Back to results

Raptiva and Sirolimus in Islet Transplantation for Type 1 Diabetes (RAPTIVA)

Primary Purpose

Type 1 Diabetes Mellitus, Hypoglycemia

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Allogeneic islets of Langerhans transplant

Raptiva

Sirolimus

anti-thymocyte globulin

About this trial

This is an interventional treatment trial for Type 1 Diabetes Mellitus focused on measuring Islet transplant, Diabetes Mellitus, Hypoglycemia

Eligibility Criteria

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

Inclusion Criteria:

Primary islet allotransplant
Type I diabetes mellitus for a minimum of 5 years
One of the following signs or symptoms despite intensive efforts made in close cooperation with their diabetic care team:
- Metabolic lability/instability characterized by hypoglycemia or ketoacidosis (>2 hospital admissions in the previous year), erratic glucose profiles (MAGE>120 mg/dL), or disruption in lifestyle of danger to life, self or others
- Reduced awareness of hypoglycemia or >1 episode in the last 1.5 years of severe hypoglycemia
- Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team)
- Progressive secondary complications as defined by (i) a new diagnosis by an ophthalmologist of proliferative retinopathy or clinically significant macular edema or therapy with photocoagulation during the last year; or (ii) urinary albumin excretion rate >300 mg/day but proteinuria <3g/day; or (iii) symptomatic autonomic neuropathy (as defined by postural hypotension in the setting of euvolemia, gastroparesis or diarrhea attributed to diabetic neuropathy, or neuropathic bladder as diagnosed by an urologist)
Age 18 to 65 years of age.

Exclusion Criteria:

Current use of immunosuppressive agents
Lymphopenia (<1000/µL) or leukopenia (<3000 total leukocytes/µL)
Presence of panel-reactive anti-HLA antibody >20%
Positive lymphocytotoxic cross-match using donor lymphocytes and serum
Evidence of acute EBV infection (IgM>IgG) OR negative screen for EBV by IgG determination
Calculated or measured GFR < 60 ml/min/m2
Portal hypertension or history of significant liver disease
History of malignancy within 10 years (except for adequately treated basal or squamous cell CA of the skin)
Active peptic ulcer disease
Severe unremitting diarrhea or other GI disorders potentially interfering with the ability to absorb oral medications
Untreated proliferative retinopathy
Pregnancy or breastfeeding
Female subjects not post-menopausal or surgically sterile, or not using an acceptable method of contraception
Active infections
Serologic evidence of infection with HIV, or HbsAg or HCV Ab positive
Major ongoing psychiatric illness
Ongoing substance abuse, drug or alcohol; or recent history of noncompliance
Any condition that in the opinion of the Principle Investigator would not allow for safe participation in the study

Sites / Locations

Universtiy of Minnesota

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

Allogeneic islets of Langerhans

Outcomes

Primary Outcome Measures

The Proportion of Insulin-independent Subjects With Full Islet Graft Function

Islet transplant recipients will be considered insulin-independent with full islet graft function if they are able to titrate off insulin therapy for at least 1 week and all of the following criteria are met: HbA1c < 7.0% or a ≥2.5% decrease from baseline; fasting capillary glucose level should not exceed 140 mg/dL (7.8 mmol/L) more than three times in the past week (based on measuring capillary glucose levels a minimum of 7 times in a seven day period); 2-hour post-prandial capillary glucose should not exceed 180 mg/dl (10.0 mmol/L) more than three times in the past week (based on measuring capillary glucose levels a minimum of 21 times in a seven day period); fasting serum glucose level ≤126 mg/dL (7.0 mmol/L); if the fasting serum glucose level is >126 mg/dL (7.0 mmol/L), it must be confirmed in an additional one out of two measurements; evidence of endogenous insulin production defined as fasting or stimulated C-peptide levels ≥0.5 ng/mL (0.16 nmol/L).

Secondary Outcome Measures

Full Information

NCT ID

NCT00672204

First Posted

May 2, 2008

Last Updated

September 22, 2017

Sponsor

University of Minnesota

Collaborators

Juvenile Diabetes Research Foundation

1. Study Identification

Unique Protocol Identification Number

NCT00672204

Brief Title

Raptiva and Sirolimus in Islet Transplantation for Type 1 Diabetes

Acronym

RAPTIVA

Official Title

Efalizumab (Raptiva) Combined With Sirolimus in Type 1 Diabetic Islet Allograft Recipients

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Terminated

Why Stopped

Raptiva was withdrawn from the market

Study Start Date

November 2007 (undefined)

Primary Completion Date

December 2010 (Actual)

Study Completion Date

August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Minnesota

Collaborators

Juvenile Diabetes Research Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The primary objective of this protocol is to test the safety and efficacy of a treatment regimen consisting of maintenance therapy with efalizumab and sirolimus for 1 year followed by withdrawal of efalizumab and maintenance therapy with sirolimus, for the prevention of the destruction and rejection of islet transplants in type 1 diabetic recipients. Genentech, the manufacturer of efalizumab voluntarily withdrew the drug from the U.S. market in April of 2009. Previously transplanted subjects have been transitioned to alternative immunosuppressives and no new subjects will be transplanted under this protocol.

Detailed Description

The purpose of this study is to improve the applicability of islet transplantation for treatment of type 1 diabetes utilizing a novel immunosuppressive regimen centered on the use of adhesion molecule blockade with an anti-LFA-1 antibody (efalizumab). The lymphocyte-function associated antigen-1 (LFA-1) adhesion molecule is expressed on multiple cellular populations including T cells, B cells, and NK cells and is important in facilitating cell migration and homing. In addition, interaction of LFA-1 with its ligand ICAM-1 on antigen presenting cells provides a powerful costimulatory signal for T cell activation. Animal models using anti-LFA-1 antibodies have shown impressive prolongation of vascularized and cellular allograft survival. These potent immunosuppressive properties have also been documented in several clinical trials with efalizumab, a humanized IgG1 monoclonal antibody directed against LFA-1. The drug was found to be safe, well tolerated, and efficacious in treating moderate to severe psoriasis. More recently, a multicenter trial employing efalizumab in conjunction with prednisone, sirolimus and cyclosporine maintenance immunosuppression in recipients of kidney allografts showed an acceptable safety profile when used at a dose of 0.5mg/kg/week and excellent rejection-free graft survival over the first 6 months after transplant. This study represents the first clinical trial that applies adhesion molecule blockade with efalizumab to prevent the immune response against pancreatic islets in the setting of type 1 diabetes mellitus, with the long-term goal of immunosuppression withdrawal. Genentech, the manufacturer of efalizumab voluntarily withdrew the drug from the U.S. market in April of 2009. Previously transplanted subjects have been transitioned to alternative immunosuppressives and no new subjects will be transplanted under this protocol.

6. Conditions and Keywords

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

Type 1 Diabetes Mellitus, Hypoglycemia

Keywords

Islet transplant, Diabetes Mellitus, Hypoglycemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

23 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Allogeneic islets of Langerhans

Intervention Type

Biological

Intervention Name(s)

Allogeneic islets of Langerhans transplant

Other Intervention Name(s)

Islets

Intervention Description

Up to 3 intraportal infusions of cadaveric pancreatic islets of Langerhans. Each infusion to contain at least 5,000 islet equivalents/kg body weight.

Intervention Type

Drug

Intervention Name(s)

Raptiva

Other Intervention Name(s)

Efalizumab

Intervention Description

Treatment Day -1 pretransplant to Treatment Day 90 after tx.: 1.0 mg/kg/wk SQ; Treatment Day 91 to Treatment Day 365: 0.5 mg/kg/wk SQ;

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

Rapamune

Intervention Description

Initial dose 0.1 mg/kg PO on day -2, followed by 0.05 mg/kg daily, whole blood 24-hour trough adjusted to target 3-15 ng/ml as tolerated

Intervention Type

Drug

Intervention Name(s)

anti-thymocyte globulin

Other Intervention Name(s)

ATG, Thymoglobulin

Intervention Description

2.0 mg/kg on days -2, and -1 IV

Primary Outcome Measure Information:

Title

The Proportion of Insulin-independent Subjects With Full Islet Graft Function

Description

Time Frame

1 year following the first islet transplant

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: Primary islet allotransplant Type I diabetes mellitus for a minimum of 5 years One of the following signs or symptoms despite intensive efforts made in close cooperation with their diabetic care team: Metabolic lability/instability characterized by hypoglycemia or ketoacidosis (>2 hospital admissions in the previous year), erratic glucose profiles (MAGE>120 mg/dL), or disruption in lifestyle of danger to life, self or others Reduced awareness of hypoglycemia or >1 episode in the last 1.5 years of severe hypoglycemia Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team) Progressive secondary complications as defined by (i) a new diagnosis by an ophthalmologist of proliferative retinopathy or clinically significant macular edema or therapy with photocoagulation during the last year; or (ii) urinary albumin excretion rate >300 mg/day but proteinuria <3g/day; or (iii) symptomatic autonomic neuropathy (as defined by postural hypotension in the setting of euvolemia, gastroparesis or diarrhea attributed to diabetic neuropathy, or neuropathic bladder as diagnosed by an urologist) Age 18 to 65 years of age. Exclusion Criteria: Current use of immunosuppressive agents Lymphopenia (<1000/µL) or leukopenia (<3000 total leukocytes/µL) Presence of panel-reactive anti-HLA antibody >20% Positive lymphocytotoxic cross-match using donor lymphocytes and serum Evidence of acute EBV infection (IgM>IgG) OR negative screen for EBV by IgG determination Calculated or measured GFR < 60 ml/min/m2 Portal hypertension or history of significant liver disease History of malignancy within 10 years (except for adequately treated basal or squamous cell CA of the skin) Active peptic ulcer disease Severe unremitting diarrhea or other GI disorders potentially interfering with the ability to absorb oral medications Untreated proliferative retinopathy Pregnancy or breastfeeding Female subjects not post-menopausal or surgically sterile, or not using an acceptable method of contraception Active infections Serologic evidence of infection with HIV, or HbsAg or HCV Ab positive Major ongoing psychiatric illness Ongoing substance abuse, drug or alcohol; or recent history of noncompliance Any condition that in the opinion of the Principle Investigator would not allow for safe participation in the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bernhard J. Hering, M.D.

Organizational Affiliation

University of Minnesota

Official's Role

Principal Investigator

Facility Information:

Facility Name

Universtiy of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Raptiva and Sirolimus in Islet Transplantation for Type 1 Diabetes

We'll reach out to this number within 24 hrs