Bet Cell Therapy in Diabetes Type 1

Study Overview
=================
Brief Summary
-----------------
Primary outcome measurement is a parameter of functional beta cell mass at 6 months PT. Functional beta-cell mass will be calculated using the AUC/min between 150 and 160 min during hyperglycemic clamp at 180 mg/dl. The investigators hypothesize that functional beta-cell mass will be more than 20% compared to healthy controls. Secondary outcome measurements: Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT. The investigators will also compare at 2, 6,12, 24,36,48 and 60 months the changes against base-line (base-line = before first intraperitoneal transplantation): metabolic control safety parameters episodes of hypoglycemia islet cell autoantibodies, lymphocyte subsets, T-cell reactivity against auto- and alloantigens using pre-transplant measurements as base-line The investigators hypothesize that metabolic control and prevalence of hypoglycemia, will be significantly improved till PT month 12. Histopathology of a biopsy specimen of the human intraperitoneal beta cell implant, at time of the second implant. Comparison with composition of graft, identification of microenvironment of host origin and correlation with functional assessment will be performed.

Detailed Description
-----------------
In recipients with loss of long-term function after intraportal implantation (Group A) To implant an alginate embedded human beta cell graft in a therapeutic dose in the intraperitoneal cavity of type 1 diabetic patients under immunosuppression with tacrolimus/MMF. To obtain histopathology of a biopsy specimen of the intraperitoneal human beta cell implant. To assess the safety profile, metabolic and immune effects of alginate embedded implants in the intraperitoneal cavity. In patients that are candidates for islet cell transplantation (Group B) To implant an alginate embedded human beta cell graft in a therapeutic dose in intraperitoneal cavity of type 1 diabetic patients under immunosuppression with tacrolimus/MMF. To obtain histopathology of a biopsy specimen of the intraperitoneal human beta cell implant To assess the safety profile, metabolic and immune effects of alginate embedded implants in the intraperitoneal cavity.

Official Title
-----------------
Functional Survival of Beta Cell Allografts After Transplantation in the Peritoneal Cavity of Non-uremic Type 1 Diabetic Patients

Conditions
-----------------
Type 1 Diabetes

Intervention / Treatment
-----------------
* Other: Transplantation of encapsulated beta cells.
* Other: Transplantation of encapsulated beta cells.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Group A: Patients with loss of long-term function after intraportal implantation (- Patients with type 1 insulin-dependent diabetes who received two intraportal implantations > 12 months ago. Random C-peptide between 0.09 and 0.5 ng/dl (glycemia between 100 and 200 mg/dl) Cooperative and reliable patient giving informed consent by signature Group B: Patients that are candidates for islet cell transplantation - 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: albuminuria 30-1000mg/ 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: Women of reproductive age Smoker EBV antibody negativity HIV 1 & 2 antibody positivity CMV IgM positivity Hepatitis B infection GFR < 45 ml/min/1.72 m2 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 clinical significant HLA antibodies Blood donation within one month prior to screening Symptoms and/or signs of infection, particularly (present or past) endocarditis, osteomyelitis 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 Use of illicit drugs or overconsumption of alcohol (> 3 IU/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 a psychiatric disorder that may be exacerbated by the transplantation procedure or interfere with compliance during follow-up Having received antidepressant medications during the last 6 months Participating in another pharmacological 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 |
| --- | --- |
| Active Comparator: Group A<br>Patients with loss of long-term function after intraportal implantation | Other: Transplantation of encapsulated beta cells.<br>* Implantation of a therapeutical dose of encapsulated beta cells.<br>* Other names: encapsulated beta cells;|
| Active Comparator: Group B<br>Patients that are candidates for islet cell transplantation | Other: Transplantation of encapsulated beta cells.<br>* Implantation of a therapeutical dose of encapsulated beta cells.<br>* Other names: encapsulated beta cells;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome measurement is a parameter of functional beta cell mass at 6 months PT. Functional beta-cell mass will be calculated using the AUC/min between 150 and 160 min during hyperglycemic clamp at 180 mg/dl. |  | 6 months PT. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT. | Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT. The investigators will also compare at 2, 6,12, 24,36,48 and 60 months the changes against base-line (base-line = before first intraperitoneal transplantation): metabolic control safety parameters episodes of hypoglycemia islet cell autoantibodies, lymphocyte subsets, T-cell reactivity against auto- and alloantigens using pre-transplant measurements as base-line | 60 months | 
| Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT. | Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT. | 60 months | 
| Changes from Baseline | The investigators will also compare at 2, 6,12, 24,36,48 and 60 months the changes against base-line (base-line = before first intraperitoneal transplantation): metabolic control safety parameters episodes of hypoglycemia islet cell autoantibodies, lymphocyte subsets, T-cell reactivity against auto- and alloantigens using pre-transplant measurements as base-line | 60 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Beta Cells, Type 1 Diabetes, Transplantation, Encapsulation