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MGA031, Sirolimus and Tacrolimus in Islet Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00265473
Recruitment Status : Completed
First Posted : December 14, 2005
Results First Posted : September 21, 2011
Last Update Posted : March 9, 2017
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE December 12, 2005
First Posted Date  ICMJE December 14, 2005
Results First Submitted Date  ICMJE April 1, 2011
Results First Posted Date  ICMJE September 21, 2011
Last Update Posted Date March 9, 2017
Study Start Date  ICMJE November 2005
Actual Primary Completion Date May 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 11, 2015)
  • Subjects With Full Islet Function. [ Time Frame: At one year after initial transplant. ]
    Proportion of subjects with full islet function (i.e. insulin independent) at one year after initial islet transplant.
  • Serious Adverse Events Related to Immunosuppressive Therapy. [ Time Frame: Day 0 - Day 365 ]
    Number of serious adverse events related to immunosuppressive therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: December 12, 2005)
  • Primary Efficacy Endpoints:
  • Insulin independence by day 75
  • Protection of transplanted islets against allo- and auto-immunity for 1 year after islet infusion
  • Primary Safety Endpoints:
  • Adverse events related to therapy at 1 year after the final islet transplant
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 11, 2015)
  • Subjects With Partial Islet Function and no Episodes of Severe Hypoglycemia; [ Time Frame: At one year after initial transplant ]
    Proportion of subjects with partial islet function and no episodes of severe hypoglycemia at one year after initial islet transplant.
  • Insulin Independent Single-donor Subjects. [ Time Frame: At 75 days after transplant ]
    Proportion of insulin independent single-donor subjects at day 75 after transplant
  • Insulin Independent Multiple-donor Subjects. [ Time Frame: At one year after final transplant ]
    Proportion of insulin independent multiple-donor subjects at one year after final transplant. Participant received more than one islet transplant.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2005)
  • Secondary Efficacy Endpoints:
  • Stable metabolic function
  • Improvement in Quality Of Life Assessments
  • Determine the mechanisms in immunological graft loss or protection of islets
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MGA031, Sirolimus and Tacrolimus in Islet Transplantation
Official Title  ICMJE hOKT3γ1 (Ala-Ala), Sirolimus and Low Dose Tacrolimus Therapy in Type 1 Diabetic Islet Allograft Recipients
Brief Summary This clinical trial is designed to extend the observations made in our pilot clinical trial (IND 8971, Study #1) on the safety and efficacy of immunotherapy with the anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala), (currently called MGA031) combined with sirolimus and tacrolimus in preventing rejection and autoimmune destruction of deceased donor pancreatic islet transplants in type 1 diabetic recipients.
Detailed Description

Type 1 diabetes mellitus continues to be a therapeutic challenge. Previous studies have shown that failure to prevent hypoglycemia and hyperglycemia results in acute and chronic complications, leading to poor quality of life, premature death, and considerable health care costs in 30% to 50% of diabetic patients. Therefore, establishing safe and effective ways to achieve and maintain normoglycemia would have substantial implications for the well-being of individuals with diabetes. Intensive insulin therapy has been shown to reduce the risk of chronic complications in patients who achieve near-normalization of glycemia. However, such therapy is labor-intensive, difficult to implement for many patients, and limited by the accompanying increased frequency of severe hypoglycemia. Currently, the only way to restore and sustain normoglycemia without the associated risk of hypoglycemia is by replacing the patient's islets of Langerhans, either by transplanting a vascularized pancreas or, much less invasively, by infusing isolated islets.

Strategies that selectively inactivate autoreactive T cells and prevent allorejection of transplanted islets in the absence of diabetogenic side effects need to be developed for islet transplants to survive in autoimmune diabetic recipients. The current clinical study will extend the observations made in our first pilot clinical trial (IND 8971, Study #1) that provided preliminary information on the safety and efficacy of immunotherapy with the anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala), (currently called MGA031) combined with sirolimus and tacrolimus in preventing rejection and autoimmune destruction of deceased donor pancreatic islet transplants in type 1 diabetic recipients.

