Diabetes Mellitus, Insulin-Dependent
Conditions
Brief summary
The purpose of this study is to test whether the islet cell transplantation procedures and results from a previous study in Edmonton, Canada, can be repeated. The study also is designed to learn more about diabetes control using islet cell transplantation. This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression.
Detailed description
This is a Phase I/II study (a study that examines effectiveness and looks for side effects). The transplanting of islet cells has been studied in Type 1 diabetic patients whose blood sugar levels will not stay normal, despite intensive insulin therapy. A recent study conducted in Edmonton, Canada, was able to demonstrate that islet transplantation led to insulin independence in a majority of the patients treated. This study extends the results obtained from the Edmonton study, which used islet transplantation in Type 1 diabetic patients with steroid-free immunosuppression. Eligible patients were randomly selected from the total pool of people who applied through the Immune Tolerance Network. Patients will receive at least 10,000 islet equivalents per kilogram (2.2 pounds) of body weight. This likely will require 2 separate islet infusions from 2 separate donors. Immediately before the first transplant, patients will be given anti-rejection (immune suppressing) drugs, including tacrolimus and sirolimus (orally) and daclizumab (intravenously). The islets will be infused into the liver through a tube placed in the portal vein. Heparin (a medication to prevent blood clots) will be administered with the islet infusion. A longer-acting form of heparin will also be given by daily injections during the next week after each transplant. After surgery, patients will receive insulin intravenously for 24 hours. Patients will have an abdominal ultrasound and blood tests to determine liver function. If fewer than 10,000 islets were transplanted, patients will continue insulin treatment, with the dosages adjusted if necessary to account for the transplanted islets. They will take daclizumab every 2 weeks for 8 weeks and tacrolimus and sirolimus daily. Patients will be given antibiotics to prevent infections. Blood tests to determine how much immunosuppressant drug is in the blood will be performed until the drug is at a stable level. Periodically there will be tests to see if the islet cells are functioning. Blood will be drawn to check drug levels and for other tests routinely. Daily insulin requirements will be checked, and these will be recorded monthly. Patients will be followed for at least 1 year post last islet transplantation. Additional follow-up may be provided at least annually for up to 9 years post first transplantation.
Interventions
DRUGSirolimus
Administered at a dose of 0.2 mg/kg by mouth once pre-transplantation then 0.1 mg/kg daily post-transplantation. Dosing will be adjusted to achieve a trough peripheral blood level of 12-15 ng/mL x3 months after transplantation and 7-12 ng/mL for the remainder of the study.
DRUGTacrolimus
Administered at a dose of 1 mg by mouth once pre-transplantation followed by 1 mg twice daily post transplantation. Levels will be adjusted to achieve a peripheral blood trough level of 3-6 ng/mL for maintenance immunosuppression.
PROCEDUREIslet Transplantation
Participants will receive portal vein islet infusions (up to 3), e.g., islet transplantations, with a targeted total of exceeding 10,000 islet equivalents per kilogram of body weight (IE/kg) per infusion. Up to three transplants are possible depending on individual results.
DRUGDaclizumab
Administered at a dose of 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation, totaling 5 doses(over 8 weeks). Further daclizumab dosing may be necessary based on individual results and islet transplantation needs.
DRUGSulfamethoxazole
An antibacterial used to prevent opportunistic infections
DRUGGanciclovir
An antiviral used to kill viruses and stop viral replication
DRUGTrimethoprim
An antibacterial used to prevent opportunistic infections
DRUGPentamidine
An antiprotozoal used to prevent disease
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Patients may be eligible for this study if they: * Have had Type 1 diabetes mellitus for more than 5 years, and are exhibiting 1 of the following, despite intensive insulin management efforts: a) hypoglycemic unawareness, as defined by inability to sense hypoglycemia until the blood glucose falls to less than 54 mg/dL; b) metabolic instability, with 2 or more episodes of severe hypoglycemia (defined as an event with symptoms consistent with hypoglycemia in which the patient requires the assistance of another person and which is associated with a blood glucose below 54 mg/dL) or 2 or more hospital visits for diabetic ketoacidosis over the last year; or c) despite efforts at optimal glucose control, progressive secondary complications of diabetes as defined by retinopathy, nephropathy, or neuropathy. * Are 18 to 65 years of age.
Exclusion criteria
Patients will not be eligible for this study if they: * Have had severe cardiac disease as defined by: a) recent myocardial infarction within the past 6 months; b) angiographic evidence of non-correctable coronary artery disease; or c) evidence of ischemia on a functional cardiac exam. * Actively abuse alcohol or substances, including cigarette smoking (must not have smoked within the last 6 months). * Have psychiatric problems that prevent them from being a suitable candidate for transplantation (such as schizophrenia, bipolar disorder, or major depression that is not controlled or stable on current medication). * Have a history of not following prescribed regimens. * Have active infection including hepatitis C virus, hepatitis B virus, human immunodeficiency virus (HIV), or Tuberculosis (TB) (or under treatment for suspected TB). * Have a history of malignancy, except squamous or basal skin cancer. * Weigh more than 70 kilograms or have a Body Mass Index (BMI) greater than 26 kg/m\^2 at time of screening. * Have a C-peptide value of 0.3 ng/ml or more following a 5.0 gram intravenous arginine infusion challenge. * Are unable to provide informed consent. * Have gallstones or hemangioma in liver. * Have untreated proliferative retinopathy. * Are breast-feeding or pregnant, or intend to try and become pregnant (females) or to father a child (males), or fail to follow birth control methods. * Have had a previous transplant, or evidence of anti-human leukocyte antigen (HLA) antibody. * Have an insulin requirement of more that 0.7 International Units (IU)/kilograms/day. * Have a blood glycosylated hemoglobin (HbA1c) higher than 12 percent. * Are unable to reach the hospital for transplantation within 2 hours of notification. * Have untreated or treated hyperlipidemia. * Have a medical condition requiring chronic use of steroids. * Use coumadin or other anticoagulants (aspirin is allowed). * Have Addison's disease. * Have a negative screen for Epstein-Barr virus (EBV).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation. | One year status post participant receipt of final islet transplantation | Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1.) a blood glycosylated hemoglobin (HbA1c) level \< 6.5% (Normal:\<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: \<140mg/dL if \<=50 years of age, \<150 mg/dL for ages 50-60 years and \<160 mg/dL for ages 60+) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation. | One year post receipt of final islet transplantation | Partial islet function definition: a fasting basal C-peptide level \>= 0.3 ng/mL and a continuing need for insulin or suboptimal glycemic control (Note: C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making). Adequate glycemic control is defined by: 1) a blood HbA1c level \<6.5%, 2) a blood glucose level after an overnight fast not exceeding 140 mg/dL more than three times in any week and, 3) a 2-hour postprandial blood glucose level not exceeding 180 mg/dL more than four times per week |
| Percent of Participants That Achieved Insulin Independence From First Transplant | First transplantation until end of study (up to six years post final transplantation) | Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1) a blood glycosylated hemoglobin (HbA1c) level \< 6.5% (Normal:\<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: \<140mg/dL if \<=50 years of age, \<150 mg/dL for ages 50-60 years and \<160 mg/dL for ages 60+) |
| Percent of Participants With Detectable Fasting Basal C-Peptide Levels | Two years post first transplantation | C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making. C-peptide secretion is used to measure the function of transplanted islets. Higher levels indicate better islet function. Detectable fasting basal levels of C-peptide secretion are \>=0.3 ng/ml. |
Countries
Canada, Germany, Italy, Switzerland, United States
Participant flow
Recruitment details
Nine centers recruited participants 18 to 65 years of age who had Type 1 diabetes mellitus for more than five years, recurrent neuroglycopenia that included reduced awareness of their hypoglycemic episodes or severe glycemic lability, and fulfilled all eligibility criteria. Refer to the Eligibility section for more details.
Participants by arm
| Arm | Count |
|---|---|
| Islet Transplantation Participants received portal vein islet infusions (up to 3), e.g., islet transplantations, with a targeted total of exceeding 10,000 islet equivalents per kilogram of body weight (IE/kg) per infusion. 25 participants received 2 transplantations and 16 participants received 3 transplantations. Participants received steroid-free post-transplantation immunosuppressive medications:
1. Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation.
2. Sirolimus 0.2 mg/kg by mouth once pre-transplantation then 0.1 mg/kg daily post-transplantation. Dosing was adjusted to achieve a trough peripheral blood level of 12-15 ng/mL x3 months after transplantation and 7-12 ng/mL for the remainder of the study.
3. Tacrolimus 1 mg by mouth x1 pre-transplantation followed by 1 mg twice daily post transplantation. Levels were adjusted to achieve a peripheral blood trough level of 3-6 ng/mL for maintenance immunosuppression. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Immunosuppression-related Side Effects | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Unknown Reasons | 2 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Islet Transplantation |
|---|---|
| Age, Continuous | 40.9 years STANDARD_DEVIATION 9.2 |
| Daily Insulin Usage | 0.5 Units of Insulin/kilogram/day (U/kg/day) STANDARD_DEVIATION 0.1 |
| Number of Years with Diabetes | 27 Years STANDARD_DEVIATION 10.4 |
| Race/Ethnicity, Customized Ethnicity: Non-Hispanic | 36 Participants |
| Race/Ethnicity, Customized Race: Unspecified | 1 Participants |
| Race/Ethnicity, Customized Race: White | 35 Participants |
| Region of Enrollment Canada | 4 participants |
| Region of Enrollment Germany | 4 participants |
| Region of Enrollment Italy | 4 participants |
| Region of Enrollment Switzerland | 5 participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 36 |
| serious Total, serious adverse events | 17 / 36 |
Outcome results
Primary
Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation.
Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1.) a blood glycosylated hemoglobin (HbA1c) level \< 6.5% (Normal:\<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: \<140mg/dL if \<=50 years of age, \<150 mg/dL for ages 50-60 years and \<160 mg/dL for ages 60+)
Time frame: One year status post participant receipt of final islet transplantation
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Islet Transplantation | Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation. | Insulin Independence at One Year | 44 Percent of Participants |
| Islet Transplantation | Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation. | Insulin Independence with One Transplant | 14 Percent of Participants |
| Islet Transplantation | Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation. | Insulin Independence with Two Transplants | 17 Percent of Participants |
| Islet Transplantation | Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation. | Insulin Independence with Three Transplants | 14 Percent of Participants |
95% CI: [30, 61]Fisher Exact
Secondary
Percent of Participants That Achieved Insulin Independence From First Transplant
Insulin independence: exogenous insulin not required and glycemic control is achieved as defined by maintaining 1) a blood glycosylated hemoglobin (HbA1c) level \< 6.5% (Normal:\<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher),2) a blood glucose level after an overnight fast not exceeding 140 mg per deciliter (dL) more than three times in any week (Normal: 70 to 120 mg/dL), and 3)not exceeding a 2-hour postprandial blood glucose level of 180 mg/dL more than four times per week (Normal: \<140mg/dL if \<=50 years of age, \<150 mg/dL for ages 50-60 years and \<160 mg/dL for ages 60+)
Time frame: First transplantation until end of study (up to six years post final transplantation)
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Transplantation | Percent of Participants That Achieved Insulin Independence From First Transplant | 58 Percent of Participants |
95% CI: [42, 63]Fisher Exact
Secondary
Percent of Participants With Detectable Fasting Basal C-Peptide Levels
C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making. C-peptide secretion is used to measure the function of transplanted islets. Higher levels indicate better islet function. Detectable fasting basal levels of C-peptide secretion are \>=0.3 ng/ml.
Time frame: Two years post first transplantation
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Transplantation | Percent of Participants With Detectable Fasting Basal C-Peptide Levels | 70 Percent of Participants |
Secondary
Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation.
Partial islet function definition: a fasting basal C-peptide level \>= 0.3 ng/mL and a continuing need for insulin or suboptimal glycemic control (Note: C-peptide is a substance that the pancreas releases into the bloodstream in equal amounts to insulin, thereby showing how much insulin the body is making). Adequate glycemic control is defined by: 1) a blood HbA1c level \<6.5%, 2) a blood glucose level after an overnight fast not exceeding 140 mg/dL more than three times in any week and, 3) a 2-hour postprandial blood glucose level not exceeding 180 mg/dL more than four times per week
Time frame: One year post receipt of final islet transplantation
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Islet Transplantation | Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation. | 28 Percent of Participants |
95% CI: [16, 44]Fisher Exact
Post Hoc
HbA1c Plasma Laboratory Values for Participants in the Extended Follow-up Study Phase
Seven participants from US sites were included in the extended follow-up. These participants were monitored yearly from year three post last transplantation (the original end of study follow-up) through August 30, 2010 (up to 9 years post first transplantation), at which point they were transferred to a new protocol (ITN040CT \[NCT01309022\]). Glycosylated hemoglobin (HbA1c) is a measure of the average plasma glucose concentration over prolonged periods of time. (Normal:\<5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher)
Time frame: First transplantation through August 30, 2010 (up to 9 years)
Population: Intent-to-Treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Islet Transplantation | HbA1c Plasma Laboratory Values for Participants in the Extended Follow-up Study Phase | 6.2 HbA1c Percentage |
Post Hoc
Serum Creatinine Levels for Participants in the Extended Follow-up Study Phase
Seven participants from US sites were included in the extended follow-up. These participants were monitored yearly from year three post last transplantation (the original end of study follow-up) through August 30, 2010 (up to 9 years post first transplantation), at which point they were transferred to a new protocol (ITN040CT \[NCT01309022\]). Serum creatinine is a measure of renal function. Normal ranges are from 0.5 to 1.0 mg/dL for females and 0.7 to 1.2 mg/dL for males.
Time frame: First transplantation through August 30, 2010 (up to 9 years)
Population: Intent-to-Treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Islet Transplantation | Serum Creatinine Levels for Participants in the Extended Follow-up Study Phase | 0.9 mg/dL |