infusion
Change History Complete list of historical versions of study NCT00434850 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2014)
  • Percent Reduction in Insulin Requirements [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Hemoglobin A1c (HbA1c) [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Mean Amplitude of Glycemic Excursions (MAGE) [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Glycemic Lability Index (LI) [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Ryan Hypoglycemia Severity Score (HYPO) [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Basal (fasting) and 90-minute Glucose and C-peptide Results [ Time Frame: 75 days following the first and subsequent islet transplant ]
    Derived from Mixed Meal Tolerance Test (MMTT)
  • Beta-score [ Time Frame: 75 days following the first and subsequent islet transplant ]
    Assesses beta-cell function after islet transplantation
  • C-peptide: Glucose Creatinine Ratio [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Acute Insulin Response to Glucose, Insulin Sensitivity, and Disposition Index [ Time Frame: 75 days following the first and subsequent islet transplant ]
    Derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test
  • Glucose Variability and Hypoglycemia Duration [ Time Frame: 75 days following the first and subsequent islet transplant ]
    Derived from the continuous glucose monitoring system (CGMS)
  • Quality of Life (QOL) Measure [ Time Frame: 75 days following the first and subsequent islet transplant ]
  • Incidence of Worsening Retinopathy [ Time Frame: 365 days following the first islet transplant ]
  • Proportion of Insulin-independent Subjects [ Time Frame: 365 days following the first and final islet transplant ]
  • Percent Reduction in Insulin Requirements [ Time Frame: 365 days following the first and final islet transplant ]
  • Hemoglobin A1c (HbA1c) [ Time Frame: 365 days following the first and final islet transplant ]
  • Mean Amplitude of Glycemic Excursions (MAGE) [ Time Frame: 365 days following the first and final islet transplant ]
  • Glycemic Lability Index (LI) [ Time Frame: 365 days following the first and final islet transplant ]
  • Clarke Score [ Time Frame: 365 days following the first and final islet transplant ]
    A hypoglycemia score
  • HYPO Score [ Time Frame: 365 days following the first and final islet transplant ]
    A hypoglycemia score
  • Basal (fasting) and 90-minute Glucose and C-peptide [ Time Frame: 365 days following the first and final islet transplant ]
    Derived from Mixed Meal Tolerance Test (MMTT)
  • Beta-score [ Time Frame: 365 days following the first and final islet transplant ]
    Assesses beta-cell function after islet transplantation
  • C-peptide: Glucose Creatinine Ratio [ Time Frame: 365 days following the first and final islet transplant ]
  • Quality of life (QOL) Measure [ Time Frame: 365 days following the first and final islet transplant ]
  • Proportion of Subjects Receiving a Second Islet Cell Transplant [ Time Frame: 365 days following the first islet transplant ]
  • Proportion of Subjects Receiving a Third Islet Cell Transplant [ Time Frame: 365 days following the first and final islet transplant ]
  • Incidence and Severity of Adverse Events Related to the Islet Cell Transplant Procedure [ Time Frame: 75 days and 365 days following the first and final islet cell infusion ]
  • Incidence and Severity of Adverse Events Related to the Immunosuppression Therapy [ Time Frame: 75 days and 365 days following the first and final islet transplant ]
  • Incidence of a Change in the Immunosuppression Drug Regimen [ Time Frame: 75 days and 365 days following the first and final islet cell transplant ]
  • Incidence of Immune Sensitization [ Time Frame: 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) [ Time Frame: 365 day following the first and final islet transplant ]
    Derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test
Original Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2007)
  • Measured 75 days following the first islet cell infusion: Percent reduction in insulin requirements
  • HbA1c
  • Mean Amplitude of Glycemic Excursions (MAGE)
  • Glycemic liability index (LI)
  • Ryan Hypoglycemia Severity Score (HYPO)
  • basal (fasting) and 90-minute glucose and C-peptide derived from mixed meal tolerance test (MTT)
  • β-score
  • C-peptide: Glucose Creatinine Ratio
  • Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test
  • Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system (CGMS)
  • Quality of life
  • Incidence of Worsening Retinopathy
  • Measured 365 days following the first islet cell infusion: Proportion of insulin-independent subjects
  • Percent Reduction in Insulin Requirements
  • MAGE
  • LI
  • Clarke Score
  • HYPO Score
  • basal (fasting) and 90-minute glucose and C-peptide (MTT)
  • proportion of participants receiving a second islet cell infusion
  • Proportion of participants receiving a third islet cell infusion
  • Measured 75 and 365 days following the first islet cell infusion: Incidence and severity of adverse events related to the islet infusion procedure
  • Incidence and Severity of Adverse Events Related to the Immunosuppression Therapy
  • Incidence of a Change in the Immunosuppression Drug Regimen
  • Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Peritransplant Deoxyspergualin in Islet Transplantation in Type 1 Diabetes
Official Title  ICMJE Peritransplant Deoxyspergualin in Islet Transplantation in Type 1 Diabetes (CIT-03)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE
  • Biological: Allogeneic Pancreatic Islet Cells
    Preparation of allogeneic pancreatic islet cells injected into the portal vein of the liver
  • Drug: Deoxyspergualin
    An anti-inflammatory agent that blocks proinflammatory cytokine production and inhibits T-cells and B-cells and affects antigen presenting cells.
  • Biological: Antithymocyte globulin
    Immunosuppressive that selectively depletes activated T-cells and depletes resting T-cells in a dose-dependent manner.
  • Biological: Daclizumab or basiliximab
    Will replace antithymocyte globulin in all islet transplantations after the first one
  • Drug: Sirolimus
    Maintenance immunosuppressive therapy
  • Drug: Tacrolimus
    Maintenance immunosuppressive therapy
  • Biological: Etanercept
    Blocks TNF-alpha which is toxic to islet cells
Study Arms  ICMJE Experimental: 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.
Interventions:
  • Biological: Allogeneic Pancreatic Islet Cells
  • Drug: Deoxyspergualin
  • Biological: Antithymocyte globulin
  • Biological: Daclizumab or basiliximab
  • Drug: Sirolimus
  • Drug: Tacrolimus
  • Biological: Etanercept
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 6, 2011)
14
Original Enrollment  ICMJE
 (submitted: February 9, 2007)
20
Actual Study Completion Date  ICMJE November 2013
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00434850
Other Study ID Numbers  ICMJE DAIT CIT-03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators  ICMJE
Principal Investigator: Bernhard Hering, MD University of Minnesota - Clinical and Translational Science Institute
Principal Investigator: Xunrong Luo, MD, PhD Northwestern University
Principal Investigator: Andrew Posselt, MD, PhD University of California, San Francisco
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date February 2016

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