Type 1 Diabetes
Conditions
Keywords
islet transplantation, brittle diabetes, type 1 diabetes
Brief summary
Our final objective is to develop an adoptive therapy with tolerogenic donor-specific Tr1 cells in T1D patients undergoing pancreatic islet transplantation (Tx). The achievement of this objective depends by the availability of an immunosuppressive treatment (IS) compatible with the survival, function, and expansion of the transferred Tr1 cells. For this purpose the investigators design a CNI-free single-group, phase 1-2 trial excluding the ATG or anti-CD25 induction therapy after the 1st islet infusion
Detailed description
We designed the clinical trial as a single-arm, phase 1-2 trial conducted in two transplant centers (San Raffaele Scientific Institute, Milan, Italy; Cell Isolation and Transplantation Center, University of Geneva, Geneva, Switzerland) which used a common protocol for islet preparation, post-transplantation patient management and data collection. The trial is exploratory in nature and the target enrollment is 10 patients. The recruitment is competitive between the two centers and each patient is to receive at least 10,000 IE/kg. Up to three islet infusions are allowed per patients until insulin independence is reached, provided that partial islet function (i.e., fasting C-peptide ≥0.3 ng/mL) is maintained between infusions. We planned an individual follow-up of 3 years after the last islet infusion. Patients with type 1 diabetes are eligible for this study. Major criteria for inclusion are: age 18-65 years; type 1 diabetes with onset \<40 years of age; insulin treatment of at least 5 years at the time of enrollment; stimulated C-peptide in response to arginine \<0.5 ng/ml; multiple (three or more) daily insulin injections or Continuous Subcutaneous Insulin Infusion; self-blood glucose monitoring ≥3 times/day; high glycemic instability and/or hypoglycemia unawareness; inability to consistently attain a glycated hemoglobin target of \<7.5 % without severe hypoglycemia (defined as an hypoglycemic episode requiring the assistance by another person for its resolution) in the past 36 months despite medical management by a diabetes specialist. Major criteria for exclusion are: HbA1c \>12%; BMI \>30 kg/m2, or insulin requirement \> 0.8 IU/kg/day; poorly controlled hypertension; untreated proliferative diabetic retinopathy; presence or history of macroalbuminuria (\>300mg/g day) or estimated glomerular filtration rate \<60 ml/min/1.73 m2 for females or \<70 ml/min/1.73 m2 for males.
Interventions
DRUGCNI free immunosuppression
Immunosuppression consisted of: (i) pre-Tx rapamycin treatment (0.1 mg/kg/day) for at least 30 days; (ii) induction therapy with ATG (1.5 mg/kg/day for 4 days starting at day -1) and a steroid bolus (methyl-prednisolone 500 mg, day -1) plus low dose steroids (prednisone, 10 mg/day) and interleukin-1 (IL-1) receptor antagonist (100 mg/day) for 2 weeks (with ATG and steroid bolus administered only prior to the 1st islet infusion; (iii) maintenance with rapamycin (0.1 mg/kg/day) plus mycophenolate mofetil (2 g/day).
Sponsors
Juvenile Diabetes Research Foundation
Ospedale San Raffaele
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
* Male and female patients aged 18-65yr * ability to provide written informed consent and comply with the study protocol procedures * clinical history of type 1 diabetes with onset \<40yr of age, on insulin for at least 5yr at the time of enrollment * absent stimulated C-peptide (\<0.5ng/ml) in response to arginine * multiple (three or more) daily insulin injections or insulin pump therapy * self blood glucose monitoring ≥3 times/day, supervised by a specialist physician * high glycemic instability and hypoglycemia unawareness * inability to consistently attain a HbA1c \< 7.5 % target without experiencing severe hypoglycemia (assistance by another person) in the past 36 months despite appropriate medical management.
