Islet Transplantation for Type 1 Diabetes

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00014911
• Collaborator: Immune Tolerance Network (ITN) (Other)
• Enrollment: 36
• Locations: 9
• Arm: 1
• Duration (Months): 112
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Insulin-Dependent	Procedure: Islet Transplantation; Drug: Sirolimus; Drug: Tacrolimus; Drug: Daclizumab; Drug: Sulfamethoxazole; Drug: Ganciclovir; Drug: Trimethoprim; Drug: Pentamidine	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Islet Transplantation for Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression (ITN005CT)
• Study Start Date: Apr 1, 2001
• Actual Primary Completion Date: Jun 1, 2005
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Islet Transplantation All study participants

Procedure: Islet 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.; Drug: Sirolimus; 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.; Drug: Tacrolimus; 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.; Drug: Daclizumab; 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.; Drug: Sulfamethoxazole; An antibacterial used to prevent opportunistic infections; Drug: Ganciclovir; An antiviral used to kill viruses and stop viral replication; Drug: Trimethoprim; An antibacterial used to prevent opportunistic infections; Drug: Pentamidine; An antiprotozoal used to prevent disease

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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+)

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami	Miami	Florida	United States	33136
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	University of Minnesota	Minneapolis	Minnesota	United States	55455
4	Washington University	St. Louis	Missouri	United States	63110
5	Benaroya Research Institute at Virginia Mason Research Center	Seattle	Washington	United States	98101
6	University of Alberta	Edmonton	Alberta	Canada
7	Justus-Leibig University	Giessen		Germany	35385
8	University of Milan	Milan		Italy
9	University of Geneva	Geneva		Switzerland

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)

Investigators

• Principal Investigator: James Shapiro, MD, PhD, University of Alberta

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network (ITN) website

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00014911
• Other Study ID Numbers: DAIT ITN005CT (DAIT NIS01)
• First Posted: Aug 31, 2001
• Last Update Posted: Mar 15, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Sirolimus; Pentamidine; Trimethoprim; Sulfamethoxazole; Ganciclovir; Ganciclovir triphosphate; Tacrolimus; Daclizumab

Study Results

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.

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Period Title: Overall Study
STARTED	36
COMPLETED	25
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Overall Participants	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.9 (9.2)
Sex: Female, Male (Count of Participants)
Female	14 38.9%
Male	22 61.1%
Race/Ethnicity, Customized (Number) [Number]
Race: White	35 97.2%
Race: Unspecified	1 2.8%
Ethnicity: Non-Hispanic	36 100%
Region of Enrollment (participants) [Number]
United States	19 52.8%
Canada	4 11.1%
Germany	4 11.1%
Italy	4 11.1%
Switzerland	5 13.9%
Number of Years with Diabetes (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	27 (10.4)
Daily Insulin Usage (Units of Insulin/kilogram/day (U/kg/day)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units of Insulin/kilogram/day (U/kg/day)]	0.5 (0.1)

Outcome Measures

1. Primary Outcome

Title	Percent of Participants That Achieved Insulin Independence With Adequate Control of Blood Glucose Levels at One Year Post Final Islet Transplantation.
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Measure Participants	36
Insulin Independence at One Year	44 122.2%
Insulin Independence with One Transplant	14 38.9%
Insulin Independence with Two Transplants	17 47.2%
Insulin Independence with Three Transplants	14 38.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Islet Transplantation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	44
	Confidence Interval	(2-Sided) 95%; 30 to 61
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent of Participants With Partial Islet Function One Year Post Final Islet Transplantation.
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Measure Participants	36
Number [Percent of Participants]	28 77.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Islet Transplantation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	28
	Confidence Interval	(2-Sided) 95%; 16 to 44
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent of Participants That Achieved Insulin Independence From First Transplant
Description	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)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Measure Participants	36
Number [Percent of Participants]	58 161.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Islet Transplantation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	58
	Confidence Interval	(2-Sided) 95%; 42 to 63
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent of Participants With Detectable Fasting Basal C-Peptide Levels
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Measure Participants	36
Number [Percent of Participants]	70 194.4%

