Long-term Function of Beta Cell Allografts in Non-uremic Type 1 Diabetic Patients

NCT00798785 | Unknown Phase 1

• 1 other identifier: BK_TX_06
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 4

Brief Summary

The present proof of concept study addresses the following specific aims: The general objectives of this work are:

1. 1.To increase and maintain the functional beta-cell mass after islet transplantation under a condition of low-dose tacrolimus
2. 2.To co-investigate the potential of alternative sites for encapsulated beta-cells

Conditions

Diabetes Mellitus, Type 1

Keywords

diabetes mellitus type 1; pancreatic beta cell; transplantation

Outcome Measures

Primary Outcomes (1)

• Evidence of clinically relevant beta cell graft function

  up to 60 months

Study Arms (4)

group I ATG-MMF-TAC

EXPERIMENTAL

Two clinical implants in the liver: First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=30

Drug: ATG-MMF-TAC

group II ATG-Rituximab-MMF-TAC

EXPERIMENTAL

Two clinical implants in the liver: First Implant: ATG fresenium + Rituximab Maintained immunosuppression: MMF-TAC n=5

Drug: ATG-Rituximab-MMF-TAC

group III ATG-Basilixumab-MMF-TAC

EXPERIMENTAL

Two clinical implants in the liver: First implant: ATG-fresenium Second implant: basilixumab Maintained immunosuppression: MMF-TAC n=5

Drug: ATG-basilixumab-MMF-TAC

group IV omentum

EXPERIMENTAL

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

Procedure: omentum

Interventions

ATG-MMF-TAC DRUG

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.

group I ATG-MMF-TAC

ATG-Rituximab-MMF-TAC DRUG

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.

group II ATG-Rituximab-MMF-TAC

ATG-basilixumab-MMF-TAC DRUG

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.

group III ATG-Basilixumab-MMF-TAC

omentum PROCEDURE

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.

group IV omentum

Eligibility Criteria

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

You may qualify if:

• 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)
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• AZ-VUB: lead

Study Sites (4)

Universitair Ziekenhuis Antwerpen

Antwerp, Belgium

RECRUITING

University Hospital Brussels

Brussels, 1090, Belgium

RECRUITING

Hopital Erasme

Brussels, Belgium

RECRUITING

University Hospital Leuven

Leuven, 3000, Belgium

RECRUITING

Related Publications (6)

• 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.

  PMID: 17090674 BACKGROUND

• 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.

  PMID: 12664214 BACKGROUND

• 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.

  PMID: 16371537 BACKGROUND

• 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.

  PMID: 32433237 DERIVED

• 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.

  PMID: 29679103 DERIVED

• 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.

  PMID: 27779572 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

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

Study Officials

• Bart Keymeulen, MD PhD

  University Hospital Brussel

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bart Keymeulen, MD PhD

CONTACT

+32 2 477 61 11; bart.keymeulen@uzbrussel.be

Bart Keymeulen, MD Phd

CONTACT

bart.keymeulen@uzbrussel.be

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: UZ Brussels

Study Record Dates

• First Submitted: November 25, 2008
• First Posted: November 26, 2008
• Study Start: October 1, 2006
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: December 30, 2013

Record last verified: 2013-12

Locations

BE (4)