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

The present proof of concept study addresses the following specific aims:

The general objectives of this work are:

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

Study Overview

• Status: Unknown
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: ATG-MMF-TAC; Drug: ATG-Rituximab-MMF-TAC; Drug: ATG-basilixumab-MMF-TAC; Procedure: omentum

Detailed Description

1. Aim 1: To increase functional beta cell mass by adding rituximab at first implantation
2. Aim 2: To increase functional beta cell mass by adding basilixumab at second implantation
3. 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.
4. Aim 4: To investigate the potential of the peritoneum and omentum as an alternative site for encapsulated beta-cells.
5. Aim 5: To investigate the potential of the brachioradial muscle as an alternative site for encapsulated beta-cells.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium
    • Recruiting
    • Universitair Ziekenhuis Antwerpen
    • Contact: Christophe De Block, MD,PhD
    • Principal Investigator: Christophe de Block, MD,PhD
  • Brussel, Belgium
    • Recruiting
    • Hôpital Erasme
    • Contact: Laurent Crenier, MD
    • Principal Investigator: Laurent Crenier, MD
  • Brussels, Belgium, 1090
    • Recruiting
    • University Hospital Brussels
  • Leuven, Belgium, 3000
    • Recruiting
    • University Hospital Leuven
    • Contact: Pieter Gillard, MD PhD; Phone Number: +32 16 34 85 54; Email: pieter.gillard@uz.kuleuven.ac.be
    • Sub-Investigator: Pieter Gillard, MD
    • Principal Investigator: Chantal Mathieu, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: group I ATG-MMF-TAC; Two clinical implants in the liver: First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=30	Drug: ATG-MMF-TAC; 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.
Experimental: group II ATG-Rituximab-MMF-TAC; Two clinical implants in the liver: First Implant: ATG fresenium + Rituximab Maintained immunosuppression: MMF-TAC n=5	Drug: ATG-Rituximab-MMF-TAC; 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.
Experimental: group III ATG-Basilixumab-MMF-TAC; Two clinical implants in the liver: First implant: ATG-fresenium Second implant: basilixumab Maintained immunosuppression: MMF-TAC n=5	Drug: ATG-basilixumab-MMF-TAC; 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.
Experimental: group IV omentum; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evidence of clinically relevant beta cell graft function	up to 60 months

Collaborators and Investigators

• Sponsor: AZ-VUB
• Investigators: Principal Investigator: Bart Keymeulen, MD PhD, University Hospital Brussel

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Anticipated): December 1, 2014

Study Registration Dates

• First Submitted: November 25, 2008
• First Submitted That Met QC Criteria: November 25, 2008
• First Posted (Estimate): November 26, 2008

Study Record Updates

• Last Update Posted (Estimate): December 30, 2013
• Last Update Submitted That Met QC Criteria: December 27, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: transplantation; diabetes mellitus type 1; pancreatic beta cell
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: BK_TX_06