Clinical trial NCT01346085: Calcineurin Inhibitor (CNI)-Free Immunosuppressive Regimen in T1D Patients Receiving Islet Transplantation
Official title: A Multi-step Trial Towards Single Donor Islet Transplantation in Type 1 Diabetic Patients, Using Calcineurin Inhibitor-free Immunosuppression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type 1 Diabetes
Keywords: islet transplantation
brittle diabetes
type 1 diabetes
Lead sponsor: Ospedale San Raffaele
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2011-05-02
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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;

Primary outcomes:
measure: The Proportion of Insulin Free Patients 3 Years After the Last Islet Infusion
timeFrame: 3 year
Secondary outcomes:
measure: Insulin Independence With Adequate Glycemic Control Throughout Follow-up
timeFrame: up to 3 years
measure: Glycated Hemoglobin Levels Throughout Follow-up
timeFrame: up to 3 years
measure: Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up
timeFrame: up to 3 year
measure: the Reduction in Insulin Requirement Compared to Baseline
timeFrame: up to 3 years
measure: Severe Hypoglycemic Events Since Completion of Transplant
timeFrame: up to 3 years
measure: Any Adverse Event Throughout Follow-up
timeFrame: up to 3 years
Other outcomes:
Locations:
city: Milan
country: Italy
facility: IRCCS San Raffaele Scientific Institute
city: Geneve
country: Switzerland
facility: Universitè de Geneve
Study officials:
affiliation: Fondazione Centro San Raffaele del Monte Tabor
name: Lorenzo Piemonti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitè de Geneve
name: Thierry Berney, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione Centro San Raffaele del Monte Tabor
name: Antonio Secchi, MD
role: STUDY_CHAIR
affiliation: Cantro San Raffaele del Monte Tabor
name: Paola Maffi, MD
role: STUDY_DIRECTOR
References:
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.
citation: 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.
citation: 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.
citation: 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.