Safety and Effectiveness of Low Molecular Weight Sulfated Dextran in Islet Transplantation

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00789308
First received: November 10, 2008
Last updated: August 29, 2013
Last verified: August 2013
  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 assess the safety and effectiveness of low molecular weight sulfated dextran (LMW-SD) on post-transplant islet function in people with type 1 diabetes who have responded to intensive insulin therapy.


Condition Intervention Phase
Diabetes Mellitus, Type I
Drug: Low Molecular Weight Sulfated Dextran (LMW-SD)
Drug: Heparin
Drug: CellCept® (Mycophenolate mofetil) OR Rapamune® (Sirolimus)
Drug: Prograf® (Tacrolimus) OR Cyclosporine
Drug: Thymoglobulin® (Anti-thymocyte Globulin) - at first transplant
Drug: Simulect® (Basiliximab) - at 2nd or 3rd transplant
Drug: Klexane® (Enoxaparinsodium)
Drug: Trombyl® or Albyl-E® (Acetylsalicylicacid- ASA)
Drug: Enbrel® (Etanercept)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open Randomized Mult-Center Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Level of stimulated c-peptide at 90-minute derived from the mixed-meal tolerance test (MMTT) [ Time Frame: At 70 to 80 days after first islet transfusion ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of participants who achieve and maintain a 7.0% HbA1c level [ Time Frame: Throughout Study ] [ Designated as safety issue: No ]
  • Number of severe hypoglycemic events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  • Percent reduction in insulin requirements [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Ryan hypoglycemia severity score ( HYPO) score [ Time Frame: : At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Proportion of participants with full graft function [ Time Frame: At 70 to 80 days after first islet transfusion and after the final islet infusion ] [ Designated as safety issue: No ]
  • C-peptide to glucose creatinine ratio [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Proportion of participants receiving a second islet infusion and proportion of participants receiving a third islet transfusion [ Time Frame: At 70 to 80 days after first islet transfusion and after the final islet infusion ] [ Designated as safety issue: No ]
  • Incidence and severity of adverse events related to islet infusion procedure [ Time Frame: At 70 to 80 days and 350 to 379 days after the first islet transfusion ] [ Designated as safety issue: Yes ]
  • Incidence of worsening retinopathy [ Time Frame: At 350 to 379 days after the first islet transfusion ] [ Designated as safety issue: Yes ]
  • HbA1c level [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Mean amplitude of glycemic excursions (MAGE) [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Glycemic lability index (LI) [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Clarke hypoglycemia awareness score [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Basal (fasting) and 90-minute glucose and c-peptide derived from MMTT [ Time Frame: : At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Beta-score [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ 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: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Glucose variability and hypoglycemic duration derived from continuous glucose monitoring system(CGMS) [ Time Frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion ] [ Designated as safety issue: No ]
  • Incidence of a change in the immunosuppression drug regimen [ Time Frame: At 70 to 80 days and 350 to 379 days after the first islet transfusion ] [ Designated as safety issue: Yes ]
  • Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation [ Time Frame: At 70 to 80 days and 350 to 379 days after the first islet transfusion ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 36
Study Start Date: July 2008
Estimated Study Completion Date: August 2014
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard of Care
18 participants randomized to protocol immunosuppression (Daclizumab OR Basiliximab; Tacrolimus OR Cyclosporine; Mycophenolate Mofetil OR Sirolimus; and heparin) without LMW-DS
Drug: Heparin
Anticoagulation
Drug: CellCept® (Mycophenolate mofetil) OR Rapamune® (Sirolimus)
Cell proliferation inhibitor
Drug: Prograf® (Tacrolimus) OR Cyclosporine
Calcineurin inhibitor
Drug: Thymoglobulin® (Anti-thymocyte Globulin) - at first transplant Drug: Simulect® (Basiliximab) - at 2nd or 3rd transplant
Monoclonal IL-2 receptor blocker
Drug: Klexane® (Enoxaparinsodium)
Anticoagulation Prophylaxis
Drug: Trombyl® or Albyl-E® (Acetylsalicylicacid- ASA)
Anticoagulation Prophylaxis
Drug: Enbrel® (Etanercept)
Anti-Inflammatory Therapy
Experimental: LMW-DS
18 participants randomized to protocol immunosuppression (Daclizumab OR Basiliximab; Tacrolimus OR Cyclosporine; Mycophenolate Mofetil OR Sirolimus; and heparin) and LMW-DS
Drug: Low Molecular Weight Sulfated Dextran (LMW-SD)
Inhibitor of IBMIR
Drug: CellCept® (Mycophenolate mofetil) OR Rapamune® (Sirolimus)
Cell proliferation inhibitor
Drug: Prograf® (Tacrolimus) OR Cyclosporine
Calcineurin inhibitor
Drug: Thymoglobulin® (Anti-thymocyte Globulin) - at first transplant Drug: Simulect® (Basiliximab) - at 2nd or 3rd transplant
Monoclonal IL-2 receptor blocker
Drug: Klexane® (Enoxaparinsodium)
Anticoagulation Prophylaxis
Drug: Trombyl® or Albyl-E® (Acetylsalicylicacid- ASA)
Anticoagulation Prophylaxis
Drug: Enbrel® (Etanercept)
Anti-Inflammatory Therapy

