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

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

Study Description
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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.

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Hypoglycemia Drug: Allogeneic Islets of Langerhans Drug: hOKT3γ1 (Ala-Ala) Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients
Study Start Date : April 2000
Actual Primary Completion Date : January 2004
Actual Study Completion Date : January 2004

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Arms and Interventions
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Outcome Measures
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Primary Outcome Measures :
  1. 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:
  2. -Physical examination
  3. -Vital signs
  4. -Body weight
  5. -Adverse events
  6. -Laboratory and diagnostic safety assessments included complete blood counts with differential and platelets, circulating T cell phenotypes, and serum chemistry.
  7. -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.

Secondary Outcome Measures :
  1. Efficacy of hOKT3γ1 (Ala-Ala) antibody induction therapy for the prevention of autoimmune destruction and rejection of islet transplants as defined by:
  2. -Proportion of subjects with full islet graft function (insulin independence and HbA1c <7%);
  3. -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%);
  4. -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;

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
Contacts and Locations
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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00285194


Locations
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United States, Minnesota
Universtiy of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota
Juvenile Diabetes Research Foundation
Investigators
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Principal Investigator: Bernhard J. Hering, M.D. University of Minnesota
More Information
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Publications of Results:

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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT00285194    
Other Study ID Numbers: 0003M44181
First Posted: February 1, 2006    Key Record Dates
Last Update Posted: August 2, 2012
Last Verified: July 2012
Additional relevant MeSH terms:
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Hypoglycemia
Glucose Metabolism Disorders
Metabolic Diseases