Exclusion criteria
* HbA1c \>12% * BMI \>30 kg/m2, or insulin requirement of \> 0.8 IU/kg/day; * poorly controlled hypertension; * untreated proliferative diabetic retinopathy; * presence or history of macroalbuminuria (\>300mg/g day) or measured glomerular filtration rate \<60 ml/min/1.73 m2 for females and \<70 ml/min/1.73 m2 for males * for female participants: positive pregnancy test, presently breast-feeding, or unwilling to use effective contraceptive measures for the duration of the study and 3 months after discontinuation * for male participants: intent to procreate during the duration of the study or within 3 months after discontinuation or unwillingness to use effective measures of contraception; * any history of malignancy within the previous 5 years, except for completely resected squamous or basal cell carcinoma of the skin;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Insulin Free Patients 3 Years After the Last Islet Infusion | 3 year | Insulin independence is defined as no need for exogenous insulin, with adequate glycemic control \[i.e., glycated hemoglobin \<7% (normal range 3.5 - 6.0%), fasting glucose levels not exceeding 140 mg/dL (7.8 mmol/L) more than three times per week and 2-hour postprandial levels not exceeding 180 mg/dL (10 mmol/L) more than four times per week\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up | up to 3 year | — |
| the Reduction in Insulin Requirement Compared to Baseline | up to 3 years | — |
| Severe Hypoglycemic Events Since Completion of Transplant | up to 3 years | — |
| Glycated Hemoglobin Levels Throughout Follow-up | up to 3 years | — |
| Any Adverse Event Throughout Follow-up | up to 3 years | Among study participants there were no reports of death, post-transplantation lymphoproliferative disease, cancer, or opportunistic infections. There was no evidence of cytomegalovirus disease, infection or serological activation (CMV early antigens negative during the whole follow-up), nor of Epstein-Barr clinical and serological reactivation (all patients were antibodies anti EBV positive before transplant, as per the inclusion criteria). |
| Insulin Independence With Adequate Glycemic Control Throughout Follow-up | up to 3 years | — |
Countries
Italy, Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CNI-free Single-group CNI free immunosuppression: Immunosuppression consisted of: (i) pre-Tx rapamycin treatment (0.1 mg/kg/day) for at least 30 days; (ii) induction therapy with ATG (1.5 mg/kg/day for 4 days starting at day -1) and a steroid bolus (methyl-prednisolone 500 mg, day -1) plus low dose steroids (prednisone, 10 mg/day) and interleukin-1 (IL-1) receptor antagonist (100 mg/day) for 2 weeks (with ATG and steroid bolus administered only prior to the 1st islet infusion; (iii) maintenance with rapamycin (0.1 mg/kg/day) plus mycophenolate mofetil (2 g/day). | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | CNI-free Single-group |
|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 4.94 |
| Region of Enrollment Italy | 8 participants |
| Region of Enrollment Switzerland | 2 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 8 / 10 |
Outcome results
Primary
The Proportion of Insulin Free Patients 3 Years After the Last Islet Infusion
Insulin independence is defined as no need for exogenous insulin, with adequate glycemic control \[i.e., glycated hemoglobin \<7% (normal range 3.5 - 6.0%), fasting glucose levels not exceeding 140 mg/dL (7.8 mmol/L) more than three times per week and 2-hour postprandial levels not exceeding 180 mg/dL (10 mmol/L) more than four times per week\].
Time frame: 3 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CNI-free Single-group | The Proportion of Insulin Free Patients 3 Years After the Last Islet Infusion | 4 participants |
Secondary
Any Adverse Event Throughout Follow-up
Among study participants there were no reports of death, post-transplantation lymphoproliferative disease, cancer, or opportunistic infections. There was no evidence of cytomegalovirus disease, infection or serological activation (CMV early antigens negative during the whole follow-up), nor of Epstein-Barr clinical and serological reactivation (all patients were antibodies anti EBV positive before transplant, as per the inclusion criteria).
Time frame: up to 3 years
Secondary
Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up
Time frame: up to 3 year
Secondary
Glycated Hemoglobin Levels Throughout Follow-up
Time frame: up to 3 years
Secondary
Insulin Independence With Adequate Glycemic Control Throughout Follow-up
Time frame: up to 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CNI-free Single-group | Insulin Independence With Adequate Glycemic Control Throughout Follow-up | 4 participants |
Secondary
Severe Hypoglycemic Events Since Completion of Transplant
Time frame: up to 3 years
Secondary
the Reduction in Insulin Requirement Compared to Baseline
Time frame: up to 3 years