Detailed Description:

Type I 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, or low blood sugar, and hyperglycemia, or 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, can make the treatment ineffective. An immune response known as instant blood-mediated inflammatory reaction (IBMIR) results in the disruption of islet integrity and islet loss within an hour of transfusion. LMW-SD inhibits IBMIR by preventing the cascade that triggers it, when combined with pancreatic islets. The purpose of this study is to determine the safety and efficacy of LMW-SD given with islet transfusion and post-transfusion along with immunosuppressive therapy, including mycophenolate mofetil or sirolimus, tacrolimus or cyclosporine, and thymoglobulin or basiliximab, on the success of islet transplantation in people with type 1 diabetes.

This study will last for 1 year after the final islet transplant. Participants may receive up to 3 islet transplants while participating in this study. Participants eligible for this study will have clinic visits every 6 months. Once a preparation of islets becomes available, participants will be randomly assigned to Arm 1 or Arm 2. Participants in Arm 1 will receive LMW-DS during and for 5 hours after infusion. Participants in Arm 2 will receive heparin at the time of infusion. In addition, all participants will receive anticoagulation prophylaxis agents consisting of Klexzane® (Enoxaparinsodium) and Trombyl® or Albyl-E® (Acetylsalicylic acid). All participants will also receive the oral immunosuppression medications consisting of mycophenolate mofetil or sirolimus and tacrolimus or cyclosporine throughout the study. In addition, they will receive intravenous thymoglobulin on days -2, -1, day 0 (transplant), +1, and +2 for the first transplant or intravenous basiliximab at the time of transplant and on Day 4 for the second and third transplant. Enbrel® (Etanercept) will be given to all participants for anti-inflammatory therapy. Islet infusions will occur at the hospital and will be given intravenously. Participants will be eligible to receive second and third islet infusions if previous infusions fail and they continue to meet the eligibility criteria. After each infusion, study visits will occur on Days 1, 3, 7, 14, 21, 28, and 75 and Months 6 and 12. At these visits, physical exams and blood collection will occur. At some visits, urine collection will also occur.

  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 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
  • At least one episode of severe hypoglycemia in the past 12 months, defined as an event with symptoms compatible with hypoglycemia in which the individual required assistance of another person 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
  • Reduced awareness of hypoglycemia OR marked glycemic lability OR a composite of a Clarke score of 3 or more or a HYPO score greater or equal to the 75th percentile in the 12 months prior to randomization. More information about this criterion, including the specific definition of hypoglycemia unawareness, is available in the protocol.

Exclusion Criteria:

  • Known IgE mediated allergy to antibiotics used in the culture medium
  • Known hypersensitivity to dextran
  • Body mass index (BMI) greater than 30 kg/m2
  • Insulin requirement of more than 1.0 IU/kg/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 (GFR) using 51Cr-EDTA, 99technetium-DPTA, or 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 20% 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
  • 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
  • Activated protein C resistance (APC-R)
  • Any coagulopathy 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
  • Acute or chronic pancreatitis
  • Active peptic ulcer disease, symptomatic gallstones, or a history of portal hypertension
  • Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with the ability to absorb oral medications
  • Currently receiving treatment for a medical condition that requires chronic use of systemic steroids
  • Treatment with any antidiabetic medication other than insulin within 4 weeks prior to study entry
  • Use of any investigational medications within the past 4 weeks
  • Received a live attenuated vaccine within the past 2 months
  • Treatment with any immunosuppressive regimen at time of study entry
  • Previous islet transplant
  • Previous pancreas transplant. Participants who had a pancreas transplant more than 6 months prior to study entry that failed within the first week due to thrombosis, followed by surgical removal of the transplanted pancreas, are not excluded.
  • Any medical condition that, in the opinion of the investigator, might interfere with safe participation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00789308

Locations
Norway
University Hospital Rikshospitalet
Oslo, Norway
Sweden
Karolinska University Hospital
Stockholm, Sweden
Uppsala University Hospital
Uppsala, Sweden
Sponsors and Collaborators
Investigators
Principal Investigator: Olle Korsgren, MD Department of Oncology, Radiology, and Clinical Immunology, Rudbeck Laboratory, Uppsala University Hospital
Study Chair: Torbjorn Lundgren, MD The Karolinska University Hospital, Department of Transplantation Surgery, Stockholm, Sweden
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00789308     History of Changes
Other Study ID Numbers: DAIT CIT-01A, Clinical Islet Transplantation
Study First Received: November 10, 2008
Last Updated: August 29, 2013
Health Authority: United States: Federal Government

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

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Antilymphocyte Serum
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Sirolimus
Everolimus
Tacrolimus
TNFR-Fc fusion protein
Basiliximab
Mycophenolic Acid
Dextrans
Heparin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on July 28, 2014