Bet Cell Therapy in Diabetes Type 1

Type 1 Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01379729
• Other study ID #: BK_TX_07
• Status: Recruiting
• Phase: Phase 2
• First received: May 2, 2011
• Last updated: December 27, 2013
• Start date: May 2011
• Est. completion date: May 2018

Study information

• Verified date: December 2013
• Source: AZ-VUB
• Contact: Bart Keymeulen, MD PhD
• Phone: +32 2 477 61 11
• Email: bart.keymeulen[@]uzbrussel.be
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health Products
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: May 2018
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Other:
• Transplantation of encapsulated beta cells.
Implantation of a therapeutical dose of encapsulated beta cells.
• Transplantation of encapsulated beta cells.
Implantation of a therapeutical dose of encapsulated beta cells.

Locations

Country	Name	City	State
Belgium	UZ Brussel	Brussels
Belgium	UZ Leuven	Leuven

Sponsors (3)

Lead Sponsor	Collaborator
AZ-VUB	Universitair Ziekenhuis Brussel, Universitaire Ziekenhuizen Leuven

Country where clinical trial is conducted

Belgium, 

References & Publications (5)

Gillard P, Keymeulen B, Mathieu C. Beta-cell transplantation in type 1 diabetic patients: a work in progress to cure. Verh K Acad Geneeskd Belg. 2010;72(1-2):71-98. — View Citation

Gillard P, Vandemeulebroucke E, Keymeulen B, Pirenne J, Maes B, De Pauw P, Vanrenterghem Y, Pipeleers D, Mathieu C. Functional beta-cell mass and insulin sensitivity is decreased in insulin-independent pancreas-kidney recipients. Transplantation. 2009 Feb 15;87(3):402-7. doi: 10.1097/TP.0b013e3181928a1c. — View Citation

Hilbrands R, Huurman VA, Gillard P, Velthuis JH, De Waele M, Mathieu C, Kaufman L, Pipeleers-Marichal M, Ling Z, Movahedi B, Jacobs-Tulleneers-Thevissen D, Monbaliu D, Ysebaert D, Gorus FK, Roep BO, Pipeleers DG, Keymeulen B. Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes. 2009 Oct;58(10):2267-76. doi: 10.2337/db09-0160. Epub 2009 Jul 14. — View Citation

Keymeulen B. Therapies aimed at preservation or restoration of beta cell function in type 1 diabetes. Verh K Acad Geneeskd Belg. 2008;70(2):85-103. Review. — View Citation

Pipeleers D, Chintinne M, Denys B, Martens G, Keymeulen B, Gorus F. Restoring a functional beta-cell mass in diabetes. Diabetes Obes Metab. 2008 Nov;10 Suppl 4:54-62. doi: 10.1111/j.1463-1326.2008.00941.x. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes