Type 1 Diabetes MellitusPhase 3NCT00434811
Islet Transplantation in Type 1 Diabetes
A Phase 3 study testing Allogeneic Pancreatic Islet Cells, Antithymocyte Globulin and Sirolimus in people with Type 1 Diabetes Mellitus, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Type 1 Diabetes Mellitus
- What is being tested?
- Allogeneic Pancreatic Islet Cells, Antithymocyte Globulin and Sirolimus
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 8 sitesin 2 countries
- Study dates
- Oct 2006to May 2014
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- Self-monitoring of glucose values no less than a mean of three times each day averaged over each week
- Administration of three or more insulin injections each day or insulin pump therapy
Show all 9Show fewer
- 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.
Who cannot join
- 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.
Show all 35Show fewer
- 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:
- Heart attack within the last 6 months
- Evidence of ischemia on functional heart exam within the year prior to study entry
- 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.
Trial locations and contacts
8 sites in 2 countries.
8 sites in 2 countries
United States7 sites
Emory University
Atlanta, Georgia, 30322
Northwestern University
Chicago, Illinois, 60611
University of Illinois, Chicago
Chicago, Illinois, 60612
University of Miami
Miami, Florida, 33136
University of Minnesota
Minneapolis, Minnesota, 55455
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of Callifornia, San Francisco
San Francisco, California, 94143
About this study
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.
- Conditions
- Type 1 Diabetes Mellitus
- Being tested
- Allogeneic Pancreatic Islet Cells, Antithymocyte Globulin, Sirolimus, Tacrolimus, Etanercept
- Keywords
- Insulin dependence, Hypoglycemia, Hypoglycemia unawareness
- Medical subject headings
- Diabetes Mellitus, Type 1, Hypoglycemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Allogeneic Pancreatic Islet CellsBiological
200 ml suspension of allogenic human purified islets
Antithymocyte GlobulinBiological
Participants will begin receiving ATG 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant.
SirolimusDrug
Also called Rapamycin
Participants will begin receiving sirolimus 2 days prior to the first islet transplant and will be given for the duration of the study.
TacrolimusDrug
Also called FK-506, Fujimycin
On Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study.
EtanerceptBiological
Etanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant.
Islet TransplantationProcedure or surgery
Transplantation of pancreatic islet cell
BasiliximabBiological
Also called chimeric mouse-human antiCD25, Ig gamma-1 chain C region
Basiliximab will be used in place of ATG for the second and third transplants, if they are necessary.
| Study group | Role | What they receive |
|---|---|---|
| Islet Transplantation | Experimental | 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. Receives: Biological: Allogeneic Pancreatic Islet Cells; Biological: Antithymocyte Globulin; Drug: Sirolimus; Drug: Tacrolimus; Biological: Etanercept; Procedure: Islet Transplantation; Biological: Basiliximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From Day 28 to Day 365 (inclusive) following the first islet transplant, with the day of transplant designated Day 0
Secondary outcomes (31)
Percent reduction in insulin requirements
Measured: 75 days following the first and subsequent islet transplant
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.
Measured: 75 days following the first and subsequent islet transplant
Mean amplitude of glycemic excursions (MAGE)
A MAGE >11.1 mmol/L (200 mg/dL) is indicative of marked glycemic lability.
Measured: 75 days following the first and subsequent islet transplant
Glycemic liability index (LI)
Measured: 75 days following the first and subsequent islet transplant
Ryan hypoglycemia severity score (HYPO)
Measured: 75 days following the first and subsequent islet transplant
Basal (fasting) and 90-minute glucose and C-peptide derived from mixed meal tolerance test (MMTT)
Measured: 75 days following the first and subsequent islet transplant
β-score on Day 75 Status Post the First and Subsequent Islet Transplant
Beta-score: an assessment of beta-cell function after islet transplantation.
Measured: 75 days following the first and subsequent islet transplant
C-peptide:glucose creatinine ratio
Measured: 75 days following the first and subsequent islet transplant
Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test
Measured: 75 days following the first and subsequent islet transplant
Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system (CGMS)
Measured: 75 days following the first and subsequent islet transplant
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.
Measured: 75 days following the first and subsequent islet transplant
Incidence of worsening retinopathy
Measured: 365 days following the first islet transplant
Proportion of insulin-independent Participants on Day 365 Status Post the First and Final Islet Transplant
Measured: 365 days following the first and final islet transplant
Percent reduction in insulin requirements
Measured: 365 days following the first and final islet transplant
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.
