Clinical trial NCT00014911: Islet Transplantation for Type 1 Diabetes
Official title: Islet Transplantation for Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression (ITN005CT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Insulin-Dependent
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2001-08-31
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation.
timeFrame: One year status post participant receipt of final islet transplantation
Secondary outcomes:
measure: Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation.
timeFrame: One year post receipt of final islet transplantation
measure: Percent of Participants That Achieved Insulin Independence From First Transplant
timeFrame: First transplantation until end of study (up to six years post final transplantation)
measure: Percent of Participants With Detectable Fasting Basal C-Peptide Levels
timeFrame: Two years post first transplantation
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason Research Center
state: Washington
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Giessen
country: Germany
facility: Justus-Leibig University
city: Milan
country: Italy
facility: University of Milan
city: Geneva
country: Switzerland
facility: University of Geneva
Study officials:
affiliation: University of Alberta
name: James Shapiro, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.