Islet Transplantation in Type 1 Diabetes

NCT ID: NCT00434811

Last Updated: 2019-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-10-31
• Study Completion Date: 2014-05-31

Brief 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 determine the safety and effectiveness of islet transplantation, combined with immunosuppressive medications, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes.

Detailed Description

Type 1 diabetes is commonly treated with the administration of insulin, either by multiple insulin injections or by a continuous supply of insulin through a wearable pump. Insulin therapy allows long-term survival in individuals with type 1 diabetes; however, it does not guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic survivors often develop vascular complications, such as diabetic retinopathy, an eye disease that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that can lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia unawareness, a life-threatening condition that is not easily treatable with medication and is characterized by reduced or absent warning signals for hypoglycemia. For such individuals, transplantation of pancreatic islets is a possible treatment option. Unfortunately, insulin independence among islet transplant recipients tends to decline over time. New strategies aimed at promoting engraftment of transplanted islets are needed to improve the clinical outcomes associated with this procedure. The purpose of this study is determine the safety and efficacy of islet transplantation, when combined with an immunosuppressive medication regimen, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes. This study will also seek to improve the understanding of determinants of success and failure of islet transplants for type 1 diabetes.

Eligible participants will be randomly assigned to this study or a site-specific Phase 2 islet transplantation study. Participants in this study will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus.

Transplantations will involve an inpatient hospital stay and infusion of islets into a branch of the portal vein. Participants who do not achieve or maintain insulin independence by Day 75 post-transplant will be considered for a second islet transplant. Participants who remain dependent on insulin for longer than 1 month after the second transplant and who show partial graft function will be considered for a third islet transplant. Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary. Participants who do not meet the criteria for a subsequent transplant and do not have a functioning graft will enter a reduced follow-up period.

There will be up to 19 study visits following each transplant. A physical exam, review of adverse events, and blood collection will occur at most visits. A chest x-ray, abdominal ultrasound, electrocardiogram, quality of life questionnaires, urine collection, and glomerular filtrating rate (GFR) testing will occur at some visits. Participants will also test their own blood glucose levels at least five times per day throughout the study. A 24-month follow-up period will take place after the participant's last transplant.

Conditions

Type 1 Diabetes Mellitus

Study Design

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

Study Groups

Islet Transplantation

Participants will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus.

Group Type: EXPERIMENTAL

Allogeneic Pancreatic Islet Cells

Intervention Type: BIOLOGICAL

200 ml suspension of allogenic human purified islets

Antithymocyte Globulin

Intervention Type: BIOLOGICAL

Participants will begin receiving ATG 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant.

Sirolimus

Intervention Type: DRUG

Participants will begin receiving sirolimus 2 days prior to the first islet transplant and will be given for the duration of the study.

Tacrolimus

Intervention Type: DRUG

On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study.

Etanercept

Intervention Type: BIOLOGICAL

Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.

Islet Transplantation

Intervention Type: PROCEDURE

Transplantation of pancreatic islet cell

Basiliximab

Intervention Type: BIOLOGICAL

Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary.

Interventions

Allogeneic Pancreatic Islet Cells

200 ml suspension of allogenic human purified islets

Intervention Type: BIOLOGICAL

Antithymocyte Globulin

Participants will begin receiving ATG 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant.

Intervention Type: BIOLOGICAL

Sirolimus

Participants will begin receiving sirolimus 2 days prior to the first islet transplant and will be given for the duration of the study.

Intervention Type: DRUG

Tacrolimus

On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study.

Intervention Type: DRUG

Etanercept

Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.

Intervention Type: BIOLOGICAL

Islet Transplantation

Transplantation of pancreatic islet cell

Intervention Type: PROCEDURE

Basiliximab

Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary.

Intervention Type: BIOLOGICAL

Other Intervention Names

Rapamycin; FK-506; Fujimycin; chimeric mouse-human antiCD25; Ig gamma-1 chain C region

Eligibility Criteria

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 a 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:

1. Self-monitoring of glucose values no less than a mean of three times each day averaged over each week

2. Administration of three or more insulin injections each day or insulin pump therapy

3. Under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least three clinical evaluations during the past 12 months prior to study enrollment

• At least one episode of severe hypoglycemia in the past 12 months, defined as an event with one of the following symptoms: memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, compatible with hypoglycemia in which the individual required assistance of another subject was unable to treat him/herself person and which was associated with either a blood glucose level less than 54 mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration in the 12 months prior to study enrollment
• Reduced awareness of hypoglycemia. More information about this criterion, including specific definition of hypoglycemia unawareness, is in the protocol.

Exclusion Criteria

• Body mass index (BMI) greater than 30 kg/m2 or weight less than or equal to 50 kg
• Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/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 using iohexol of less than 80 ml/min/1.73mm2. More information about this criterion is in the protocol.
• Presence or history of macroalbuminuria (greater than 300 mg/g creatinine)
• Presence or history of panel-reactive anti-HLA antibody levels greater than background by flow cytometry. More information about this criterion is in the protocol.
• Pregnant, breastfeeding, or unwilling to use effective contraception throughout the study and 4 months after study completion
• Presence or history of active infection, including hepatitis B, hepatitis C, HIV, or tuberculosis.
• Negative for Epstein-Barr virus by IgG determination
• Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection in the past year
• History of malignancy except for 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
• History of Factor V deficiency
• Any coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or individuals with an INR greater than 1.5
• Severe coexisting cardiac disease, characterized by any one of the following conditions:

