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

Type 1 Diabetes Clinical Trial

— ECIT-1  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01346085
• Other study ID #: ECIT-1
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: April 29, 2011
• Last updated: April 9, 2014
• Start date: October 2006
• Est. completion date: June 2012

Study information

• Verified date: April 2014
• Source: Ospedale San Raffaele
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: June 2012
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

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).

Locations

Country	Name	City	State
Italy	IRCCS San Raffaele Scientific Institute	Milan
Switzerland	Universitè de Geneve	Geneve

Sponsors (2)

Lead Sponsor	Collaborator
Ospedale San Raffaele	Juvenile Diabetes Research Foundation

Countries where clinical trial is conducted

Italy,  Switzerland, 

References & Publications (2)

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 — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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].	3 year	No
Secondary	Insulin Independence With Adequate Glycemic Control Throughout Follow-up		up to 3 years	No
Secondary	Glycated Hemoglobin Levels Throughout Follow-up		up to 3 years	No
Secondary	Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up		up to 3 year	No
Secondary	the Reduction in Insulin Requirement Compared to Baseline		up to 3 years	No
Secondary	Severe Hypoglycemic Events Since Completion of Transplant		up to 3 years	Yes
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).	up to 3 years	Yes