Diabetes Mellitus, Type 1
Conditions
Keywords
diabetes mellitus type 1, pancreatic beta cell, transplantation
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.
Interventions
DRUGATG-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.
DRUGATG-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.
DRUGATG-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.
PROCEDUREomentum
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.
Sponsors
AZ-VUB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Evidence of clinically relevant beta cell graft function | up to 60 months |
Countries
Belgium
Contacts
Primary ContactBart Keymeulen, MD PhD
Backup ContactBart Keymeulen, MD Phd
Outcome results
None listed