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Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes (GRIIF)

Primary Purpose

Patients With Type 1 Diabetes

Status
Unknown status
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Allogeneic transplantation of intrahepatic islet
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Patients With Type 1 Diabetes focused on measuring diabetes, transplantation

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with type 1 diabetes
  • 18 <Age <55 years
  • Plasma C-peptide <0.2 ng/ml basal and stimulated glucagon
  • Evolution of diabetes for more than 5 years
  • Regular patient follow-up (> or equal to 2 visits per year from the same diabetologist)
  • Patient who received the information and have given their consent in writing
  • Absence of HIV, hepatitis B and hepatitis C, HTLV-1-2
  • ABO compatibility with the donor
  • Cross match negative
  • Anti-HLA antibodies (class I and / or class II) detected by lymphocytotoxicity <20%
  • PCR negative for the BK virus in the blood (so as not to amplify the BK virus replication with the ATG).
  • Accepting patients effective contraception during the study period

For patients in group IA

  • Glomerular filtration rate estimated by the MDRD> 50 ml/min/1.73m2
  • No perception of hypoglycaemia (less than 0.54 mg/dl glucose) at least one value documented in the two years preceding and/or
  • Occurrence of at least one severe hypoglycemic episode (with a third required) and unexplained in the two years before and/or at least two episodes of ketoacidosis per year

  • Average HbA1c> 8.5% over two years, despite intensified treatment (basal pattern, bolus)

    • For patients in the IAK

  • functional renal graft for at least 1 year
  • glomerular filtration rate> 50 ml/min/1.73 m2
  • proteinuria <0.5 g/day
  • Absence of acute rejection in renal previous 6 months

Exclusion Criteria:

  • BMI > 28
  • Need insulin > 1 U/kg per day
  • Pregnancy, lactation
  • Intention of childbearing for the two sexes
  • Psychiatric Disorders
  • Inability to communicate or cooperate with the investigator
  • Lack of therapeutic compliance, including HbA1C > 12%
  • Chronic liver disease
  • Progressive heart disease myocardial infarction within 6 months prior to inclusion, unbalanced CHD)
  • Proliferative retinopathy unstabilized
  • History of cancer, whatever the date, except for basal or squamous cell skin cancers over 1 year.
  • Systemic infection
  • Chronic high risk of requiring corticosteroids
  • Need for long-term corticosteroid, outside that specified in renal transplantation, the patients will be weaned before transplantation
  • Anticoagulant vitamin K or antiplatelet treatments
  • Disorders of hemostasis TP <60 % TCA > 1.5 times the control
  • Anti-HLA antibodies ( class I and/or class II ) detected by lymphocytotoxicity > 20%
  • Platelets < 100 giga/L and/or neutrophils <1.5 giga/L
  • Chronic intoxication by alcohol, tobacco, or other substance (abstinence > 6 months required)
  • Active infection by hepatitis B, hepatitis C and HIV, HTLV-1-HTLV2
  • Ascites

Sites / Locations

  • Saint Louis hospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Allogeneic transplantation of intrahepatic islet

Arm Description

Allogeneic transplantation of intrahepatic islet number required for insulin independence of obtaining, with a threshold dose of 9,000 IEQ/kg body weight of the recipient and a maximum sequence number of 3 infusions. The patient will receive after transplantation immunosuppressive therapy with Thymoglobulin for induction, Prograf and Cellcept, both of which are given throughout the duration of the study

Outcomes

Primary Outcome Measures

restoration of normal glycemic control without insulin
the restoration of normal glycemic control without insulin therapy will be evaluated by measuring - A fasting glucose (> 8 hours) less than 1.25 g/L and a 2 hours glucose after oral intake of 75g of glucose, less than 2 g/L in a patient without insulin for at least 15 consecutive days during the the first 6 months from day 0.

Secondary Outcome Measures

Restoration of normal glycemic control without insulin for a year
Obtaining an improvement in glycemic control
HbA1c <6.5%, with lower insulin doses by 30%
Obtaining a remission of diabetes
The remission of diabetes is defined by the normality of blood glucose or insulin without lHbA1c. The normality of blood glucose is defined below 1.20 g/L and postprandial fasting glycemia less than 1.60 g/L in the book self-monitoring (including 6/7 blood glucoses during the previous 3 days evaluation visit). Normal HbA1c is defined as less than 6.5%.
Improved metabolic profile determined by the OGTT and hyperglycemic clamp
Decreased glycemic variability
defined on blood glucose and / or glucose holter
Reduction of oxidative stress assessed by the urinary excretion of 24 hours of 8-iso-PGF2 rates.
Decrease in the frequency, severity or poor perception of hypoglycaemia defined Hypo score
quality of life
defined by questionnaires DQOL and SF-36
term graft survival
defined by the rate of C-peptide
beta-cell function
based on beta-score
potential of each infusion of islets
number of IEQ/kg of recipient required to reduce the daily insulin dose of 1 unit
degenerative complications of diabetes

