Raptiva and Sirolimus in Islet Transplantation for Type 1 Diabetes

Condition(s) targeted: Type 1 Diabetes Mellitus; Hypoglycemia

Intervention: Allogeneic islets of Langerhans transplant (Biological); Raptiva (Drug); Sirolimus (Drug); anti-thymocyte globulin (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: University of Minnesota

Official(s) and/or principal investigator(s):
Bernhard J. Hering, M.D., Principal Investigator, Affiliation: University of Minnesota

Overall contact:
Jayne Pedersen, Phone: 612 624-8402, Email: peder059@umn.edu

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.

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

Study design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Primary outcome:

Insulin independence as defined by HbA1c ≤ 6.5% or a ≥ 2.5% decrease from baseline; Fasting capillary glucose < 140 mg/dL (7.8 mmol/L); 2-hour post-prandial capillary glucose <180 mg/dl (10.0 mmol/L)

The incidence, timing, and severity of adverse events during the 3 years after the first and any subsequent islet transplants

Secondary outcome:

To assess the metabolic stability of subjects treated with efalizumab and sirolimus by monitoring fasting glucose, insulin and C-peptide, mixed meal tests and IV glucose tolerance tests, and peripheral resistance to insulin

To assess subject's immunological responses to islet autoantigens and donor alloantigens.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Primary islet allotransplant

2. Type I diabetes mellitus for a minimum of 5 years

3. 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)

4. Age 18 and older

Exclusion Criteria:

1. Current use of immunosuppressive agents

2. Lymphopenia (<1000/µL) or leukopenia (>3000 total leukocytes/µL)

3. Presence of panel-reactive anti-HLA antibody >20%

4. Positive lymphocytotoxic cross-match using donor lymphocytes and serum

5. Evidence of acute EBV infection (IgM>IgG) OR no serologic evidence of previous exposure to EBV (IgG>IgM)

6. Calculated or measured GFR < 60 ml/min/m2

7. Portal hypertension or history of significant liver disease

8. History of malignancy within 10 years (except for adequately treated basal or squamous cell CA of the skin)

9. Active peptic ulcer disease

10. Severe unremitting diarrhea or other GI disorders potentially interfering with the ability to absorb oral medications

11. Untreated proliferative retinopathy

12. Pregnancy or breastfeeding

13. Female subjects not post-menopausal or surgically sterile, or not using an acceptable method of contraception

14. Active infections

15. Serologic evidence of infection with HIV, or HbsAg or HCV Ab positive

16. Major ongoing psychiatric illness

17. Ongoing substance abuse, drug or alcohol; or recent history of noncompliance

18. Any condition that in the opinion of the Principle Investigator would not allow for safe participation in the study

Jayne Pedersen, Phone: 612 624-8402, Email: peder059@umn.edu

Universtiy of Minnesota, Minneapolis, Minnesota 55455, United States; Recruiting
Jayne Pederson, Phone: 612-624-8402, Email: peder059@umn.edu
Bernhard J. Hering, M.D., Principal Investigator
David ER Sutheland, M.D., Ph.D., Sub-Investigator
Raja Kandaswamy, M.D., Sub-Investigator
David W. Hunter, M.D., Sub-Investigator
Melena Bellin, M.D., Sub-Investigator
Antoinette Moran, M.D., Sub-Investigator
James V. Harmon, M.D., Sub-Investigator

U of MN Diabetes Institute for Immunology and Transplantation

Starting date: November 2007
Ending date: November 2013
Last updated: May 2, 2008