Islet Transplantation for Type 1 Diabetes

NCT ID: NCT00014911

Last Updated: 2017-03-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2001-04-30
• Study Completion Date: 2010-08-31

Brief Summary

The purpose of this study is to test whether the islet cell transplantation procedures and results from a previous study in Edmonton, Canada, can be repeated. The study also is designed to learn more about diabetes control using islet cell transplantation.

This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression.

Detailed Description

This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression.

Eligible patients were randomly selected from the total pool of people who applied through the Immune Tolerance Network. Patients will receive at least 10,000 "islet equivalents" per kilogram (2.2 pounds) of body weight. This likely will require 2 separate islet infusions from 2 separate donors. Immediately before the first transplant, patients will be given anti-rejection (immune suppressing) drugs, including tacrolimus and sirolimus (orally) and daclizumab (intravenously). The islets will be infused into the liver through a tube placed in the portal vein. Heparin (a medication to prevent blood clots) will be administered with the islet infusion. A longer-acting form of heparin will also be given by daily injections during the next week after each transplant. After surgery, patients will receive insulin intravenously for 24 hours. Patients will have an abdominal ultrasound and blood tests to determine liver function. If fewer than 10,000 islets were transplanted, patients will continue insulin treatment, with the dosages adjusted if necessary to account for the transplanted islets. They will take daclizumab every 2 weeks for 8 weeks and tacrolimus and sirolimus daily. Patients will be given antibiotics to prevent infections. Blood tests to determine how much immunosuppressant drug is in the blood will be performed until the drug is at a stable level. Periodically there will be tests to see if the islet cells are functioning. Blood will be drawn to check drug levels and for other tests routinely. Daily insulin requirements will be checked, and these will be recorded monthly. Patients will be followed for at least 1 year post last islet transplantation. Additional follow-up may be provided at least annually for up to 9 years post first transplantation.

Conditions

Diabetes Mellitus, Insulin-Dependent

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Islet Transplantation

All study participants

Group Type: EXPERIMENTAL

Islet Transplantation

Intervention Type: PROCEDURE

Participants will receive portal vein islet infusions (up to 3), e.g., islet transplantations, with a targeted total of exceeding 10,000 islet equivalents per kilogram of body weight (IE/kg) per infusion. Up to three transplants are possible depending on individual results.

Sirolimus

Intervention Type: DRUG

Administered at a dose of 0.2 mg/kg by mouth once pre-transplantation then 0.1 mg/kg daily post-transplantation. Dosing will be adjusted to achieve a trough peripheral blood level of 12-15 ng/mL x3 months after transplantation and 7-12 ng/mL for the remainder of the study.

Tacrolimus

Intervention Type: DRUG

Administered at a dose of 1 mg by mouth once pre-transplantation followed by 1 mg twice daily post transplantation. Levels will be adjusted to achieve a peripheral blood trough level of 3-6 ng/mL for maintenance immunosuppression.

Daclizumab

Intervention Type: DRUG

Administered at a dose of 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation, totaling 5 doses(over 8 weeks). Further daclizumab dosing may be necessary based on individual results and islet transplantation needs.

Sulfamethoxazole

Intervention Type: DRUG

An antibacterial used to prevent opportunistic infections

Ganciclovir

Intervention Type: DRUG

An antiviral used to kill viruses and stop viral replication

Trimethoprim

Intervention Type: DRUG

An antibacterial used to prevent opportunistic infections

Pentamidine

Intervention Type: DRUG

An antiprotozoal used to prevent disease

Interventions

Islet Transplantation

Participants will receive portal vein islet infusions (up to 3), e.g., islet transplantations, with a targeted total of exceeding 10,000 islet equivalents per kilogram of body weight (IE/kg) per infusion. Up to three transplants are possible depending on individual results.

Intervention Type: PROCEDURE

Sirolimus

Administered at a dose of 0.2 mg/kg by mouth once pre-transplantation then 0.1 mg/kg daily post-transplantation. Dosing will be adjusted to achieve a trough peripheral blood level of 12-15 ng/mL x3 months after transplantation and 7-12 ng/mL for the remainder of the study.

Intervention Type: DRUG

Tacrolimus

Administered at a dose of 1 mg by mouth once pre-transplantation followed by 1 mg twice daily post transplantation. Levels will be adjusted to achieve a peripheral blood trough level of 3-6 ng/mL for maintenance immunosuppression.

Intervention Type: DRUG

Daclizumab

Administered at a dose of 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation, totaling 5 doses(over 8 weeks). Further daclizumab dosing may be necessary based on individual results and islet transplantation needs.

