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

NCT ID: NCT01346085

Last Updated: 2014-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-10-31
• Study Completion Date: 2012-06-30

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.

Conditions

Type 1 Diabetes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CNI-free single-group

Group Type: EXPERIMENTAL

CNI free immunosuppression

Intervention Type: DRUG

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).

Interventions

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).

Intervention Type: DRUG

Other Intervention Names

Kineret, Rapamune, Thymoglobulin, Myfortic

Eligibility Criteria

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;

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

Ospedale San Raffaele

OTHER

Sponsor Role: lead

Responsible Party

Piemonti Lorenzo

Director Islet Transplantation Program

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lorenzo Piemonti, MD

Role: PRINCIPAL_INVESTIGATOR

Fondazione Centro San Raffaele del Monte Tabor

Thierry Berney, MD

Role: PRINCIPAL_INVESTIGATOR

Universitè de Geneve

Antonio Secchi, MD

Role: STUDY_CHAIR

Fondazione Centro San Raffaele del Monte Tabor

Paola Maffi, MD

Role: STUDY_DIRECTOR

Cantro San Raffaele del Monte Tabor

Locations

IRCCS San Raffaele Scientific Institute

Milan, , Italy

Universitè de Geneve

Geneva, , Switzerland

Countries

Italy; Switzerland

References

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.

Reference Type: BACKGROUND

PMID: 21046356 (View on PubMed)

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.

Reference Type: RESULT

PMID: 21084848 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25286053 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23274902 (View on PubMed)

Other Identifiers

ECIT-1

Identifier Type: -

Identifier Source: org_study_id