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CompletedNCT00789308Updated Sep 28, 2021

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

A Phase 2 interventional study of Low Molecular Weight Sulfated Dextran (LMW-SD) and Heparin in Diabetes Mellitus, Type I, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 3 sites in 2 countries. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2021-09-28.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 2, Interventional, and Treatment

From the registry’s dates

  • Registered 3 months after the study started (first participant enrolled Jul 2008, registered Nov 2008).
Phase
Phase 2
Study type
Interventional
Enrollment
24
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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 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.

Read the 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.

02

Conditions studied

  • Diabetes Mellitus, Type I

Keywords

  • Insulin dependence
03

In context

Diabetes Mellitus, Type 1

3,522 studies on the registry are indexed under Diabetes Mellitus, Type 1; 577 are open to participants now.

This study's enrollment of 24 is below the median of 40 across 2,649 interventional studies indexed under Diabetes Mellitus, Type 1.

Browse Diabetes Mellitus, Type 1 studies →

Lead sponsor

National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,401 studies on the registry; 179 are open to participants now.

Of its 396 completed or terminated interventional studies of FDA-regulated products, 294 (74%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
24 participants (actual)

Study arms

  • 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 · 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)

  • 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) · 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)

Interventions

  • DrugLow Molecular Weight Sulfated Dextran (LMW-SD)

    Inhibitor of IBMIR

  • DrugHeparin

    Anticoagulation

  • DrugCellCept® (Mycophenolate mofetil) OR Rapamune® (Sirolimus)

    Cell proliferation inhibitor

  • DrugPrograf® (Tacrolimus) OR Cyclosporine

    Calcineurin inhibitor

  • DrugThymoglobulin® (Anti-thymocyte Globulin) - at first transplant
  • DrugSimulect® (Basiliximab) - at 2nd or 3rd transplant

    Monoclonal IL-2 receptor blocker

  • DrugKlexane® (Enoxaparinsodium)

    Anticoagulation Prophylaxis

  • DrugTrombyl® or Albyl-E® (Acetylsalicylicacid- ASA)

    Anticoagulation Prophylaxis

  • DrugEnbrel® (Etanercept)

    Anti-Inflammatory Therapy

06

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. Number of participants who achieve and maintain a 7.0% HbA1c level

    Time frame: Throughout Study

  2. Number of severe hypoglycemic events

    Time frame: Throughout study

  3. 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

  4. 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

  5. Proportion of participants with full graft function

    Time frame: At 70 to 80 days after first islet transfusion and after the final islet infusion

  6. 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

  7. 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

  8. 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

  9. Incidence of worsening retinopathy

    Time frame: At 350 to 379 days after the first islet transfusion

  10. HbA1c level

    Time frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion

  11. 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

  12. Glycemic lability index (LI)

    Time frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion

  13. Clarke hypoglycemia awareness score

    Time frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion

  14. 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

  15. Beta-score

    Time frame: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion

  16. 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

  17. 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

  18. 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

  19. 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

07

Study locations

3 sites
  • University Hospital Rikshospitalet
    Oslo, Norway
  • Karolinska University Hospital
    Stockholm, Sweden
  • Uppsala University Hospital
    Uppsala, Sweden
08

References and documents

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. PubMed 30211831 ↗

Individual participant data

Plan to share: Yes — 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.

Supporting information: Study protocol, Sap, Icf

09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 28, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT00789308
Lead sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Clinical Islet Transplantation Consortium
Responsible party
Sponsor
First posted
Nov 11, 2008
Start date
Jul 11, 2008
Primary completion
Jul 2013
Completion
Aug 21, 2014
Last update
Sep 28, 2021

Study contacts

Olle Korsgren, MD
principal investigator · Uppsala University Hospital, Sweden
Torbjörn Lundgren, MD
study chair · Karolinska University Hospital

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Sep 2021. You cannot join it, but the record below documents what was studied.

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