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CompletedNCT00434811Updated Jul 17, 2019

Islet Transplantation in Type 1 Diabetes

A Phase 3 interventional study of Allogeneic Pancreatic Islet Cells and Antithymocyte Globulin in Type 1 Diabetes Mellitus, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 8 sites in 2 countries. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2019-07-17.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 3, Interventional, and Treatment

From the registry’s dates

  • Primary completion was Sep 2012, 14 years 1 month ago, and no results have been posted to the registry; the sponsor requested a delay in submitting them in Nov 2011.
Phase
Phase 3
Study type
Interventional
Enrollment
48
Allocation
Not applicable
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 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.

Read the 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.

02

Conditions studied

  • Type 1 Diabetes Mellitus

Keywords

  • Insulin dependence
  • Hypoglycemia
  • Hypoglycemia unawareness
03

In context

Diabetes Mellitus

10,925 studies on the registry are indexed under Diabetes Mellitus; 1,318 are open to participants now.

This study's enrollment of 48 is below the median of 80 across 8,367 interventional studies indexed under Diabetes Mellitus.

Browse Diabetes Mellitus 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 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

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.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
48 participants (actual)

Study arms

  • Experimental
    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.

    Biological: Allogeneic Pancreatic Islet Cells · Biological: Antithymocyte Globulin · Drug: Sirolimus · Drug: Tacrolimus · Biological: Etanercept · Procedure: Islet Transplantation · Biological: Basiliximab

Interventions

  • BiologicalAllogeneic Pancreatic Islet Cells

    200 ml suspension of allogenic human purified islets

  • BiologicalAntithymocyte 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.

  • DrugSirolimus

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

    Also known as: Rapamycin

  • DrugTacrolimus

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

    Also known as: FK-506, Fujimycin

  • BiologicalEtanercept

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

  • ProcedureIslet Transplantation

    Transplantation of pancreatic islet cell

  • BiologicalBasiliximab

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

    Also known as: chimeric mouse-human antiCD25, Ig gamma-1 chain C region

06

What researchers measure

Primary outcomes

  1. Proportion of participants with a HbA1c less than 7.0% AND free of severe hypoglycemic events

    The proportion of participants with HbA1c ≤7.0% AND free of severe hypoglycemic events from Day 28 to Day 365 inclusive, following the first islet transplant, with the day of transplant designated Day 0.

    Time frame: From Day 28 to Day 365 (inclusive) following the first islet transplant, with the day of transplant designated Day 0

Secondary outcomes

  1. Percent reduction in insulin requirements

    Time frame: 75 days following the first and subsequent islet transplant

  2. HbA1c on Day 75 Status Post the First and Subsequent Islet Transplant

    The target level for HbA1c for this study is 7.0%. This value is the level recommended by the American Diabetes Association and is considered to be the clinically relevant goal for subjects with Type 1 diabetes (T1D). A HbA1c level of 6.5% is the goal recommended by the American College of Endocrinology.

    Time frame: 75 days following the first and subsequent islet transplant

  3. Mean amplitude of glycemic excursions (MAGE)

    A MAGE \>11.1 mmol/L (200 mg/dL) is indicative of marked glycemic lability.

    Time frame: 75 days following the first and subsequent islet transplant

  4. Glycemic liability index (LI)

    Time frame: 75 days following the first and subsequent islet transplant

  5. Ryan hypoglycemia severity score (HYPO)

    Time frame: 75 days following the first and subsequent islet transplant

  6. Basal (fasting) and 90-minute glucose and C-peptide derived from mixed meal tolerance test (MMTT)

    Time frame: 75 days following the first and subsequent islet transplant

  7. β-score on Day 75 Status Post the First and Subsequent Islet Transplant

    Beta-score: an assessment of beta-cell function after islet transplantation.

    Time frame: 75 days following the first and subsequent islet transplant

  8. C-peptide:glucose creatinine ratio

    Time frame: 75 days following the first and subsequent islet transplant

  9. Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test

    Time frame: 75 days following the first and subsequent islet transplant

  10. Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system (CGMS)

    Time frame: 75 days following the first and subsequent islet transplant

  11. Assessment of Quality of Life Using the Short Form 36 Health Survey: Day 75 Status Post First and Final Islet Transplant

    The Short-Form 36 Health Survey (SF-36®) is comprised of 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component is transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. SF-36 results unit of measure: Units on a Scale.

    Time frame: 75 days following the first and subsequent islet transplant

  12. Incidence of worsening retinopathy

    Time frame: 365 days following the first islet transplant

  13. Proportion of insulin-independent Participants on Day 365 Status Post the First and Final Islet Transplant

    Time frame: 365 days following the first and final islet transplant

  14. Percent reduction in insulin requirements

    Time frame: 365 days following the first and final islet transplant

  15. HbA1c on Day 365 Status Post the First and Final Islet Transplant

    The target level for HbA1c for this study is 7.0%. This value is the level recommended by the American Diabetes Association and is considered to be the clinically relevant goal for subjects with Type 1 diabetes (T1D). A HbA1c level of 6.5% is the goal recommended by the American College of Endocrinology.