5. Post-Hoc Outcome

Title	HbA1c Plasma Laboratory Values for Participants in the Extended Follow-up Study Phase
Description	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)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Measure Participants	7
Mean (Full Range) [HbA1c Percentage]	6.2

6. Post-Hoc Outcome

Title	Serum Creatinine Levels for Participants in the Extended Follow-up Study Phase
Description	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)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
Measure Participants	7
Mean (Full Range) [mg/dL]	0.9

Adverse Events

Time Frame	First transplant until end of study (up to 9 years post first transplant)
Adverse Event Reporting Description	This study graded the severity of adverse events experienced by the study participant according to criteria set forth in the National Cancer Institute's Common Toxicity Criteria Version 2.0 (April 30, 1999)
Arm/Group Title	Islet Transplantation
Arm/Group Description	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: Daclizumab 1 mg/kg intravenously immediately pre-transplantation and 2, 4, 6, and 8 weeks post-transplantation. 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. 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.
All Cause Mortality
	Islet Transplantation
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Islet Transplantation
	Affected / at Risk (%)	# Events
Total	17/36 (47.2%)
Blood and lymphatic system disorders
Anaemia	1/36 (2.8%)	1
Neutropenia	4/36 (11.1%)	4
Cardiac disorders
Myocardial infarction	1/36 (2.8%)	1
Pericardial effusion	1/36 (2.8%)	1
Ear and labyrinth disorders
Vertigo	1/36 (2.8%)	1
Gastrointestinal disorders
Ascites	1/36 (2.8%)	1
Diarrhoea	2/36 (5.6%)	2
Gastritis	1/36 (2.8%)	1
Gastrointestinal haemorrhage	1/36 (2.8%)	1
Mouth ulceration	1/36 (2.8%)	1
Peritoneal haemorrhage	1/36 (2.8%)	1
Peritonitis	1/36 (2.8%)	1
Vomiting	1/36 (2.8%)	1
Diarrhoea hemorrhage	1/36 (2.8%)	1
Gastroenteritis	1/36 (2.8%)	1
General disorders
Chest pain	1/36 (2.8%)	1
Fatigue	1/36 (2.8%)	1
Pyrexia	2/36 (5.6%)	3
Infections and infestations
Appendiceal abscess	1/36 (2.8%)	1
Cystitis	1/36 (2.8%)	1
Herpes virus infection	1/36 (2.8%)	1
Pyelonephritis	2/36 (5.6%)	2
Upper respiratory tract infection	1/36 (2.8%)	1
Injury, poisoning and procedural complications
Hepatic haematoma	1/36 (2.8%)	1
Hip fracture	1/36 (2.8%)	1
Metabolism and nutrition disorders
Dehydration	2/36 (5.6%)	2
Hyperglycaemia	1/36 (2.8%)	1
Hypoglycaemia	1/36 (2.8%)	1
Musculoskeletal and connective tissue disorders
Myalgia	1/36 (2.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic haemangioma rupture	1/36 (2.8%)	1
Psychiatric disorders
Conversion disorder	1/36 (2.8%)	1
Depression	1/36 (2.8%)	1
Suicidal ideation	1/36 (2.8%)	1
