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

Open Randomized Mult-Center Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation (CIT-01)

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type I
• Intervention / Treatment: 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); Drug: Low Molecular Weight Sulfated Dextran (LMW-SD)

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway
    • University Hospital Rikshospitalet
• Sweden
  • Stockholm, Sweden
    • Karolinska University Hospital
  • Uppsala, Sweden
    • Uppsala University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  • Self-monitoring of glucose values no less than a mean of three times each day, averaged over each week,
  • Administration of three or more insulin injections each day or insulin pump therapy,
  • 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; and
• 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.

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/m^2;
• 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/1.73m^2;
• 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;
• 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;
• Negative for Epstein-Barr virus by IgG determination;
• History of malignancy with exception of 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:

  • Heart attack within the last 6 months,
  • Evidence of ischemia on functional heart exam within the year prior to study entry, or
  • 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.

  --Note: 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.

• Or any medical condition that, in the opinion of the investigator, might interfere with safe participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: 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; Drug: Low Molecular Weight Sulfated Dextran (LMW-SD); Inhibitor of IBMIR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Level of stimulated c-peptide at 90-minute derived from the mixed-meal tolerance test (MMTT)	At 70 to 80 days after first islet transfusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants who achieve and maintain a 7.0% HbA1c level	Throughout Study
Number of severe hypoglycemic events	Throughout study
Percent reduction in insulin requirements	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Ryan hypoglycemia severity score ( HYPO) score	: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Proportion of participants with full graft function	At 70 to 80 days after first islet transfusion and after the final islet infusion
C-peptide to glucose creatinine ratio	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Proportion of participants receiving a second islet infusion and proportion of participants receiving a third islet transfusion	At 70 to 80 days after first islet transfusion and after the final islet infusion
Incidence and severity of adverse events related to islet infusion procedure	At 70 to 80 days and 350 to 379 days after the first islet transfusion
Incidence of worsening retinopathy	At 350 to 379 days after the first islet transfusion
HbA1c level	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Mean amplitude of glycemic excursions (MAGE)	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Glycemic lability index (LI)	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Clarke hypoglycemia awareness score	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Basal (fasting) and 90-minute glucose and c-peptide derived from MMTT	: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Beta-score	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance (FSIGT) test,	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Glucose variability and hypoglycemic duration derived from continuous glucose monitoring system(CGMS)	At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion
Incidence of a change in the immunosuppression drug regimen	At 70 to 80 days and 350 to 379 days after the first islet transfusion
Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation	At 70 to 80 days and 350 to 379 days after the first islet transfusion

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Clinical Islet Transplantation Consortium
• Investigators: Study Chair: Torbjörn Lundgren, MD, Karolinska University Hospital; Principal Investigator: Olle Korsgren, MD, Uppsala University Hospital, Sweden

Publications and helpful links

General Publications

• von Zur-Muhlen B, Lundgren T, Bayman L, Berne C, Bridges N, Eggerman T, Foss A, Goldstein J, Jenssen T, Jorns C, Morrison Y, Ryden M, Schwieger T, Tufveson G, Nilsson B, Korsgren O. Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation. Transplantation. 2019 Mar;103(3):630-637. doi: 10.1097/TP.0000000000002425.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Clinical Islet Transplantation Consortium website

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2008
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): August 21, 2014

Study Registration Dates

• First Submitted: November 10, 2008
• First Submitted That Met QC Criteria: November 10, 2008
• First Posted (Estimate): November 11, 2008

Study Record Updates

• Last Update Posted (Actual): September 28, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Insulin dependence
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Anticoagulants; Antitubercular Agents; Antibiotics, Antitubercular; Plasma Substitutes; Blood Substitutes; Calcineurin Inhibitors; Etanercept; Heparin; Tacrolimus; Mycophenolic Acid; Sirolimus; Basiliximab; Dextrans; Thymoglobulin; Antilymphocyte Serum; Cyclosporine; Cyclosporins
• Other Study ID Numbers: DAIT CIT-01; CIT-01 (Other Identifier: Clinical Islet Transplantation Consortium); 2008-001210-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: Accession ID: SDY1437
   Information comments: Digital object identifier (DOI): 10.21430/M3YZY4PXCS. Location of data: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
2. Study Protocol
   Information identifier: Accession ID: SDY1437
   Information comments: Digital object identifier (DOI): 10.21430/M3YZY4PXCS. Location of data: Immunology Database and Analysis Portal (ImmPort).
3. Statistical Analysis Plan
   Information identifier: Accession ID: SDY1437
   Information comments: Digital object identifier (DOI): 10.21430/M3YZY4PXCS. Location of data: Immunology Database and Analysis Portal (ImmPort).
4. Informed Consent Form
   Information identifier: Accession ID: SDY1437
   Information comments: Digital object identifier (DOI): 10.21430/M3YZY4PXCS. Location of data: Immunology Database and Analysis Portal (ImmPort).