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

NCT01346085 | Completed Phase 1 Results DMC

• 1 other identifier: ECIT-1
• Study Type: interventional
• Target: 10
• Locations: 2 countries
• Sites: 2

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

Conditions

Type 1 Diabetes

Keywords

islet transplantation; brittle diabetes; type 1 diabetes

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• 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

Study Arms (1)

CNI-free single-group

EXPERIMENTAL

Drug: CNI free immunosuppression

Interventions

CNI free immunosuppression 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).

Also known as: Kineret, Rapamune, Thymoglobulin, Myfortic

CNI-free single-group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Ospedale San Raffaele: lead
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (2)

IRCCS San Raffaele Scientific Institute

Milan, 20132, Italy

Location

Universitè de Geneve

Geneva, 1211, Switzerland

Location

Related Publications (4)

• 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.

  PMID: 21046356 BACKGROUND

• 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.

  PMID: 21084848 RESULT

• 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.

  PMID: 25286053 DERIVED

• 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.

  PMID: 23274902 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Interleukin 1 Receptor Antagonist Protein; Sirolimus; thymoglobulin; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Dr Lorenzo Piemonti
• Organization: Ospedale San Raffaele

piemonti.lorenzo@hsr.it

+390226432706

Study Officials

• Lorenzo Piemonti, MD

  Fondazione Centro San Raffaele del Monte Tabor

  PRINCIPAL INVESTIGATOR

• Thierry Berney, MD

  Universitè de Geneve

  PRINCIPAL INVESTIGATOR

• Antonio Secchi, MD

  Fondazione Centro San Raffaele del Monte Tabor

  STUDY CHAIR

• Paola Maffi, MD

  Cantro San Raffaele del Monte Tabor

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director Islet Transplantation Program

Study Record Dates

• First Submitted: April 29, 2011
• First Posted: May 2, 2011
• Study Start: October 1, 2006
• Primary Completion: June 1, 2009
• Study Completion: June 1, 2012
• Last Updated: May 9, 2014
• Results First Posted: May 9, 2014

Record last verified: 2014-04

Locations

IT (1); CH (1)