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

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00798785
• Other study ID #: BK_TX_06
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: November 25, 2008
• Last updated: December 27, 2013
• Start date: October 2006
• Est. completion date: December 2014

Study information

• Verified date: December 2013
• Source: AZ-VUB
• Contact: Bart Keymeulen, MD PhD
• Phone: +32 2 477 61 11
• Email: bart.keymeulen[@]uzbrussel.be
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health Products
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

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.
• 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.
• 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.

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.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Antwerpen	Antwerpen
Belgium	Hopital Erasme	Brussel
Belgium	University Hospital Brussels	Brussels
Belgium	University Hospital Leuven	Leuven

Sponsors (1)

Lead Sponsor	Collaborator
AZ-VUB

Country where clinical trial is conducted

Belgium, 

References & Publications (3)

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. Epub 2006 Nov 7. — View 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. — View 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. Epub 2003 Feb 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evidence of clinically relevant beta cell graft function		up to 60 months	Yes