Intervention Type: DRUG

Sulfamethoxazole

An antibacterial used to prevent opportunistic infections

Intervention Type: DRUG

Ganciclovir

An antiviral used to kill viruses and stop viral replication

Intervention Type: DRUG

Trimethoprim

An antibacterial used to prevent opportunistic infections

Intervention Type: DRUG

Pentamidine

An antiprotozoal used to prevent disease

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Patients may be eligible for this study if they:

• Have had Type 1 diabetes mellitus for more than 5 years, and are exhibiting 1 of the following, despite intensive insulin management efforts: a) hypoglycemic unawareness, as defined by inability to sense hypoglycemia until the blood glucose falls to less than 54 mg/dL; b) metabolic instability, with 2 or more episodes of severe hypoglycemia (defined as an event with symptoms consistent with hypoglycemia in which the patient requires the assistance of another person and which is associated with a blood glucose below 54 mg/dL) or 2 or more hospital visits for diabetic ketoacidosis over the last year; or c) despite efforts at optimal glucose control, progressive secondary complications of diabetes as defined by retinopathy, nephropathy, or neuropathy.
• Are 18 to 65 years of age.

Exclusion Criteria

Patients will not be eligible for this study if they:

• Have had severe cardiac disease as defined by: a) recent myocardial infarction within the past 6 months; b) angiographic evidence of non-correctable coronary artery disease; or c) evidence of ischemia on a functional cardiac exam.
• Actively abuse alcohol or substances, including cigarette smoking (must not have smoked within the last 6 months).
• Have psychiatric problems that prevent them from being a suitable candidate for transplantation (such as schizophrenia, bipolar disorder, or major depression that is not controlled or stable on current medication).
• Have a history of not following prescribed regimens.
• Have active infection including hepatitis C virus, hepatitis B virus, human immunodeficiency virus (HIV), or Tuberculosis (TB) (or under treatment for suspected TB).
• Have a history of malignancy, except squamous or basal skin cancer.
• Weigh more than 70 kilograms or have a Body Mass Index (BMI) greater than 26 kg/m^2 at time of screening.
• Have a C-peptide value of 0.3 ng/ml or more following a 5.0 gram intravenous arginine infusion challenge.
• Are unable to provide informed consent.
• Have gallstones or hemangioma in liver.
• Have untreated proliferative retinopathy.
• Are breast-feeding or pregnant, or intend to try and become pregnant (females) or to father a child (males), or fail to follow birth control methods.
• Have had a previous transplant, or evidence of anti-human leukocyte antigen (HLA) antibody.
• Have an insulin requirement of more that 0.7 International Units (IU)/kilograms/day.
• Have a blood glycosylated hemoglobin (HbA1c) higher than 12 percent.
• Are unable to reach the hospital for transplantation within 2 hours of notification.
• Have untreated or treated hyperlipidemia.
• Have a medical condition requiring chronic use of steroids.
• Use coumadin or other anticoagulants (aspirin is allowed).
• Have Addison's disease.
• Have a negative screen for Epstein-Barr virus (EBV).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Immune Tolerance Network (ITN)

NETWORK

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

James Shapiro, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Alberta

Locations

University of Miami

Miami, Florida, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Washington University

St Louis, Missouri, United States

Benaroya Research Institute at Virginia Mason Research Center

Seattle, Washington, United States

University of Alberta

Edmonton, Alberta, Canada

Justus-Leibig University

Giessen, , Germany

University of Milan

Milan, , Italy

University of Geneva

Geneva, , Switzerland

Countries

United States; Canada; Germany; Italy; Switzerland

References

Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone J, Lakey JR. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006 Sep 28;355(13):1318-30. doi: 10.1056/NEJMoa061267.

Reference Type: RESULT

PMID: 17005949 (View on PubMed)

Brennan DC, Shannon MB, Koch MJ, Polonsky KS, Desai N, Shapiro J. Portal vein thrombosis complicating islet transplantation in a recipient with the Factor V Leiden mutation. Transplantation. 2004 Jul 15;78(1):172-3. doi: 10.1097/01.tp.0000128332.71657.ea. No abstract available.

Reference Type: RESULT

PMID: 15257060 (View on PubMed)

Benedini S, Ermetici F, Briganti S, Codella R, Terruzzi I, Maffi P, Caldara R, Secchi A, Nano R, Piemonti L, Alejandro R, Ricordi C, Luzi L. Insulin-mimetic effects of short-term rapamycin in type 1 diabetic patients prior to islet transplantation. Acta Diabetol. 2018 Jul;55(7):715-722. doi: 10.1007/s00592-018-1141-z. Epub 2018 Apr 13.

Reference Type: DERIVED

PMID: 29654388 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23438305 (View on PubMed)

Study Documents

Document Type: Individual Participant Data Set

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Document Type: Study overview & protocol synopsis, -navigator, -schedule of assessments, -data&reports, -specimens, etc.

TrialShare is a clinical trials research portal developed by the Immune Tolerance Network (ITN) that makes data from the consortium's clinical trials publicly available without charge.

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Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID) website

https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT) website

http://www.immunetolerance.org

Immune Tolerance Network (ITN) website

Other Identifiers

DAIT ITN005CT (DAIT NIS01)

Identifier Type: -

Identifier Source: org_study_id