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

Study Overview
=================
Brief Summary
-----------------
The present proof of concept study addresses the following specific aims: The general objectives of this work are: To increase and maintain the functional beta-cell mass after islet transplantation under a condition of low-dose tacrolimus To co-investigate the potential of alternative sites for encapsulated beta-cells

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

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

Conditions
-----------------
Diabetes Mellitus, Type 1

Intervention / Treatment
-----------------
* Drug: ATG-MMF-TAC
* Drug: ATG-Rituximab-MMF-TAC
* Drug: ATG-basilixumab-MMF-TAC
* Procedure: omentum


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diabetes mellitus type 1, pancreatic beta cell, transplantation