Raptiva and Sirolimus in Islet Transplantation for Type 1 Diabetes - Full Text View

Sponsor:	University of Minnesota
Collaborator:	Juvenile Diabetes Research Foundation
Information provided by:	University of Minnesota
ClinicalTrials.gov Identifier:	NCT00672204

Purpose

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.

Condition	Intervention	Phase
Type 1 Diabetes Mellitus Hypoglycemia	Biological: Allogeneic islets of Langerhans transplant Drug: Raptiva Drug: Sirolimus Drug: anti-thymocyte globulin	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Efalizumab (Raptiva) Combined With Sirolimus in Type 1 Diabetic Islet Allograft Recipients

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Type 1 Hypoglycemia

Drug Information available for: Sirolimus Efalizumab

U.S. FDA Resources

Further study details as provided by University of Minnesota:

Primary Outcome Measures:

The proportion of insulin-independent subjects with full islet graft function [ Time Frame: 1 year following the first islet transplant ] [ Designated as safety issue: No ]
The proportion of subjects who have experienced serious adverse events likely or definitely related to the islet transplant protocol [ Time Frame: At 1 year following the first islet transplant ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Insulin independence and islet graft function by monitoring insulin requirements, HbA1c, mixed-meal tolerance test, β-score, frequently-sampled IV glucose tolerance, glucose variability and hypoglycemia duration [ Time Frame: 75 days and 1 year following first and subsequent islet transplants ] [ Designated as safety issue: No ]
The proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events from Day 28 to Day 365 inclusive. [ Time Frame: 1 year post first islet transplant ] [ Designated as safety issue: No ]
The proportion of subjects with an HbA1c <7.0% AND free of severe hypoglycemic events from Day 28 to Day 1095 inclusive. [ Time Frame: 3 years post final islet transplant ] [ Designated as safety issue: No ]

Estimated Enrollment:	10
Study Start Date:	November 2007
Estimated Study Completion Date:	March 2012
Estimated Primary Completion Date:	March 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Allogeneic islets of Langerhans	Biological: Allogeneic islets of Langerhans transplant Up to 3 intraportal infusions of cadaveric pancreatic islets of Langerhans. Each infusion to contain at least 5,000 islet equivalents/kg body weight. Drug: Raptiva 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; Drug: Sirolimus 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 Drug: anti-thymocyte globulin 2.0 mg/kg on days -2, and -1 IV

Arms

Assigned Interventions

1: Experimental

Allogeneic islets of Langerhans

Biological: Allogeneic islets of Langerhans transplant

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

Drug: Raptiva

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;

Drug: Sirolimus

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

Drug: anti-thymocyte globulin

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

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.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00672204

Locations

United States, Minnesota
Universtiy of Minnesota
Minneapolis, Minnesota, United States, 55455

Sponsors and Collaborators

University of Minnesota

Juvenile Diabetes Research Foundation

Investigators

Principal Investigator:

Bernhard J. Hering, M.D.

University of Minnesota

More Information

Additional Information:

U of MN Diabetes Institute for Immunology and Transplantation This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	University of Minnesota ( Bernhard J. Hering, M.D. )
Study ID Numbers:	0612M98726
Study First Received:	May 2, 2008
Last Updated:	April 22, 2009
ClinicalTrials.gov Identifier:	NCT00672204 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Minnesota:

Islet transplant
Diabetes Mellitus
Hypoglycemia

Additional relevant MeSH terms:

Sirolimus
Anti-Infective Agents
Metabolic Diseases
Autoimmune Diseases
Immune System Diseases
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Diabetes Mellitus
Endocrine System Diseases

Antibiotics, Antineoplastic
Hypoglycemia
Immunosuppressive Agents
Pharmacologic Actions
Antilymphocyte Serum
Anti-Bacterial Agents
Diabetes Mellitus, Type 1
Antifungal Agents
Therapeutic Uses
Glucose Metabolism Disorders

ClinicalTrials.gov processed this record on November 27, 2009