Calcineurin Inhibitor (CNI)-Free Immunosuppressive Regimen in T1D Patients Receiving Islet Transplantation (ECIT-1)

A Multi-step Trial Towards Single Donor Islet Transplantation in Type 1 Diabetic Patients, Using Calcineurin Inhibitor-free Immunosuppression

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

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: CNI free immunosuppression

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • IRCCS San Raffaele Scientific Institute
• Switzerland
  • Geneve, Switzerland, 1211
    • Université de Genève

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CNI-free single-group

Drug: 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).; Other Names: Kineret, Rapamune, Thymoglobulin, Myfortic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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].	3 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Independence With Adequate Glycemic Control Throughout Follow-up		up to 3 years
Glycated Hemoglobin Levels 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
the Reduction in Insulin Requirement Compared to Baseline		up to 3 years
Severe Hypoglycemic Events Since Completion of Transplant		up to 3 years
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).	up to 3 years

Collaborators and Investigators

• Sponsor: Ospedale San Raffaele
• Collaborators: Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Lorenzo Piemonti, MD, Fondazione Centro San Raffaele del Monte Tabor; Principal Investigator: Thierry Berney, MD, Université de Genève; Study Chair: Antonio Secchi, MD, Fondazione Centro San Raffaele del Monte Tabor; Study Director: Paola Maffi, MD, Cantro San Raffaele del Monte Tabor

Publications and helpful links

General Publications

• Piemonti L, Maffi P, Monti L, Lampasona V, Perseghin G, Magistretti P, Secchi A, Bonifacio E. Beta cell function during rapamycin monotherapy in long-term type 1 diabetes. Diabetologia. 2011 Feb;54(2):433-9. doi: 10.1007/s00125-010-1959-6. Epub 2010 Nov 3.
• Melzi R, Maffi P, Nano R, Sordi V, Mercalli A, Scavini M, Secchi A, Bonifacio E, Piemonti L. Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans. Islets. 2009 Jul-Aug;1(1):42-9. doi: 10.4161/isl.1.1.8881.
• Maffi P, Berney T, Nano R, Niclauss N, Bosco D, Melzi R, Mercalli A, Magistretti P, De Cobelli F, Battaglia M, Scavini M, Demuylder-Mischler S, Secchi A, Piemonti L. Calcineurin inhibitor-free immunosuppressive regimen in type 1 diabetes patients receiving islet transplantation: single-group phase 1/2 trial. Transplantation. 2014 Dec 27;98(12):1301-9. doi: 10.1097/TP.0000000000000396.
• Piemonti L, Everly MJ, Maffi P, Scavini M, Poli F, Nano R, Cardillo M, Melzi R, Mercalli A, Sordi V, Lampasona V, Espadas de Arias A, Scalamogna M, Bosi E, Bonifacio E, Secchi A, Terasaki PI. Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes. 2013 May;62(5):1656-64. doi: 10.2337/db12-1258. Epub 2012 Dec 28.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: April 29, 2011
• First Submitted That Met QC Criteria: April 29, 2011
• First Posted (Estimate): May 2, 2011

Study Record Updates

• Last Update Posted (Estimate): May 9, 2014
• Last Update Submitted That Met QC Criteria: April 9, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: islet transplantation; type 1 diabetes; brittle diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Thymoglobulin
• Other Study ID Numbers: ECIT-1