Calcineurin Inhibitor (CNI)-Free Immunosuppressive Regimen in T1D Patients Receiving Islet Transplantation

Phase 1

Completed

Conditions: Type 1 Diabetes

Interventions: Drug: CNI free immunosuppression

Registration Number: NCT01346085

Lead Sponsor: Ospedale San Raffaele

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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;

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CNI-free single-group	CNI free immunosuppression	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Glycated Hemoglobin Levels Throughout Follow-up	up to 3 years
the Reduction in Insulin Requirement Compared to Baseline	up to 3 years
Insulin Independence With Adequate Glycemic Control Throughout Follow-up	up to 3 years
Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up	up to 3 year
Severe Hypoglycemic Events Since Completion of Transplant	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).