Type 1 Diabetes
Conditions
Keywords
Type 1 Diabetes, Transplantation, Beta Cells, Encapsulation
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) 1. 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. 2. To obtain histopathology of a biopsy specimen of the intraperitoneal human beta cell implant. 3. 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) 4. 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. 5. To obtain histopathology of a biopsy specimen of the intraperitoneal human beta cell implant 6. To assess the safety profile, metabolic and immune effects of alginate embedded implants in the intraperitoneal cavity.
Interventions
OTHERTransplantation of encapsulated beta cells.
Implantation of a therapeutical dose of encapsulated beta cells.
Sponsors
Universitair Ziekenhuis Brussel
Universitaire Ziekenhuizen KU Leuven
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
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT. | 60 months | 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 |
| Changes from Baseline | 60 months | 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 |
Countries
Belgium
Contacts
Primary ContactBart Keymeulen, MD PhD
Backup ContactRobert Hilbrands, MD PhD
Outcome results
None listed