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Bet Cell Therapy in Diabetes Type 1

Primary Purpose

Type 1 Diabetes

Status

Unknown status

Phase

Phase 2

Locations

Belgium

Study Type

Interventional

Intervention

Transplantation of encapsulated beta cells.

About this trial

This is an interventional treatment trial for Type 1 Diabetes focused on measuring Type 1 Diabetes, Transplantation, Beta Cells, Encapsulation

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

UZ BrusselRecruiting
UZ LeuvenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Group A

Group B

Arm Description

Patients with loss of long-term function after intraportal implantation

Patients that are candidates for islet cell transplantation

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

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

Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT.

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

Full Information

NCT ID

NCT01379729

First Posted

May 2, 2011

Last Updated

December 27, 2013

Sponsor

AZ-VUB

Collaborators

Universitair Ziekenhuis Brussel, Universitaire Ziekenhuizen KU Leuven

1. Study Identification

Unique Protocol Identification Number

NCT01379729

Brief Title

Bet Cell Therapy in Diabetes Type 1

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2013

Overall Recruitment Status

Unknown status

Study Start Date

May 2011 (undefined)

Primary Completion Date

December 2013 (Anticipated)

Study Completion Date

May 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

AZ-VUB

Collaborators

Universitair Ziekenhuis Brussel, Universitaire Ziekenhuizen KU Leuven

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 1 Diabetes

Keywords

Type 1 Diabetes, Transplantation, Beta Cells, Encapsulation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Active Comparator

Arm Description

Patients with loss of long-term function after intraportal implantation

Arm Title

Group B

Arm Type

Active Comparator

Arm Description

Patients that are candidates for islet cell transplantation

Intervention Type

Other

Intervention Name(s)

Transplantation of encapsulated beta cells.

Other Intervention Name(s)

encapsulated beta cells

Intervention Description

Implantation of a therapeutical dose of encapsulated beta cells.

Intervention Type

Other

Intervention Name(s)

Transplantation of encapsulated beta cells.

Other Intervention Name(s)

encapsulated beta cells

Intervention Description

Implantation of a therapeutical dose of encapsulated beta cells.

Primary Outcome Measure Information:

Title

Time Frame

6 months PT.

Secondary Outcome Measure Information:

Title

Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT.

Description

Time Frame

60 months

Title

Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT.

Description

Functional beta-cell mass at 2,12,18,24,36,48 and 60 months PT.

Time Frame

60 months

Title

Changes from Baseline

Description

Time Frame

60 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Bart Keymeulen, MD PhD

Phone

+32 2 477 61 11

bart.keymeulen@uzbrussel.be

First Name & Middle Initial & Last Name or Official Title & Degree

Robert Hilbrands, MD PhD

Phone

+32 2 476 37 34

Robert.Hilbrands@uzbrussel.be

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bart Keymeulen, MD PhD

Organizational Affiliation

Universitair Ziekenhuis Brussel

Official's Role

Principal Investigator

Facility Information:

Facility Name

UZ Brussel

City

Brussels

ZIP/Postal Code

1090

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bart Keymeulen, MD PhD

Phone

+32 2 477 61 11

bart.keymeulen@uzbrussel.be

First Name & Middle Initial & Last Name & Degree

Bart Keymeulen, MD PhD

Facility Name

UZ Leuven

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pieter, Gillard

pieter.gillard@uzleuven.be

First Name & Middle Initial & Last Name & Degree

Da Hae Lee, MD

Phone

+32 16 34 23 98

dahae.lee@uzleuven.be

First Name & Middle Initial & Last Name & Degree

Pieter Gillard, MD PhD

12. IPD Sharing Statement

Citations:

PubMed Identifier

20726441

Citation

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.

Results Reference

background

PubMed Identifier

19602536

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.

Results Reference

background

PubMed Identifier

19202446

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.

Results Reference

background

PubMed Identifier

18834433

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.

Results Reference

background

PubMed Identifier

18630722

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.

Results Reference

background

PubMed Identifier

23620058

Citation

Jacobs-Tulleneers-Thevissen D, Chintinne M, Ling Z, Gillard P, Schoonjans L, Delvaux G, Strand BL, Gorus F, Keymeulen B, Pipeleers D; Beta Cell Therapy Consortium EU-FP7. Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient. Diabetologia. 2013 Jul;56(7):1605-14. doi: 10.1007/s00125-013-2906-0. Epub 2013 Apr 26.

Results Reference

derived

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