Renal and urinary disorders
Renal failure acute	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/36 (2.8%)	1
Pulmonary embolism	1/36 (2.8%)	1
Other (Not Including Serious) Adverse Events
	Islet Transplantation
	Affected / at Risk (%)	# Events
Total	36/36 (100%)
Blood and lymphatic system disorders
Anaemia	29/36 (80.6%)	133
Iron deficiency anaemia	4/36 (11.1%)	4
Leukopenia	27/36 (75%)	119
Lymphopenia	9/36 (25%)	30
Neutropenia	19/36 (52.8%)	114
Thrombocytopenia	8/36 (22.2%)	43
Cardiac disorders
Bradycardia	2/36 (5.6%)	2
Palpitations	3/36 (8.3%)	4
Pericardial effusion	2/36 (5.6%)	2
Ear and labyrinth disorders
Ear pain	3/36 (8.3%)	3
Vertigo	2/36 (5.6%)	2
Eye disorders
Vision blurred	3/36 (8.3%)	4
Vitreous floaters	3/36 (8.3%)	3
Vitreous haemorrhage	2/36 (5.6%)	3
Gastrointestinal disorders
Abdominal distension	2/36 (5.6%)	3
Abdominal pain	12/36 (33.3%)	20
Abdominal pain lower	2/36 (5.6%)	2
Abdominal pain upper	10/36 (27.8%)	13
Aphthous stomatitis	4/36 (11.1%)	6
Constipation	4/36 (11.1%)	6
Diarrhoea	23/36 (63.9%)	52
Dyspepsia	4/36 (11.1%)	8
Flatulence	2/36 (5.6%)	2
Haemorrhoids	2/36 (5.6%)	2
Lip ulceration	2/36 (5.6%)	2
Loose stools	2/36 (5.6%)	2
Mouth ulceration	33/36 (91.7%)	138
Nausea	19/36 (52.8%)	28
Tongue ulceration	3/36 (8.3%)	4
Vomiting	15/36 (41.7%)	31
General disorders
Asthenia	5/36 (13.9%)	8
Chest discomfort	2/36 (5.6%)	2
Chest pain	2/36 (5.6%)	5
Fatigue	14/36 (38.9%)	24
Influenza like illness	3/36 (8.3%)	4
Malaise	2/36 (5.6%)	3
Mucosal ulceration	3/36 (8.3%)	4
Oedema	6/36 (16.7%)	6
Oedema peripheral	9/36 (25%)	13
Pain	6/36 (16.7%)	8
Pyrexia	11/36 (30.6%)	15
Rigors	3/36 (8.3%)	4
Hepatobiliary disorders
Portal hypertension	4/36 (11.1%)	4
Immune system disorders
Hypersensitivity	2/36 (5.6%)	2
Infections and infestations
Bronchitis	3/36 (8.3%)	3
Cellulitis	3/36 (8.3%)	3
Clostridium colitis	2/36 (5.6%)	2
Folliculitis	4/36 (11.1%)	4
Fungal infection	3/36 (8.3%)	7
Herpes simplex	2/36 (5.6%)	2
Herpes zoster	2/36 (5.6%)	2
Hordeolum	2/36 (5.6%)	4
Influenza	3/36 (8.3%)	3
Nasopharyngitis	11/36 (30.6%)	12
Onychomycosis	4/36 (11.1%)	4
Rhinitis	3/36 (8.3%)	3
Sinusitis	4/36 (11.1%)	4
Tonsillitis	2/36 (5.6%)	3
Tooth abscess	2/36 (5.6%)	2
Upper respiratory tract infection	8/36 (22.2%)	10
Urinary tract infection	9/36 (25%)	13
Vaginal candidiasis	2/36 (5.6%)	2
Vaginal mycosis	4/36 (11.1%)	6
Viral infection	2/36 (5.6%)	3
Injury, poisoning and procedural complications
Contusion	3/36 (8.3%)	4
Excoriation	3/36 (8.3%)	3
Incision site complication	2/36 (5.6%)	2
Investigations
Alanine aminotransferase increased	9/36 (25%)	14
Aspartate aminotransferase increased	10/36 (27.8%)	17
Band neutrophil percentage increased	2/36 (5.6%)	2
Blood albumin decreased	2/36 (5.6%)	2
Blood alkaline phosphatase increased	3/36 (8.3%)	4