Full Information

First Posted
October 28, 2013
Last Updated
September 28, 2016
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT01974674
Brief Title
Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes
Acronym
GRIIF
Official Title
Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Unknown status
Study Start Date
July 2013 (undefined)
Primary Completion Date
December 2016 (Anticipated)
Study Completion Date
January 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
It is a multicentre, sequential, phase II clinical trial, aiming at evaluating the allogeneic islet transplantation for the treatment of type 1 diabetes. 19 patients with type 1 diabetes will be included and ideally distributed evenly: patients with unstable diabetes without renal insufficiency (AI group for "islet alone" by the international customary determination) and patients with a functioning kidney transplant (IAK group for "islet after kidney"). The main endpoint will be defined by the restoration of normal glycemic control without insulin at 6 months after graft.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Patients With Type 1 Diabetes
Keywords
diabetes, transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Allogeneic transplantation of intrahepatic islet
Arm Type
Experimental
Arm Description
Allogeneic transplantation of intrahepatic islet number required for insulin independence of obtaining, with a threshold dose of 9,000 IEQ/kg body weight of the recipient and a maximum sequence number of 3 infusions. The patient will receive after transplantation immunosuppressive therapy with Thymoglobulin for induction, Prograf and Cellcept, both of which are given throughout the duration of the study
Intervention Type
Procedure
Intervention Name(s)
Allogeneic transplantation of intrahepatic islet
Primary Outcome Measure Information:
Title
restoration of normal glycemic control without insulin
Description
the restoration of normal glycemic control without insulin therapy will be evaluated by measuring - A fasting glucose (> 8 hours) less than 1.25 g/L and a 2 hours glucose after oral intake of 75g of glucose, less than 2 g/L in a patient without insulin for at least 15 consecutive days during the the first 6 months from day 0.
Time Frame
6 months after graft
Secondary Outcome Measure Information:
Title
Restoration of normal glycemic control without insulin for a year
Time Frame
1 year
Title
Obtaining an improvement in glycemic control
Description
HbA1c <6.5%, with lower insulin doses by 30%
Time Frame
within 2 years after inclusion
Title
Obtaining a remission of diabetes
Description
The remission of diabetes is defined by the normality of blood glucose or insulin without lHbA1c. The normality of blood glucose is defined below 1.20 g/L and postprandial fasting glycemia less than 1.60 g/L in the book self-monitoring (including 6/7 blood glucoses during the previous 3 days evaluation visit). Normal HbA1c is defined as less than 6.5%.
Time Frame
within 2 years after inclusion
Title
Improved metabolic profile determined by the OGTT and hyperglycemic clamp
Time Frame
within 2 years after inclusion
Title
Decreased glycemic variability
Description
defined on blood glucose and / or glucose holter
Time Frame
within 2 years after inclusion
Title
Reduction of oxidative stress assessed by the urinary excretion of 24 hours of 8-iso-PGF2 rates.
Time Frame
within 2 years after inclusion
Title
Decrease in the frequency, severity or poor perception of hypoglycaemia defined Hypo score
Time Frame
within the 2 years after inclusion
Title
quality of life
Description
defined by questionnaires DQOL and SF-36
Time Frame
within 2 years after inclusion
Title
term graft survival
Description
defined by the rate of C-peptide
Time Frame
within 2 years of inclusion
Title
beta-cell function
Description
based on beta-score
Time Frame
2 years
Title
potential of each infusion of islets
Description
number of IEQ/kg of recipient required to reduce the daily insulin dose of 1 unit
Time Frame
within 2 years after inclusion
Title
degenerative complications of diabetes
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with type 1 diabetes 18 <Age <55 years Plasma C-peptide <0.2 ng/ml basal and stimulated glucagon Evolution of diabetes for more than 5 years Regular patient follow-up (> or equal to 2 visits per year from the same diabetologist) Patient who received the information and have given their consent in writing Absence of HIV, hepatitis B and hepatitis C, HTLV-1-2 ABO compatibility with the donor Cross match negative Anti-HLA antibodies (class I and / or class II) detected by lymphocytotoxicity <20% PCR negative for the BK virus in the blood (so as not to amplify the BK virus replication with the ATG). Accepting patients effective contraception during the study period For patients in group IA Glomerular filtration rate estimated by the MDRD> 50 ml/min/1.73m2 No perception of hypoglycaemia (less than 0.54 mg/dl glucose) at least one value documented in the two years preceding and/or Occurrence of at least one severe hypoglycemic episode (with a third required) and unexplained in the two years before and/or at least two episodes of ketoacidosis per year Average HbA1c> 8.5% over two years, despite intensified treatment (basal pattern, bolus) • For patients in the IAK functional renal graft for at least 1 year glomerular filtration rate> 50 ml/min/1.73 m2 proteinuria <0.5 g/day Absence of acute rejection in renal previous 6 months Exclusion Criteria: BMI > 28 Need insulin > 1 U/kg per day Pregnancy, lactation Intention of childbearing for the two sexes Psychiatric Disorders Inability to communicate or cooperate with the investigator Lack of therapeutic compliance, including HbA1C > 12% Chronic liver disease Progressive heart disease myocardial infarction within 6 months prior to inclusion, unbalanced CHD) Proliferative retinopathy unstabilized History of cancer, whatever the date, except for basal or squamous cell skin cancers over 1 year. Systemic infection Chronic high risk of requiring corticosteroids Need for long-term corticosteroid, outside that specified in renal transplantation, the patients will be weaned before transplantation Anticoagulant vitamin K or antiplatelet treatments Disorders of hemostasis TP <60 % TCA > 1.5 times the control Anti-HLA antibodies ( class I and/or class II ) detected by lymphocytotoxicity > 20% Platelets < 100 giga/L and/or neutrophils <1.5 giga/L Chronic intoxication by alcohol, tobacco, or other substance (abstinence > 6 months required) Active infection by hepatitis B, hepatitis C and HIV, HTLV-1-HTLV2 Ascites
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pierre CATTAN, MD PhD
Phone
33 1 42494786
Email
pierre.cattan@sls.aphp.fr
Facility Information:
Facility Name
Saint Louis hospital
City
Paris
State/Province
Ile de France
ZIP/Postal Code
75010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pierre CATTAN, MD PhD
Phone
33 1 42494786
Email
pierre.cattan@sls.aphp.fr

12. IPD Sharing Statement

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Allogeneic Islet Transplantation for the Treatment of Type 1 Diabetes

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