1. Heart attack within the last 6 months

2. Evidence of ischemia on functional heart exam within the year prior to study entry

3. Left ventricular ejection fraction less than 30%

• Persistent elevation of liver function tests at the time of study entry
• Symptomatic cholecystolithiasis
• Acute or chronic pancreatitis
• Symptomatic peptic ulcer disease
• Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with the ability to absorb oral medications
• Hyperlipidemia despite medical therapy, defined as fasting LDL cholesterol greater than 130 mg/dl (treated or untreated) and/or fasting triglycerides greater than 200 mg/dl
• Currently receiving treatment for a medical condition that requires chronic use of systemic steroids except for the use of 5 mg or less of prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only
• Treatment with any antidiabetic medication other than insulin within the past 4 weeks
• Use of any study medications within the past 4 weeks
• Received a live attenuated vaccine(s) within the past 2 months
• Any medical condition that, in the opinion of the investigator, might interfere with safe participation in the trial

• Treatment with any immunosuppressive regimen at the time of enrollment.
• A previous islet transplant.
• A previous pancreas transplant, unless the graft failed within the first week due to thrombosis, followed by pancreatectomy and the transplant occurred more than 6 months prior to enrollment.

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

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bernhard Hering, MD

Role: STUDY_CHAIR

University of Minnesota

Olle Korsgren, PhD

Role: STUDY_CHAIR

Uppsala University Hospital

Ali Naji, PhD

Role: STUDY_CHAIR

University of Pennsylvania

Camillo Ricordi, MD

Role: STUDY_CHAIR

University of Miami

James Shapiro, MD, PhD

Role: STUDY_CHAIR

University of Alberta

Andrew Posselt, MD, PhD

Role: STUDY_CHAIR

University of California, San Francisco

Nicole Turgeon, MD

Role: STUDY_CHAIR

Emory University

Xunrong Luo, MD, PhD

Role: STUDY_CHAIR

Northwestern Univerity

Locations

University of Callifornia, San Francisco

San Francisco, California, United States

University of Miami

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

University of Illinois, Chicago

Chicago, Illinois, United States

University of Minnesota

Minneapolis, Minnesota, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Alberta

Edmonton, Alberta, Canada

Countries

United States; Canada

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: BACKGROUND

PMID: 17005949 (View on PubMed)

Harlan DM. Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor. Diabetes Care. 2016 Jul;39(7):1072-4. doi: 10.2337/dci16-0008. No abstract available.

Reference Type: BACKGROUND

PMID: 27330121 (View on PubMed)

Rickels MR, Liu C, Shlansky-Goldberg RD, Soleimanpour SA, Vivek K, Kamoun M, Min Z, Markmann E, Palangian M, Dalton-Bakes C, Fuller C, Chiou AJ, Barker CF, Luning Prak ET, Naji A. Improvement in beta-cell secretory capacity after human islet transplantation according to the CIT07 protocol. Diabetes. 2013 Aug;62(8):2890-7. doi: 10.2337/db12-1802. Epub 2013 Apr 29.

Reference Type: RESULT

PMID: 23630300 (View on PubMed)

Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, Kaufman DB, Korsgren O, Larsen CP, Luo X, Markmann JF, Naji A, Oberholzer J, Posselt AM, Rickels MR, Ricordi C, Robien MA, Senior PA, Shapiro AM, Stock PG, Turgeon NA; Clinical Islet Transplantation Consortium. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. 2016 Jul;39(7):1230-40. doi: 10.2337/dc15-1988. Epub 2016 Apr 18.

Reference Type: RESULT

PMID: 27208344 (View on PubMed)

Ricordi C, Goldstein JS, Balamurugan AN, Szot GL, Kin T, Liu C, Czarniecki CW, Barbaro B, Bridges ND, Cano J, Clarke WR, Eggerman TL, Hunsicker LG, Kaufman DB, Khan A, Lafontant DE, Linetsky E, Luo X, Markmann JF, Naji A, Korsgren O, Oberholzer J, Turgeon NA, Brandhorst D, Chen X, Friberg AS, Lei J, Wang LJ, Wilhelm JJ, Willits J, Zhang X, Hering BJ, Posselt AM, Stock PG, Shapiro AM, Chen X. National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. Diabetes. 2016 Nov;65(11):3418-3428. doi: 10.2337/db16-0234. Epub 2016 Jul 27.

Reference Type: RESULT

PMID: 27465220 (View on PubMed)

Foster ED, Bridges ND, Feurer ID, Eggerman TL, Hunsicker LG, Alejandro R; Clinical Islet Transplantation Consortium. Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. 2018 May;41(5):1001-1008. doi: 10.2337/dc17-1779. Epub 2018 Mar 21.

Reference Type: DERIVED

PMID: 29563196 (View on PubMed)

Senior PA, Bellin MD, Alejandro R, Yankey JW, Clarke WR, Qidwai JC, Schwieger TR, Eggerman TL, Robien MA, Rickels MR; Clinical Islet Transplantation Consortium. Consistency of quantitative scores of hypoglycemia severity and glycemic lability and comparison with continuous glucose monitoring system measures in long-standing type 1 diabetes. Diabetes Technol Ther. 2015 Apr;17(4):235-42. doi: 10.1089/dia.2014.0289. Epub 2015 Jan 28.

Reference Type: DERIVED

PMID: 25629445 (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: Study Protocol

ImmPort study ID is SDY1178.

View Document

Document Type: Complete set of descriptive data and results

ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts. This archive is in support of the NIH mission to share data with the public.

View Document

Related Links

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

National Institute of Allergy and Infectious Diseases (NIAID)

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

Division of Allergy, Immunology, and Transplantation (DAIT)

Other Identifiers

DAIT CIT-07

Identifier Type: -

Identifier Source: org_study_id