Measured: 365 days following the first and final islet transplant
MAGE
A MAGE >11.1 mmol/L (200 mg/dL) is indicative of marked glycemic lability.
Measured: 365 days following the first and final islet transplant
Glycemic liability index (LI): Day 365 Status Post First and Final Islet Transplant
Measured: 365 days following the first and final islet transplant
Clarke score
The Clarke survey provides a composite indices of hypoglycemia frequency, severity, and symptom recognition.
Measured: 365 days following the first and final islet transplant
HYPO score
The HYPO(glycemia) score provides a composite indices of hypoglycemia frequency, severity, and symptom recognition.
Measured: 365 days following the first and final islet transplant
Basal (fasting) and 90-minute glucose and C-peptide (MTT)
Measured: 365 days following the first and final islet transplant
β-score on Day 365 Status Post First and Final Islet Transplant
Beta-score: an assessment of beta-cell function after islet transplantation.
Measured: 365 days following the first and final islet transplant
C-peptide: glucose creatinine ratio
Measured: 365 days following the first and final islet transplant
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.
Measured: 365 days following the first and final islet transplant
Proportion of participants receiving a second islet transplant
Measured: 365 days following the first and final islet transplant
Proportion of participants receiving a third islet transplant
Measured: 365 days following the first and final islet transplant
Incidence and severity of adverse events related to the islet transplant procedure
Measured: 75 days following each transplant and 365 days following the first and final islet transplant
Incidence and severity of adverse events related to the immunosuppression therapy
Measured: 75 days following each transplant and 365 days following the first and final islet transplant
Incidence of a change in the immunosuppression drug regimen
Measured: 75 days following each transplant and 365 days following the first and final islet transplant
Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation
Measured: 75 days following each transplant and 365 days following the first and final islet transplant
Proportion of insulin-independent participants on Day 75 Status Post First and Subsequent Islet Transplant
Measured: 75 days following first and subsequent islet transplant
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.
Measured: 365 days following the first and final islet transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2007 (estimated)
- Study startOct 2006
- Primary completionSep 2012
- Study completionMay 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Type 1 Diabetes MellitusStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Bernhard Hering, MD, Study chair, University of MinnesotaOlle Korsgren, PhD, Study chair, Uppsala University HospitalAli Naji, PhD, Study chair, University of PennsylvaniaCamillo Ricordi, MD, Study chair, University of MiamiJames Shapiro, MD, PhD, Study chair, University of AlbertaAndrew Posselt, MD, PhD, Study chair, University of California, San FranciscoNicole Turgeon, MD, Study chair, Emory UniversityXunrong Luo, MD, PhD, Study chair, Northwestern Univerity
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00434811
- Sponsor's protocol ID
- DAIT CIT-07
- Status last verified
- Jul 2019
- First submitted
- 9 Feb 2007
- Last updated
- 17 Jul 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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.
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 17005949Harlan 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 27330121Rickels 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 23630300Hering 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 27208344Ricordi 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.
PubMed 27465220Foster 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 29563196Senior 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 25629445Gala-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
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Islet Transplantation in Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT00434811
- Acronym / sponsor ID
- DAIT CIT-07
- Conditions
- Type 1 Diabetes Mellitus
- Keywords
- Insulin dependence, Hypoglycemia, Hypoglycemia unawareness
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Oct 2006
- Primary completion
- Sep 2012 (actual)
- Study completion
- May 2014 (actual)
- First posted
- 13 Feb 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Islet Transplantation | Experimental | Biological: Allogeneic Pancreatic Islet Cells, Biological: Antithymocyte Globulin, Drug: Sirolimus, Drug: Tacrolimus, Biological: Etanercept, Procedure: Islet Transplantation, Biological: BasiliximabParticipants will receive up to three separate islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte globulin (ATG), sirolimus, and low-dose tacrolimus. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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:
- 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
Key exclusion criteria (35 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Allogeneic Pancreatic Islet Cells200 ml suspension of allogenic human purified islets | Biological | Islet Transplantation |
| Antithymocyte GlobulinParticipants will begin receiving ATG 2 days prior to the first islet transplant. ATG will continue to be given until Day 2 post-transplant. | Biological | Islet Transplantation |
| SirolimusAlso: RapamycinParticipants will begin receiving sirolimus 2 days prior to the first islet transplant and will be given for the duration of the study. | Drug | Islet Transplantation |
| TacrolimusAlso: FK-506, FujimycinOn Day 1 post-transplant, participants will receive tacrolimus, which will also be taken for the duration of the study. | Drug | Islet Transplantation |
| EtanerceptEtanercept will be taken on the day of transplant and Days 3, 7, and 10 post-transplant. | Biological | Islet Transplantation |
| Islet TransplantationTransplantation of pancreatic islet cell | Procedure or surgery | Islet Transplantation |
| BasiliximabAlso: chimeric mouse-human antiCD25, Ig gamma-1 chain C regionBasiliximab will be used in place of ATG for the second and third transplants, if they are necessary. | Biological | Islet Transplantation |
Primary outcome
Proportion of participants with a HbA1c less than 7.0% AND free of severe hypoglycemic events
Time frame: From Day 28 to Day 365 (inclusive) following the first islet transplant, with the day of transplant designated Day 0
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.