In the pilot study 4 of 6 single islet transplant recipients remained insulin independent with normal HbA1c and no episodes of hypoglycemia throughout the 1 year post-transplant period. Three of those four participants have maintained insulin independence for > 3.5, >4.5 and >5 years post islet transplant. These preliminary findings warrant an extension study involving more recipients and more comprehensive immunologic monitoring to examine in greater detail the impact of MGA031 induction immunotherapy on T cell responses operative in rejection and autoimmune destruction of transplanted islets as well as on formation of regulatory T cell function for the protection of transplanted islets.

A total of 5 patients with type 1 diabetes will be transplanted under this protocol. Islet transplant recipients will be admitted for 5 days and followed for one year after transplantation.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 1 Diabetes Mellitus
  • Hypoglycemia
Intervention  ICMJE Biological: Allogeneic Islets of Langerhans
Intraportal infusion of islets of Langerhans
Study Arms  ICMJE Experimental: Allogeneic Islets of Langerhans
Islet infusion
Intervention: Biological: Allogeneic Islets of Langerhans
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 16, 2011)
5
Original Enrollment  ICMJE
 (submitted: December 12, 2005)
10
Actual Study Completion Date  ICMJE June 2010
Actual Primary Completion Date May 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age 18 to 65 years of age.
  2. Ability to provide written informed consent.
  3. Mentally stable and able to comply with the procedures of the study.
  4. Clinical history compatible with type 1 diabetes with onset of disease at <40 years of age and insulin-dependence for > 5 years at the time of enrollment.
  5. Absent stimulated C-peptide (<0.3ng/ml) in response to a mixed meal tolerance test.
  6. Involvement in intensive diabetes management defined as self monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the previous 12 months.
  7. At least one episode of severe hypoglycemia in the past 3 years defined as an event with symptoms compatible with hypoglycemia in which the subject required the assistance of another person and which was associated with either a blood glucose level < 50 mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration).
  8. Reduced awareness of hypoglycemia.

Exclusion Criteria:

  1. Any previous transplant.
  2. BMI >27 kg/m2 or patient weight ≤ 50kg.
  3. Insulin requirement of > 0.8 IU/kg/day or 50 IU/day.
  4. HbA1c >10%.
  5. Untreated proliferative diabetic retinopathy.
  6. Uncontrolled Hypertension.
  7. Estimated glomerular filtration rate <70 ml/min/1.73 m2 for females and <80 ml/min/1.73 m2 for males
  8. Presence or history of macroalbuminuria (>300mg/d).
  9. Presence or history of panel-reactive anti-HLA antibodies >20% by flow cytometry.
  10. Females: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 3 months after discontinuation. Males: intent to procreate during the duration of the study or within 3 months after discontinuation or unwillingness to use effective measures of contraception.
  11. Active infection.
  12. Negative screen for Epstein-Barr Virus (EBV).
  13. Invasive aspergillus infection within one year prior to study entry.
  14. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
  15. Active alcohol, tobacco or substance abuse.
  16. Baseline Hgb below the lower limits of normal at the local laboratory; lymphopenia, neutropenia, or thrombocytopenia.
  17. A history of Factor V deficiency.
  18. Any coagulopathy or medical condition requiring long-term anticoagulant therapy.
  19. Severe co-existing cardiac disease.
  20. Persistent elevation of liver function tests.
  21. Symptomatic cholecystolithiasis.
  22. Acute or chronic pancreatitis.
  23. Symptomatic peptic ulcer disease.
  24. Unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with absorption.
  25. Hyperlipidemia despite medical therapy (fasting LDL cholesterol > 130 mg/dl, treated or untreated; and/or fasting triglycerides > 200 mg/dl).
  26. Chronic use of systemic steroids.
  27. Use of any other investigational agents within 4 weeks of participation.
  28. Administration of live attenuated vaccine(s) within 2 months of enrollment.
  29. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00265473
Other Study ID Numbers  ICMJE 0407M62505
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • Juvenile Diabetes Research Foundation
Investigators  ICMJE
Principal Investigator: Bernhard J. Hering, M.D. University of Minnesota
PRS Account University of Minnesota
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP