Back to resultsLong-term Function of Beta Cell Allografts in Non-uremic Type 1 Diabetic Patients
Primary Purpose
Diabetes Mellitus, Type 1
Status
Unknown status
Phase
Phase 1
Locations
Belgium
Study Type
Interventional
Intervention
ATG-MMF-TAC
ATG-Rituximab-MMF-TAC
ATG-basilixumab-MMF-TAC
omentum
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring diabetes mellitus type 1, pancreatic beta cell, transplantation
Eligibility Criteria
Inclusion Criteria:
- Age 18-65 years, male or female, Caucasian or not; only subjects < 50 yrs will be allocated to the rituximab treatment arm
- Body weight < 100 kg; patients with a bodyweight of < 80kg, will receive priority
- Patients with a BMI ≤ 27 kg/m2 will receive priority
- Type 1 insulin-dependent diabetes
- C-peptide < 0.07 nmol/l (<0.2 µg/l) 6 min. after glucagon IV (1mg) (glycemia > 180 mg/dl)
- Intensive insulin therapy for more than two years, patients with insulin pump during at least 2 months before inclusion will receive priority
Patients should have at least one of the following chronic complications of diabetes:
- Plasma creatinine <2 mg/dl and albuminuria 30-1000 mg/ 24hrs on 3 separate determinations (>1 month) outside an episode of illness, despite intake of ACE inhibitors; mean systolic blood pressure should be under 130 mmHg and mean diastolic blood pressure under 85 mmHg, when measured at home with ambulatory BP monitoring
- Moderate or severe non-proliferative or proliferative retinopathy
- Hypoglycemic unawareness
- Cooperative and reliable patient giving informed consent by signature
Exclusion Criteria:
- Smoker
- EBV antibody negativity
- HIV 1 & 2 antibody positivity
- CMV IgM positivity
- Plasma creatinine ≥ 2 mg/dl and/or albuminuria ≥1000 mg/24 hrs
- History of thrombosis or pulmonary embolism
- History of malignancy, tuberculosis or chronic viral hepatitis
- History of any other serious illness which could be relevant for the protocol
- Presence of HLA antibodies
- Blood donation within one month prior to screening or during the study
- Symptoms and/or signs of infection, particularly (present or past) endocarditis, osteomyelitis, past tuberculosis with requirement for therapy
- Any history of hepatic or neoplastic disease
- Any history of renal disease (except diabetes)
- Abnormal liver function tests and /or NMR of liver
- Hemoglobinopathy
- History of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the patient
- Pregnancy or use of inadequate contraception by female patients of childbearing potential
- Use of illicit drugs or overconsumption of alcohol (> 3 beers/day) or history of drug or alcohol abuse
- Being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders
- Having received antidepressant medications during the last 6 months
- Having participated the last 12 months or participating in another clinical study
Sites / Locations
- Universitair Ziekenhuis AntwerpenRecruiting
- University Hospital BrusselsRecruiting
- Hopital ErasmeRecruiting
- University Hospital LeuvenRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
group I ATG-MMF-TAC
group II ATG-Rituximab-MMF-TAC
group III ATG-Basilixumab-MMF-TAC
group IV omentum
Arm Description
Two clinical implants in the liver: First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=30
Two clinical implants in the liver: First Implant: ATG fresenium + Rituximab Maintained immunosuppression: MMF-TAC n=5
Two clinical implants in the liver: First implant: ATG-fresenium Second implant: basilixumab Maintained immunosuppression: MMF-TAC n=5
Two clinical implants: first in the omentum followed by a clinical implant in the liver: First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=10
Outcomes
Primary Outcome Measures
Evidence of clinically relevant beta cell graft function
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00798785
Brief Title
Long-term Function of Beta Cell Allografts in Non-uremic Type 1 Diabetic Patients
Official Title
Long-term Function of Beta Cell Allografts in Non-uremic Type 1 Diabetic Patients
Study Type
Interventional
2. Study Status
Record Verification Date
December 2013
Overall Recruitment Status
Unknown status
Study Start Date
October 2006 (undefined)
Primary Completion Date
December 2014 (Anticipated)
Study Completion Date
December 2014 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
AZ-VUB
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The present proof of concept study addresses the following specific aims:
The general objectives of this work are:
To increase and maintain the functional beta-cell mass after islet transplantation under a condition of low-dose tacrolimus
To co-investigate the potential of alternative sites for encapsulated beta-cells
Detailed Description
Aim 1: To increase functional beta cell mass by adding rituximab at first implantation
Aim 2: To increase functional beta cell mass by adding basilixumab at second implantation
Aim 3: To assess the influence of down-tapering the tacrolimus dose during posttransplant years 2-5 on these data, on metabolic control, on the prevalence of hypoglycemia and on safety parameters.
Aim 4: To investigate the potential of the peritoneum and omentum as an alternative site for encapsulated beta-cells.
Aim 5: To investigate the potential of the brachioradial muscle as an alternative site for encapsulated beta-cells.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
Keywords
diabetes mellitus type 1, pancreatic beta cell, transplantation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
group I ATG-MMF-TAC
Arm Type
Experimental
Arm Description
Two clinical implants in the liver:
First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=30
Arm Title
group II ATG-Rituximab-MMF-TAC
Arm Type
Experimental
Arm Description
Two clinical implants in the liver:
First Implant: ATG fresenium + Rituximab Maintained immunosuppression: MMF-TAC n=5
Arm Title
group III ATG-Basilixumab-MMF-TAC
Arm Type
Experimental
Arm Description
Two clinical implants in the liver:
First implant: ATG-fresenium Second implant: basilixumab Maintained immunosuppression: MMF-TAC n=5
Arm Title
group IV omentum
Arm Type
Experimental
Arm Description
Two clinical implants: first in the omentum followed by a clinical implant in the liver:
First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=10
Intervention Type
Drug
Intervention Name(s)
ATG-MMF-TAC
Intervention Description
ATG-fresenium for max 6 consecutive days depending on CD3 count, starting the day before transplantation.
Tacrolimus levels for 2 years between 8-10 ng/ml.
At year 2: randomization:
group A: till 48 months: tacrolimus levels 8-10 ng/ml 48-60 months: tacrolimus levels 6-8 ng/ml group B: 24-36 months: 6-8 ng/ml 36-60 months: 4-6 ng/ml A subgroup of these patients will receive a sub clinical implant subcutaneous (total n=5) at the time of the first clinical implant in the liver.
Intervention Type
Drug
Intervention Name(s)
ATG-Rituximab-MMF-TAC
Intervention Description
ATG-fresenium for max 6 consecutive days depending on CD3 count, starting the day before transplantation.
Rituximab: the day before transplantation, day 5; 12 and 19 after implantation. Tacrolimus levels for 2 years between 8-10 ng/ml.
At year 2: randomization:
group A: till 48 months: tacrolimus levels 8-10 ng/ml 48-60 months: tacrolimus levels 6-8 ng/ml group B: 24-36 months: 6-8 ng/ml 36-60 months: 4-6 ng/ml A subgroup of these patients will receive a sub clinical implant, subcutaneous at the time of the first clinical implant in the liver.
Intervention Type
Drug
Intervention Name(s)
ATG-basilixumab-MMF-TAC
Intervention Description
First transplantation:
ATG-fresenium for max 6 consecutive days depending on CD3 count, starting the day before transplantation.
Second transplantation:
Basilixumab:
the day before the second transplantation followed by 4days after transplantation.
Tacrolimus levels for 2 years between 8-10 ng/ml.
At year 2: randomization:
group A: till 48 months: tacrolimus levels 8-10 ng/ml 48-60 months: tacrolimus levels 6-8 ng/ml group B: 24-36 months: 6-8 ng/ml 36-60 months: 4-6 ng/ml A subgroup of these patients will receive a sub clinical implant, subcutaneous at the time of the first clinical implant in the liver.
Intervention Type
Procedure
Intervention Name(s)
omentum
Intervention Description
Two clinical implants: first in omentum followed by a clinical implant in the liver:
In a group of 10 patients, a clinical implant in the omentum will be implanted. If random C-peptide levels >= 0.5 ng/ml are measured at 2 months post-transplantation, a second omental implant will be done. If no clinical relevant beta cell graft function is measured, two intraportal implants will be given as a compassionate use procedure. An interim analysis after 5 patients has to shown clinical relevant function at month 2 in 3 out of 5 patients before the subsequent 5 patients can be transplanted in the omentum.
Primary Outcome Measure Information:
Title
Evidence of clinically relevant beta cell graft function
Time Frame
up to 60 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18-65 years, male or female, Caucasian or not; only subjects < 50 yrs will be allocated to the rituximab treatment arm
Body weight < 100 kg; patients with a bodyweight of < 80kg, will receive priority
Patients with a BMI ≤ 27 kg/m2 will receive priority
Type 1 insulin-dependent diabetes
C-peptide < 0.07 nmol/l (<0.2 µg/l) 6 min. after glucagon IV (1mg) (glycemia > 180 mg/dl)
Intensive insulin therapy for more than two years, patients with insulin pump during at least 2 months before inclusion will receive priority
Patients should have at least one of the following chronic complications of diabetes:
Plasma creatinine <2 mg/dl and albuminuria 30-1000 mg/ 24hrs on 3 separate determinations (>1 month) outside an episode of illness, despite intake of ACE inhibitors; mean systolic blood pressure should be under 130 mmHg and mean diastolic blood pressure under 85 mmHg, when measured at home with ambulatory BP monitoring
Moderate or severe non-proliferative or proliferative retinopathy
Hypoglycemic unawareness
Cooperative and reliable patient giving informed consent by signature
Exclusion Criteria:
Smoker
EBV antibody negativity
HIV 1 & 2 antibody positivity
CMV IgM positivity
Plasma creatinine ≥ 2 mg/dl and/or albuminuria ≥1000 mg/24 hrs
