Islet Cell Transplants for Diabetes - Full Text View

Sponsored by:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00014911

Purpose

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.

Condition	Intervention	Phase
Diabetes Mellitus, Insulin-Dependent	Procedure: Islet cells infusion Drug: Sirolimus Drug: Tacrolimus Drug: Daclizumab Drug: Sulfamethoxazole Drug: Ganciclovir Drug: Trimethoprim Drug: Pentamidine	Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label, Single Group Assignment
Official Title:	Islet Transplantation for Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Type 1 Islet Cell Transplantation

Drug Information available for: Sirolimus Ganciclovir Pentamidine Tacrolimus anhydrous Ganciclovir sodium Tacrolimus Dacliximab Pentamidine isetionate Sulfamethoxazole Trimethoprim

U.S. FDA Resources

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

Primary Outcome Measures:

Insulin independence at one year post-transplant [ Time Frame: At 2 weeks, and 1, 3, 6 and 12 months following final transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Partial graft function [ Time Frame: At 2 weeks, and 1, 3, 6 and 12 months following final transplant, but more or fewer assessments are possible ] [ Designated as safety issue: No ]
Stimulated C-peptide greater than 0.5 mg/ml [ Time Frame: At 2 weeks, and 1, 3, 6 and 12 months following final transplant, but more or fewer assessments are possible ] [ Designated as safety issue: No ]
HbA1c less than 6.5% [ Time Frame: At 2 weeks, and 1, 3, 6 and 12 months following final transplant, but more or fewer assessments are possible ] [ Designated as safety issue: No ]
Absence of hypoglycemic coma/unawareness [ Time Frame: At 2 weeks, and 1, 3, 6 and 12 months following final transplant, but more or fewer assessments are possible ] [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	April 2001
Estimated Primary Completion Date:	June 2005 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Experimental All study participants	Procedure: Islet cells infusion A target total of greater than or equal to 10,000 IE (islet equivalent) per kilogram of the recipient's body weight will be infused into the portal vein with a precutaneous tranhepatic catheter. Up to three transplants are possible depending on individual results. Drug: Sirolimus Administered orally at a loading dose of 0.2 mg/kg daily, immediately pre-transplant and continued at a dose of 0.1 mg/kg daily each morning. Three months after the most recent transplant the dose will be changed to 12-15ng/mL. After three months following the last transplant the dose will again change to 7-10 ng/mL. Drug: Tacrolimus Administered orally at a dose of 1 mg, given immediately before transplantation, and continued at a dose of 1 mg twice daily. When possible the dose will be changed to 3-6ng/mL and will remain at this level for the remainder of the study. Drug: Daclizumab Administered at a dose of 1 mg/kg via peripheral IV and given immediately before transplantation.Additionally administered at weeks 2, 4, 6, and 8 following transplantation, totaling 5 doses (over 8 weeks). Further daclizumab dosing may be necessary based on individual results and transplantation needs. Drug: Sulfamethoxazole An antibacterial used to prevent opportunistic infections Drug: Ganciclovir An antiviral used to kill viruses and stop viral replication Drug: Trimethoprim An antibacterial used to prevent opportunistic infections Drug: Pentamidine An antiprotozoal used to prevent disease

Arms

Assigned Interventions

A: Experimental

All study participants

Procedure: Islet cells infusion

A target total of greater than or equal to 10,000 IE (islet equivalent) per kilogram of the recipient's body weight will be infused into the portal vein with a precutaneous tranhepatic catheter. Up to three transplants are possible depending on individual results.

Drug: Sirolimus

Administered orally at a loading dose of 0.2 mg/kg daily, immediately pre-transplant and continued at a dose of 0.1 mg/kg daily each morning. Three months after the most recent transplant the dose will be changed to 12-15ng/mL. After three months following the last transplant the dose will again change to 7-10 ng/mL.

Drug: Tacrolimus

Administered orally at a dose of 1 mg, given immediately before transplantation, and continued at a dose of 1 mg twice daily. When possible the dose will be changed to 3-6ng/mL and will remain at this level for the remainder of the study.

Drug: Daclizumab

Administered at a dose of 1 mg/kg via peripheral IV and given immediately before transplantation.Additionally administered at weeks 2, 4, 6, and 8 following transplantation, totaling 5 doses (over 8 weeks). Further daclizumab dosing may be necessary based on individual results and transplantation needs.

Drug: Sulfamethoxazole

An antibacterial used to prevent opportunistic infections

Drug: Ganciclovir

An antiviral used to kill viruses and stop viral replication

Drug: Trimethoprim

An antibacterial used to prevent opportunistic infections

Drug: Pentamidine

An antiprotozoal used to prevent disease

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 see 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 final transplant. Additional follow-up may be provided at least annually for up to 5 years.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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, hepatitis B, HIV, or TB (or under treatment for suspected TB).
Have a history of malignancy, except squamous or basal skin cancer.
Weigh more than 70 kg or have a BMI greater than 26 kg/m2 at time of screening.
Have a C-peptide value of 0.3 ng/ml or more following a 5.0 gram intravenous arginine infusion.
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-HLA antibody.
Have an insulin requirement of more that 0.7 IU/kg/day.
Have an 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).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00014911

Locations

United States, Illinois
Immune Tolerance Network
Chicago, Illinois, United States, 60637

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Principal Investigator:

James Shapiro

More Information

Publications:

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.

Responsible Party:	DAIT/NIAID ( Associate Director, Clinical Research Program )
Study ID Numbers:	DAIT NIS01
Study First Received:	April 13, 2001
Last Updated:	September 26, 2008
ClinicalTrials.gov Identifier:	NCT00014911 History of Changes
Health Authority:	United States: Federal Government

Study placed in the following topic categories:

Sirolimus
Anti-Infective Agents
Trimethoprim
Immunologic Factors
Folate
Diabetes Mellitus Type 1
Tacrolimus
Vitamin B9
Anti-Bacterial Agents
Antimalarials
Antifungal Agents
Pentamidine
Metabolic Disorder
Autoimmune Diseases
Metabolic Diseases

Sulfamethoxazole
Daclizumab
Diabetes Mellitus
Endocrine System Diseases
Ganciclovir
Anti-Infective Agents, Urinary
Folinic Acid
Folic Acid Antagonists
Antiviral Agents
Immunosuppressive Agents
Folic Acid
Diabetes Mellitus, Type 1
Endocrinopathy
Glucose Metabolism Disorders

Additional relevant MeSH terms:

Anti-Infective Agents
Trypanocidal Agents
Trimethoprim
Antiprotozoal Agents
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Tacrolimus
Renal Agents
Antimalarials
Antiparasitic Agents
Therapeutic Uses
Antifungal Agents
Pentamidine
Autoimmune Diseases

Metabolic Diseases
Sulfamethoxazole
Immune System Diseases
Daclizumab
Diabetes Mellitus
Endocrine System Diseases
Enzyme Inhibitors
Ganciclovir
Anti-Infective Agents, Urinary
Folic Acid Antagonists
Immunosuppressive Agents
Antiviral Agents
Pharmacologic Actions
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders

ClinicalTrials.gov processed this record on August 25, 2009