Clinical trial NCT00798785: 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
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: diabetes mellitus type 1
pancreatic beta cell
transplantation
Lead sponsor: AZ-VUB
Sponsor class: OTHER
First posted: 2008-11-26
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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.

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

Primary outcomes:
measure: Evidence of clinically relevant beta cell graft function
timeFrame: up to 60 months
Secondary outcomes:
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Brussels
country: Belgium
facility: University Hospital Brussels
city: Brussel
country: Belgium
facility: Hopital Erasme
city: Leuven
country: Belgium
facility: University Hospital Leuven
Study officials:
affiliation: University Hospital Brussel
name: Bart Keymeulen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.