Type 1 Diabetes, Hypoglycemia, Metabolic Diseases
Conditions
Keywords
diabetes, hypoglycemia
Brief summary
The restoration of endogenous insulin secretion carries significant hopes for shifting the paradigm of life long exogenous insulin therapy in selected groups of patients with type 1 diabetes(T1D). After decades of frustrating clinical attempts, the Edmonton group set up in 2000 new standards for islet transplantation in patients with brittle T1D by achieving insulin independence in 80 percent of patients. These seminal results have however proved much more difficult to duplicate than initially expected. This single center phase 2 clinical trial, duplicating the Edmonton protocol, is designed for confirming the consistent short term efficacy and safety of sequential islet allotransplantation with steroid free immunosuppression in patients with severe T1D.
Detailed description
The short term effectiveness of islet transplantation for alleviating hypoglycemia and controlling glucose homeostasis while limiting or even avoiding the nedd for exogenous insulin has been established despite protocol modifications in donor selection, islet preparation or recipient treatment, insulin independence with adequate metabolic control was however rarely prolonged beyond two years. The most frequently proposed explanations include chronic allogenic rejection, recurrence of autoimmunity and beta cell toxicity from administered immunosuppressive drugs. Fourteen patients were enrolled in this single center phase 2 trial initiated in 2003. Eligible patients were males or females between 18 and 65 years of age, with type 1 diabeted documented for more than 5 years, arginine stimulated C-peptide lower than 0.2ng/ml, and hypoglycemia awareness or documented metabolic lability. Exclusion criteria included body mass index greater than 28Kg/m2, unstable arteriopathy or heart disease, active infection, previous transplantation, insulin daily requirements above 1.2 UI/kg, creatinin clearance below 60 ml/mn/m2 or urinary albumin excretion above 300 mg/day, malignancy, smoking, desire for pregnancy, psychiatric disorders and lack of compliance. The study primary efficacy endpoint was graft survival defined as insulin independence and HbA1c\<6.5%. Secondary outcomes were graft function and metabolic control.
Interventions
PROCEDUREislet transplantation
Islet transplantation consisted of up to three sequential fresh islet infusions within three months. Access to the portal vein was gained under general anesthesia by percutaneous catheterisation of a peripheral portal branch under ultrasound guidance or by surgical catheterisation of a small mesenteric vein.
DRUGdaclizumab - sirolimus - tacrolimus
Immunosuppressive consisted of Tacrolimus, target through level at 3-6 ng/ml, Sirolimus, target through level at 12-15 ng/ml for three months and at 7-10 ng/ml thereafter. A five-dose induction course of Daclizumab 1mg/Kg was administered biweekly beginning one hour prior to the first infusion
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
University Hospital, Lille
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
* type 1 diabetes documented for more than 5 years * arginine stimulated C-peptide lower than 0.2 ng/mL * one of the following:hypoglycemia unawareness OR metabolic lability documented by one or more severe hypoglycemias or two or more hospital admissions for ketoacidosis within the previous year.
Exclusion criteria
* body mass index greater than 28 kg/m2 * non stable arteriopathy or heart disease * active infection * previous transplantation * hyperimmunization * insulin daily needs above 1.2 U/Kg * creatinine clearance below 60 ml/mn or urinary albumin excretion above 300 mg/d * malignancy * smoking * desire for pregnancy * psychiatric disorders * lack of compliance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Criteria: Insulin Independence and Glycosylated Hemoglobin (HbA1c) Under 6.5% at One Year | 1 year | The percentage of insulin independents subjects with an HbA1c less than 6.5% at one year after last transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypoglycemic Events | day 0 to day 365 | Percentage of subjects free of severe hypoglycemic events from day 0 to day 365 with the day of transplant designated day 0 |
| Plasma C-peptide | 1 year | Level of plasma C-peptide at 1 year after the first transplant |
| HbA1c < 6.5% | 1 year | The percentage of subjects with HbA1c \< 6.5% at 1 year after the first transplant |
| Percentage of Time Spent in Hypoglycemia (<0.70 mg/L) | 1 year | percentage of time spent in hypoglycemia derived from CGMS (Continuous Glucose Monitoring System) |
| Number of Adverse Events | 1 year | The number of adverse events related to the procedure and to the immunosuppression |
Countries
France
Participant flow
Recruitment details
Recruitment period: 2003-2006 University Lille Hospital
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Group Islet Allotransplantation Group | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Single Arm Group |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age Continuous | 44 years STANDARD_DEVIATION 13 |
| Region of Enrollment France | 14 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 14 |
| serious Total, serious adverse events | 12 / 14 |
Outcome results
Primary
Composite Criteria: Insulin Independence and Glycosylated Hemoglobin (HbA1c) Under 6.5% at One Year
The percentage of insulin independents subjects with an HbA1c less than 6.5% at one year after last transplant
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Arm Group | Composite Criteria: Insulin Independence and Glycosylated Hemoglobin (HbA1c) Under 6.5% at One Year | 71 Percentage of patients | Standard Deviation 29 |
Secondary
HbA1c < 6.5%
The percentage of subjects with HbA1c \< 6.5% at 1 year after the first transplant
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Arm Group | HbA1c < 6.5% | 64.3 Percentage of participants | Standard Deviation 35.7 |
Secondary
Hypoglycemic Events
Percentage of subjects free of severe hypoglycemic events from day 0 to day 365 with the day of transplant designated day 0
Time frame: day 0 to day 365
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Arm Group | Hypoglycemic Events | 0 Percentage of patients | Standard Deviation 0 |
Secondary
Number of Adverse Events
The number of adverse events related to the procedure and to the immunosuppression
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm Group | Number of Adverse Events | 33 number events |
Secondary
Percentage of Time Spent in Hypoglycemia (<0.70 mg/L)
percentage of time spent in hypoglycemia derived from CGMS (Continuous Glucose Monitoring System)
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Arm Group | Percentage of Time Spent in Hypoglycemia (<0.70 mg/L) | 11.37 percentage of time | Standard Deviation 3.92 |
Secondary
Plasma C-peptide
Level of plasma C-peptide at 1 year after the first transplant
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Arm Group | Plasma C-peptide | 1.7 ng/ml | Standard Deviation 0.9 |