History of thrombosis or pulmonary embolism
History of malignancy, tuberculosis or chronic viral hepatitis
History of any other serious illness which could be relevant for the protocol
Presence of HLA antibodies
Blood donation within one month prior to screening or during the study
Symptoms and/or signs of infection, particularly (present or past) endocarditis, osteomyelitis, past tuberculosis with requirement for therapy
Any history of hepatic or neoplastic disease
Any history of renal disease (except diabetes)
Abnormal liver function tests and /or NMR of liver
Hemoglobinopathy
History of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the patient
Pregnancy or use of inadequate contraception by female patients of childbearing potential
Use of illicit drugs or overconsumption of alcohol (> 3 beers/day) or history of drug or alcohol abuse
Being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders
Having received antidepressant medications during the last 6 months
Having participated the last 12 months or participating in another clinical study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bart Keymeulen, MD PhD
Phone
+32 2 477 61 11
Email
bart.keymeulen@uzbrussel.be
First Name & Middle Initial & Last Name or Official Title & Degree
Bart Keymeulen, MD Phd
Email
bart.keymeulen@uzbrussel.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bart Keymeulen, MD PhD
Organizational Affiliation
University Hospital Brussel
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitair Ziekenhuis Antwerpen
City
Antwerpen
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christophe De Block, MD,PhD
First Name & Middle Initial & Last Name & Degree
Christophe de Block, MD,PhD
Facility Name
University Hospital Brussels
City
Brussels
ZIP/Postal Code
1090
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bart Keymeulen, MD PhD
Phone
+32 2 477 61 11
Email
bart.keymeulen@uzbrussel.be
First Name & Middle Initial & Last Name & Degree
Bart Keymeulen, MD PhD
Facility Name
Hopital Erasme
City
Brussel
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Laurent Crenier, MD
First Name & Middle Initial & Last Name & Degree
Laurent Crenier, MD
Facility Name
University Hospital Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pieter Gillard, MD PhD
Phone
+32 16 34 85 54
Email
pieter.gillard@uz.kuleuven.ac.be
First Name & Middle Initial & Last Name & Degree
Da Hae Lee, MD
Phone
+32 16 34 23 98
Email
dahae.lee@uzleuven.be
First Name & Middle Initial & Last Name & Degree
Pieter Gillard, MD
First Name & Middle Initial & Last Name & Degree
Chantal Mathieu, MD PhD
12. IPD Sharing Statement
Citations:
PubMed Identifier
17090674
Citation
Keymeulen B, Gillard P, Mathieu C, Movahedi B, Maleux G, Delvaux G, Ysebaert D, Roep B, Vandemeulebroucke E, Marichal M, In 't Veld P, Bogdani M, Hendrieckx C, Gorus F, Ling Z, van Rood J, Pipeleers D. Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17444-9. doi: 10.1073/pnas.0608141103. Epub 2006 Nov 7.
Results Reference
background
PubMed Identifier
12664214
Citation
Movahedi B, Keymeulen B, Lauwers MH, Goes E, Cools N, Delvaux G. Laparoscopic approach for human islet transplantation into a defined liver segment in type-1 diabetic patients. Transpl Int. 2003 Mar;16(3):186-90. doi: 10.1007/s00147-002-0517-7. Epub 2003 Feb 15.
Results Reference
background
PubMed Identifier
16371537
Citation
Maleux G, Gillard P, Keymeulen B, Pipeleers D, Ling Z, Heye S, Thijs M, Mathieu C, Marchal G. Feasibility, safety, and efficacy of percutaneous transhepatic injection of beta-cell grafts. J Vasc Interv Radiol. 2005 Dec;16(12):1693-7. doi: 10.1097/01.RVI.0000182506.88739.39.
Results Reference
background
PubMed Identifier
32433237
Citation
Lee D, Gillard P, Hilbrands R, Ling Z, Van de Velde U, Jacobs-Tulleneers-Thevissen D, Maleux G, Lapauw B, Crenier L, De Block C, Mathieu C, Pipeleers D, Keymeulen B. Use of Culture to Reach Metabolically Adequate Beta-cell Dose by Combining Donor Islet Cell Isolates for Transplantation in Type 1 Diabetes Patients. Transplantation. 2020 Oct;104(10):e295-e302. doi: 10.1097/TP.0000000000003321.
Results Reference
derived
PubMed Identifier
29679103
Citation
Balke EM, Demeester S, Lee D, Gillard P, Hilbrands R, Van de Velde U, Van der Auwera BJ, Ling Z, Roep BO, Pipeleers DG, Keymeulen B, Gorus FK. SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients. Diabetologia. 2018 Jul;61(7):1623-1632. doi: 10.1007/s00125-018-4609-z. Epub 2018 Apr 20.
Results Reference
derived
PubMed Identifier
27779572
Citation
Lee D, Keymeulen B, Hilbrands R, Ling Z, Van de Velde U, Jacobs-Tulleneers-Thevissen D, Maleux G, Lapauw B, Crenier L, De Block C, Mathieu C, Pipeleers D, Gillard P. Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression. Transplantation. 2017 Sep;101(9):2218-2227. doi: 10.1097/TP.0000000000001543. Erratum In: Transplantation. 2017 Dec;101(12 ):e353.
Results Reference
derived
Learn more about this trial
Long-term Function of Beta Cell Allografts in Non-uremic Type 1 Diabetic Patients
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