    Time frame: 365 days following the first and final islet transplant

  16. MAGE

    A MAGE \>11.1 mmol/L (200 mg/dL) is indicative of marked glycemic lability.

    Time frame: 365 days following the first and final islet transplant

  17. Glycemic liability index (LI): Day 365 Status Post First and Final Islet Transplant

    Time frame: 365 days following the first and final islet transplant

  18. Clarke score

    The Clarke survey provides a composite indices of hypoglycemia frequency, severity, and symptom recognition.

    Time frame: 365 days following the first and final islet transplant

  19. HYPO score

    The HYPO(glycemia) score provides a composite indices of hypoglycemia frequency, severity, and symptom recognition.

    Time frame: 365 days following the first and final islet transplant

  20. Basal (fasting) and 90-minute glucose and C-peptide (MTT)

    Time frame: 365 days following the first and final islet transplant

  21. β-score on Day 365 Status Post First and Final Islet Transplant

    Beta-score: an assessment of beta-cell function after islet transplantation.

    Time frame: 365 days following the first and final islet transplant

  22. C-peptide: glucose creatinine ratio

    Time frame: 365 days following the first and final islet transplant

  23. Assessment of Quality of Life Using the Short Form 36 Health Survey: Day 365 Status Post First and Final Islet Transplant

    The Short-Form 36 Health Survey (SF-36®) is comprised of 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component is transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. SF-36 results unit of measure: Units on a Scale.

    Time frame: 365 days following the first and final islet transplant

  24. Proportion of participants receiving a second islet transplant

    Time frame: 365 days following the first and final islet transplant

  25. Proportion of participants receiving a third islet transplant

    Time frame: 365 days following the first and final islet transplant

  26. Incidence and severity of adverse events related to the islet transplant procedure

    Time frame: 75 days following each transplant and 365 days following the first and final islet transplant

  27. Incidence and severity of adverse events related to the immunosuppression therapy

    Time frame: 75 days following each transplant and 365 days following the first and final islet transplant

  28. Incidence of a change in the immunosuppression drug regimen

    Time frame: 75 days following each transplant and 365 days following the first and final islet transplant

  29. Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation

    Time frame: 75 days following each transplant and 365 days following the first and final islet transplant

  30. Proportion of insulin-independent participants on Day 75 Status Post First and Subsequent Islet Transplant

    Time frame: 75 days following first and subsequent islet transplant

  31. Acute insulin response to glucose insulin sensitivity, and disposition index derived from the FSIGT test

    Frequently Sampled Intravenous Glucose Tolerance (FSIGT), a measure of insulin-independence, a clinically relevant measure of islet graft function.

    Time frame: 365 days following the first and final islet transplant

07

Study locations

8 sites
  • University of Callifornia, San Francisco
    San Francisco, California 94143, United States
  • University of Miami
    Miami, Florida 33136, United States
  • Emory University
    Atlanta, Georgia 30322, United States
  • Northwestern University
    Chicago, Illinois 60611, United States
  • University of Illinois, Chicago
    Chicago, Illinois 60612, United States
  • University of Minnesota
    Minneapolis, Minnesota 55455, United States
  • University of Pennsylvania
    Philadelphia, Pennsylvania 19104, United States
  • University of Alberta
    Edmonton, Alberta T6G028, Canada
08

References and documents

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. doi: 10.1056/NEJMoa061267. PubMed 17005949 ↗
  • 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. PubMed 27330121 ↗
  • 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. PubMed 23630300 ↗
  • 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. PubMed 27208344 ↗
  • 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. Erratum In: Diabetes. 2017 Sep;66(9):2531. doi: 10.2337/db17-er09a. PubMed 27465220 ↗
  • 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. PubMed 29563196 ↗
  • 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. PubMed 25629445 ↗
  • 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. PubMed 23438305 ↗

Individual participant data

Plan to share: Yes — Participant level data access and additional relevant materials are available to researchers and the public at: https://www.immport.org/home. The study Identifier in ImmPort is SDY1178.

Supporting information: Study protocol, Sap, Icf, Analytic code

09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jul 17, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT00434811
Lead sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Responsible party
Sponsor
First posted
Feb 13, 2007
Start date
Oct 2006
Primary completion
Sep 2012
Completion
May 2014
Last update
Jul 17, 2019

Study contacts

Bernhard Hering, MD
study chair · University of Minnesota
Olle Korsgren, PhD
study chair · Uppsala University Hospital
Ali Naji, PhD
study chair · University of Pennsylvania
Camillo Ricordi, MD
study chair · University of Miami
James Shapiro, MD, PhD
study chair · University of Alberta
Andrew Posselt, MD, PhD
study chair · University of California, San Francisco
Nicole Turgeon, MD
study chair · Emory University
Xunrong Luo, MD, PhD
study chair · Northwestern Univerity

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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