31 secondary outcomes
Percent reduction in insulin requirements
Time frame: 75 days following the first and subsequent islet transplant
HbA1c on Day 75 Status Post the First and Subsequent Islet Transplant
Time frame: 75 days following the first and subsequent islet transplant
Mean amplitude of glycemic excursions (MAGE)
Time frame: 75 days following the first and subsequent islet transplant
Glycemic liability index (LI)
Time frame: 75 days following the first and subsequent islet transplant
Ryan hypoglycemia severity score (HYPO)
Time frame: 75 days following the first and subsequent islet transplant
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
β-score on Day 75 Status Post the First and Subsequent Islet Transplant
Time frame: 75 days following the first and subsequent islet transplant
C-peptide:glucose creatinine ratio
Time frame: 75 days following the first and subsequent islet transplant
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
Glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system (CGMS)
Time frame: 75 days following the first and subsequent islet transplant
Assessment of Quality of Life Using the Short Form 36 Health Survey: Day 75 Status Post First and Final Islet Transplant
Time frame: 75 days following the first and subsequent islet transplant
Incidence of worsening retinopathy
Time frame: 365 days following the first islet transplant
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
Percent reduction in insulin requirements
Time frame: 365 days following the first and final islet transplant
HbA1c on Day 365 Status Post the First and Final Islet Transplant
Time frame: 365 days following the first and final islet transplant
MAGE
Time frame: 365 days following the first and final islet transplant
Glycemic liability index (LI): Day 365 Status Post First and Final Islet Transplant
Time frame: 365 days following the first and final islet transplant
Clarke score
Time frame: 365 days following the first and final islet transplant
HYPO score
Time frame: 365 days following the first and final islet transplant
Basal (fasting) and 90-minute glucose and C-peptide (MTT)
Time frame: 365 days following the first and final islet transplant
β-score on Day 365 Status Post First and Final Islet Transplant
Time frame: 365 days following the first and final islet transplant
C-peptide: glucose creatinine ratio
Time frame: 365 days following the first and final islet transplant
Assessment of Quality of Life Using the Short Form 36 Health Survey: Day 365 Status Post First and Final Islet Transplant
Time frame: 365 days following the first and final islet transplant
Proportion of participants receiving a second islet transplant
Time frame: 365 days following the first and final islet transplant
Proportion of participants receiving a third islet transplant
Time frame: 365 days following the first and final islet transplant
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
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
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
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
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
Acute insulin response to glucose insulin sensitivity, and disposition index derived from the FSIGT test
Time frame: 365 days following the first and final islet transplant
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2019.
- Background: PubMed 17005949Shapiro 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.
- Background: PubMed 27330121Harlan 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.
- Results publication: PubMed 23630300Rickels 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.
- Results publication: PubMed 27208344Hering 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.
- Results publication: PubMed 27465220Ricordi 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.
- Derived from this study: PubMed 29563196Foster 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.
- Derived from this study: PubMed 25629445Senior 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.
- Derived from this study: PubMed 23438305Gala-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.
- National Institute of Allergy and Infectious Diseases (NIAID)Link provided by the sponsor.
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository Data for this StudyLink provided by the sponsor.
- Division of Allergy, Immunology, and Transplantation (DAIT)Link provided by the sponsor.
- Individual participant dataSharing planned: 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bernhard Hering, MD study chair
University of Minnesota
Olle Korsgren, PhD study chair
Uppsala University Hospital
Ali Naji, PhD study chair
University of Pennsylvania
8 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Allogeneic Pancreatic Islet Cells, Antithymocyte Globulin and Sirolimus in people with Type 1 Diabetes Mellitus, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of participants with a HbA1c less than 7.0% AND free of severe hypoglycemic events (time frame: From Day 28 to Day 365 (inclusive) following the first islet transplant, with the day of transplant designated Day 0). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00434811, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2019.