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hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients

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. Identifier: NCT00285194
Recruitment Status : Completed
First Posted : February 1, 2006
Last Update Posted : August 2, 2012
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE January 30, 2006
First Posted Date  ICMJE February 1, 2006
Last Update Posted Date August 2, 2012
Study Start Date  ICMJE April 2000
Actual Primary Completion Date January 2004   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2006)
  • Safety, tolerability, immune activity, and pharmacokinetics of hOKT3γ1 (Ala-Ala) antibody induction therapy for the prevention of autoimmune destruction and rejection of allogeneic islet transplants as measured by:
  • -Physical examination
  • -Vital signs
  • -Body weight
  • -Adverse events
  • -Laboratory and diagnostic safety assessments included complete blood counts with differential and platelets, circulating T cell phenotypes, and serum chemistry.
  • -Immune activity and pharmacokinetic assessments included hOKT3γ1 (Ala-Ala) level and half-life, monoclonal antibody coating and modulation of CD3 on peripheral blood T cells, and anti-hOKT3γ1 (Ala-Ala) antibody responses.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2006)
  • Efficacy of hOKT3γ1 (Ala-Ala) antibody induction therapy for the prevention of autoimmune destruction and rejection of islet transplants as defined by:
  • -Proportion of subjects with full islet graft function (insulin independence and HbA1c <7%);
  • -Proportion of subjects with partial islet graft function (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/ml and HbA1c <7%);
  • -Proportion of subjects with slet graft loss will be defined as a return to insulin therapy for >30 days, absence of basal and arginine-stimulated C-peptide, re-transplantation, or patient death;
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients
Official Title  ICMJE hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients
Brief Summary The collective effects of two-layer pancreas preservation, pretransplant islet culture, day -2 pretransplant immunosuppression, and induction immunosuppression with the FcR-nonbinding anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala)to facilitate diabetes reversal after single-donor islet transplantation.
Detailed Description

This is an open-label, one-year follow-up study of type 1 diabetic islet allograft recipients who receive FcR non-binding OKT3 antibody hOKT3γ1 (Ala-Ala) plus sirolimus induction immunotherapy combined with sirolimus and delayed tacrolimus maintenance immunosuppression. Six subjects were transplanted.

The premise behind the proposal is that hOKT3γ1(Ala-Ala) corrects the imbalance between autoreactive and regulatory T cells and consequently prevents autoimmune destruction of transplanted islets. To prevent allorejection, hOKT3γ1(Ala-Ala)was combined with sirolimus and delayed tacrolimus. Additionally, the safety and efficacy of the maintenance immunosuppressive regimen of sirolimus combined with tacrolimus was monitored.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 1 Diabetes
  • Hypoglycemia
Intervention  ICMJE
  • Drug: Allogeneic Islets of Langerhans
  • Drug: hOKT3γ1 (Ala-Ala)
Study Arms  ICMJE Not Provided
Publications * Hering BJ, Kandaswamy R, Harmon JV, Ansite JD, Clemmings SM, Sakai T, Paraskevas S, Eckman PM, Sageshima J, Nakano M, Sawada T, Matsumoto I, Zhang HJ, Sutherland DE, Bluestone JA. Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant. 2004 Mar;4(3):390-401.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Enrollment  ICMJE
 (submitted: January 30, 2006)
Original Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 2004
Actual Primary Completion Date January 2004   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Primary islet allotransplant
  2. Type 1 diabetes mellitus, complicated by at least one of the following situations that persist despite intensive efforts in close cooperation with their diabetes care team:

    1. Metabolic lability/instability;
    2. Reduced awareness of hypoglycemia;
    3. Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team);
    4. Progressive secondary complications.
  3. Age 18 and older
  4. Able to give written informed consent

Exclusion Criteria:

  1. Age less than 18 years
  2. Body weight greater than75 kg.
  3. BMI greater than 26 kg/m2 for male and females
  4. Waist-to-hip ratio 0.80 (female) and 0.95 (male)
  5. First degree relative with type 2 diabetes
  6. Insulin requirement of greater than 0.7 IU/kg/day
  7. HbA1C greater than 12%
  8. Positive C-peptide response to intravenous arginine stimulation
  9. Untreated proliferative retinopathy
  10. Macroalbuminuria (urinary albumin excretion greater than 300 mg/24hrs)
  11. Creatinine clearance greater than 85 ml/min/1.73 m2 in females, greater than 95 ml/min/1.73 m2 in males
  12. Serum creatinine greater than 1.2 mg/dl
  13. Previous pancreas or islet transplant
  14. Previous OKT3 antibody therapy
  15. Presence of history of panel-reactive anti-HLA antibodies greater than 10%
  16. Abnormal T4 and TSH despite thyroid replacement therapy
  17. Positive pregnancy test, or presently breast-feeding
  18. Active infection
  19. Negative screen for Epstein-Barr Virus (EBV) by an EBNA method
  20. Invasive aspergillus infection within year prior to study entry
  21. Any history of malignancy
  22. Active alcohol or substance abuse
  23. History of non-adherence to prescribed regimens
  24. Psychiatric disorder making the subject not a suitable candidate for transplantation
  25. Karnofsky performance score greater than 70
  26. Baseline Hgb greater than 11.7 g/dl; lymphopenia (greater than 1,000/L), or leukopenia (greater than 4,000 total leukocytes/L), or an absolute CD4+ count <500/L
  27. Thrombocytopenia greater than 150 x 109/L
  28. Use of warfarin or other anticoagulant therapy (except aspirin) or patient with PT-INR greater than 1.5
  29. Severe co-existing cardiac disease
  30. Baseline liver function tests outside of normal range
  31. Presence of gallstones on baseline ultrasound exam
  32. Active peptic ulcer disease
  33. Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications
  34. Celiac disease
  35. Hyperlipidemia (fasting LDL cholesterol greater than 130 mg/dl, treated or untreated; and/or fasting triglycerides greater than 200 mg/dl)
  36. Addison's disease.
  37. Under treatment for a medical condition requiring chronic use of systemic steroids
  38. 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 Yes
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 NCT00285194
Other Study ID Numbers  ICMJE 0003M44181
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE Juvenile Diabetes Research Foundation
Investigators  ICMJE
Principal Investigator: Bernhard J. Hering, M.D. University of Minnesota
PRS Account University of Minnesota
Verification Date July 2012

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