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

• Sponsor: Ospedale San Raffaele (Other)
• Overall Status: Completed
• CT.gov ID: NCT01346085
• Collaborator: Juvenile Diabetes Research Foundation (Other)
• Enrollment: 10
• Locations: 2
• Arm: 1
• Duration (Months): 68
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: CNI free immunosuppression	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-step Trial Towards Single Donor Islet Transplantation in Type 1 Diabetic Patients, Using Calcineurin Inhibitor-free Immunosuppression
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. The Proportion of Insulin Free Patients 3 Years After the Last Islet Infusion [3 year]

   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].

Secondary Outcome Measures

1. Insulin Independence With Adequate Glycemic Control Throughout Follow-up [up to 3 years]

2. Glycated Hemoglobin Levels Throughout Follow-up [up to 3 years]

3. Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up [up to 3 year]

4. the Reduction in Insulin Requirement Compared to Baseline [up to 3 years]

5. Severe Hypoglycemic Events Since Completion of Transplant [up to 3 years]

6. Any Adverse Event Throughout Follow-up [up to 3 years]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	IRCCS San Raffaele Scientific Institute	Milan		Italy	20132
2	Universitè de Geneve	Geneve		Switzerland	1211

Sponsors and Collaborators

• Ospedale San Raffaele
• Juvenile Diabetes Research Foundation

Investigators

• Principal Investigator: Lorenzo Piemonti, MD, Fondazione Centro San Raffaele del Monte Tabor
• Principal Investigator: Thierry Berney, MD, Universitè de Geneve
• Study Chair: Antonio Secchi, MD, Fondazione Centro San Raffaele del Monte Tabor
• Study Director: Paola Maffi, MD, Cantro San Raffaele del Monte Tabor

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Piemonti Lorenzo, Director Islet Transplantation Program, Ospedale San Raffaele
• ClinicalTrials.gov Identifier: NCT01346085
• Other Study ID Numbers: ECIT-1
• First Posted: May 2, 2011
• Last Update Posted: May 9, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Piemonti Lorenzo, Director Islet Transplantation Program, Ospedale San Raffaele: islet transplantation; brittle diabetes; type 1 diabetes
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Thymoglobulin

Study Results

Participant Flow

Arm/Group Title	CNI-free Single-group
Arm/Group Description	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).
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	CNI-free Single-group
Arm/Group Description	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).
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.6 (4.94)
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Region of Enrollment (participants) [Number]
Italy	8 80%
Switzerland	2 20%

Outcome Measures

1. Primary Outcome

Title	The Proportion of Insulin Free Patients 3 Years After the Last Islet Infusion
Description	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].
Time Frame	3 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CNI-free Single-group
Arm/Group Description	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).
Measure Participants	10
Number [participants]	4 40%

2. Secondary Outcome

Title	Insulin Independence With Adequate Glycemic Control Throughout Follow-up
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CNI-free Single-group
Arm/Group Description	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).
Measure Participants	10
Number [participants]	4 40%

3. Secondary Outcome

Title	Glycated Hemoglobin Levels Throughout Follow-up
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Basal and Stimulated Blood C-peptide Levels in Response to Arginine Challenge Throughout Follow-up
Time Frame	up to 3 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	the Reduction in Insulin Requirement Compared to Baseline
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Severe Hypoglycemic Events Since Completion of Transplant
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Any Adverse Event Throughout Follow-up
Description	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).
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 3 years after last islet infusion
Adverse Event Reporting Description	AEs were recorded according to the "Terminology Criteria for Adverse Events (TCAE) In Trials of Adult Pancreatic Islet Transplantation, Version 4.1 (16 July 2008)" (http://www.isletstudy.org/CITDocs/CIT-TCAE%20V4.pdf).
Arm/Group Title	CNI-free Single-group
Arm/Group Description	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).
All Cause Mortality
	CNI-free Single-group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	CNI-free Single-group
	Affected / at Risk (%)	# Events
Total	8/10 (80%)
Blood and lymphatic system disorders
Anemia	1/10 (10%)	1
Gastrointestinal disorders
Gastrointestinal conditions	2/10 (20%)	2
Immune system disorders
Leucopenia	8/10 (80%)	8
Neutropenia	1/10 (10%)	1
ATG reaction during third infusion	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	CNI-free Single-group
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Anemia	6/10 (60%)	6
Cardiac disorders
Hypertension	1/10 (10%)	1
Gastrointestinal disorders
Transient liver enzyme increase exceeding 5 times the baseline level	2/10 (20%)	2
Mouth ulcers	9/10 (90%)	9
Gastrointestinal conditions	1/10 (10%)	1
Immune system disorders
Leucopenia	2/10 (20%)	2
Neutropenia	7/10 (70%)	7
Infections and infestations
Fungal infection	3/10 (30%)	3
Lower urinary tract infection	1/10 (10%)	1
Otitis externa	1/10 (10%)	1
Metabolism and nutrition disorders
Hyperlipemia	4/10 (40%)	4
Musculoskeletal and connective tissue disorders
Joint pain	2/10 (20%)	2
Renal and urinary disorders
Proteinuria	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Acne or rash	6/10 (60%)	6
Peripheral edema	2/10 (20%)	2
Surgical and medical procedures
Hemorrhage/bleeding from percutaneous transhepatic portal access	5/10 (50%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.