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

Phase 1

• Conditions: Diabetes Mellitus, Type 1
• Interventions: Drug: ATG-MMF-TAC; Drug: ATG-Rituximab-MMF-TAC; Drug: ATG-basilixumab-MMF-TAC; Procedure: omentum

• Registration Number: NCT00798785
• Lead Sponsor: AZ-VUB

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.

Study Timeline

• Study Start: 2006-10
• Study First Submitted: 2008-11-25
• Study First Submitted QC: 2008-11-25
• Study First Posted: 2008-11-26
• Status Verified: 2013-12
• Last Update Submitted: 2013-12-27
• Last Update Posted: 2013-12-30
• Primary Completion: 2014-12
• Study Completion: 2014-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 50

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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
group I ATG-MMF-TAC	ATG-MMF-TAC	Two clinical implants in the liver: First implant: ATG-fresenium Maintained immunosuppression: MMF-TAC n=30
group II ATG-Rituximab-MMF-TAC	ATG-Rituximab-MMF-TAC	Two clinical implants in the liver: First Implant: ATG fresenium + Rituximab Maintained immunosuppression: MMF-TAC n=5
group III ATG-Basilixumab-MMF-TAC	ATG-basilixumab-MMF-TAC	Two clinical implants in the liver: First implant: ATG-fresenium Second implant: basilixumab Maintained immunosuppression: MMF-TAC n=5
group IV omentum	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

Primary Outcome Measures

Name	Time	Method
Evidence of clinically relevant beta cell graft function	up to 60 months

Trial Locations

Locations (4)

Universitair Ziekenhuis Antwerpen; 🇧🇪 Antwerpen, Belgium

Hopital Erasme; 🇧🇪 Brussel, Belgium

University Hospital Brussels; 🇧🇪 Brussels, Belgium

University Hospital Leuven; 🇧🇪 Leuven, Belgium