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

This study has been completed.
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT00672204
First received: May 2, 2008
Last updated: February 20, 2013
Last verified: February 2013
  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 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efalizumab (Raptiva) Combined With Sirolimus in Type 1 Diabetic Islet Allograft Recipients

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

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 ]

    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:
  • 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 ]
  • The Proportion of Subjects Who Have Experienced Serious Adverse Events Likely or Definitely Related to the Islet Transplant Protocol [ Time Frame: At 365 days following the 1st islet transplant ] [ Designated as safety issue: Yes ]

Enrollment: 3
Study Start Date: November 2007
Study Completion Date: August 2012
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
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.
Other Name: Islets
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;
Other Name: Efalizumab
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
Other Name: Rapamune
Drug: anti-thymocyte globulin
2.0 mg/kg on days -2, and -1 IV
Other Names:
  • ATG
  • Thymoglobulin

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:

  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 to 65 years of age.

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 negative screen for EBV by IgG determination
  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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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 - Clinical and Translational Science Institute
Juvenile Diabetes Research Foundation
Investigators
Principal Investigator: Bernhard J. Hering, M.D. University of Minnesota - Clinical and Translational Science Institute
  More Information

No publications provided

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT00672204     History of Changes
Other Study ID Numbers: 0612M98726
Study First Received: May 2, 2008
Results First Received: February 20, 2013
Last Updated: February 20, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
Islet transplant
Diabetes Mellitus
Hypoglycemia

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hypoglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Antilymphocyte Serum
Sirolimus
Everolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 24, 2014