Blood bicarbonate decreased	5/36 (13.9%)	18
Blood chloride increased	2/36 (5.6%)	9
Blood cholesterol increased	2/36 (5.6%)	2
Blood lactate dehydrogenase increased	2/36 (5.6%)	2
Blood urea increased	3/36 (8.3%)	3
Hepatic enzyme increased	12/36 (33.3%)	20
Liver function test abnormal	14/36 (38.9%)	20
Mean cell volume decreased	3/36 (8.3%)	4
Red blood cell count decreased	5/36 (13.9%)	14
Weight decreased	9/36 (25%)	11
White blood cell count decreased	3/36 (8.3%)	7
Metabolism and nutrition disorders
Anorexia	2/36 (5.6%)	2
Decreased appetite	4/36 (11.1%)	5
Hyperchloraemia	3/36 (8.3%)	6
Hypercholesterolaemia	12/36 (33.3%)	18
Hyperglycaemia	2/36 (5.6%)	2
Hyperlipidaemia	7/36 (19.4%)	9
Hypernatraemia	2/36 (5.6%)	8
Hypertriglyceridaemia	3/36 (8.3%)	3
Hypocalcaemia	5/36 (13.9%)	9
Hypoglycaemia	11/36 (30.6%)	24
Hypoglycaemia unawareness	2/36 (5.6%)	2
Hypokalaemia	3/36 (8.3%)	7
Hypomagnesaemia	5/36 (13.9%)	25
Hyponatraemia	3/36 (8.3%)	4
Hypophosphataemia	4/36 (11.1%)	10
Musculoskeletal and connective tissue disorders
Arthralgia	8/36 (22.2%)	17
Back pain	4/36 (11.1%)	6
Chest wall pain	2/36 (5.6%)	2
Joint swelling	2/36 (5.6%)	6
Muscle cramp	6/36 (16.7%)	9
Musculoskeletal discomfort	3/36 (8.3%)	3
Musculoskeletal stiffness	2/36 (5.6%)	3
Myalgia	4/36 (11.1%)	4
Pain in extremity	3/36 (8.3%)	5
Nervous system disorders
Amnesia	2/36 (5.6%)	2
Burning sensation	3/36 (8.3%)	3
Dizziness	4/36 (11.1%)	5
Headache	20/36 (55.6%)	53
Hypoaesthesia	2/36 (5.6%)	2
Memory impairment	3/36 (8.3%)	4
Migraine	4/36 (11.1%)	4
Paraesthesia	3/36 (8.3%)	4
Tremor	9/36 (25%)	13
Psychiatric disorders
Anxiety	2/36 (5.6%)	3
Depression	4/36 (11.1%)	5
Insomnia	6/36 (16.7%)	8
Renal and urinary disorders
Nocturia	2/36 (5.6%)	4
Proteinuria	3/36 (8.3%)	6
Renal cyst	2/36 (5.6%)	2
Reproductive system and breast disorders
Menstrual disorder	2/36 (5.6%)	2
Menstruation irregular	5/36 (13.9%)	7
Ovarian cyst	3/36 (8.3%)	7
Vaginal discharge	2/36 (5.6%)	3
Respiratory, thoracic and mediastinal disorders
Cough	11/36 (30.6%)	16
Dyspnoea	2/36 (5.6%)	4
Epistaxis	2/36 (5.6%)	2
Nasal congestion	3/36 (8.3%)	5
Pharyngolaryngeal pain	13/36 (36.1%)	19
Rhinorrhoea	4/36 (11.1%)	4
Sinus congestion	4/36 (11.1%)	4
Skin and subcutaneous tissue disorders
Acne	15/36 (41.7%)	25
Dermatitis acneiform	3/36 (8.3%)	3
Dermatitis contact	2/36 (5.6%)	2
Eczema	2/36 (5.6%)	7
Erythema	2/36 (5.6%)	2
Ingrowing nail	3/36 (8.3%)	4
Nail disorder	3/36 (8.3%)	3
Pruritus	7/36 (19.4%)	10
Purpura	2/36 (5.6%)	2
Rash	13/36 (36.1%)	18
Rash papular	3/36 (8.3%)	6
Rash pruritic	2/36 (5.6%)	2
Skin lesion	3/36 (8.3%)	4
Vascular disorders
Haematoma	4/36 (11.1%)	5
Hot flush	2/36 (5.6%)	2
Hypertension	7/36 (19.4%)	11
Hypotension	6/36 (16.7%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.