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Anti-Thymocyte Globulin, Cyclosporine, and RAD in Islet Transplantation (NITA)

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: NCT00286624
Recruitment Status : Completed
First Posted : February 3, 2006
Last Update Posted : May 8, 2008
Juvenile Diabetes Research Foundation
National Institutes of Health (NIH)
Information provided by:
University of Minnesota

Brief Summary:
This study was designed to test the safety and efficacy of up to 3 pancreatic alloislet transplants in type 1 diabetic patients with hypoglycemia unawareness. 6 subjects were transplanted under this protocol using anti-thymocyte globulin induction immunosuppression and everolimus with cyclosporine maintenance immunosuppression.

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Hypoglycemia Biological: Allogeneic Islets of Langerhans Drug: Everolimus Drug: anti-thymocyte globulin Drug: Cyclosporine Phase 1 Phase 2

Detailed Description:

This is a Phase I/II study designed to assess the safety and efficacy of sequential islet allotransplantation for the reestablishment of stable glycemic control in type 1 diabetic recipients. A total of 6 patients with type 1 diabetes have received up to three transplants of islets from different donor pancreases.

Potential candidates for islet allotransplantation included patients age 18 and older with type 1 diabetes. Induction immunotherapy for the first transplant consisted of anti-thymocyte globulin; basiliximab was used for any subsequent transplants. Peritransplant anti-inflammatory treatment with etanercept was given for each islet transplant. Maintenance immunosuppression is with cyclosporine and RAD. It is felt that those patients in whom metabolic lability/instability, reduced awareness of hypoglycemia, poor glycemic control, and progressive secondary complications persist despite continued and intensive efforts made in close cooperation with their diabetes care team are particularly likely to have a favorable benefit/risk ratio.

Adverse events, irrespective of their presumed relationship to the transplantation of allogeneic islets and/or protocol-regulated treatment products (concomitant therapy), are being monitored and recorded throughout the first year after the final islet transplant.

The proportion of single and sequential donor islet allograft recipients with full (insulin independence and HbA1c <7%) and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/mL and HbA1c <7%) islet graft function at one year after the final islet transplant will be assessed. The impact of islet transplantation on quality of life will also be assessed.

The predictive value for posttransplant insulin independence of factors such as insulin resistance before and at intervals after pancreatectomy, cellular composition of the transplant, number of beta cells transplanted; and viability and insulin secretory response of isolated islets are being assessed.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A One-Year, Single-Center, Prospective, Open-Label Study of the Safety, Tolerability, and Preliminary Efficacy of Anti-Thymocyte Globulin, Cyclosporine, and RAD in Type 1 Diabetic Islet Transplant Recipients
Study Start Date : March 2003
Actual Primary Completion Date : August 2006
Actual Study Completion Date : August 2006

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hypoglycemia

Arm Intervention/treatment
Experimental: 1
Allogeneic islet transplantation with anti-thymocyte globulin induction and cyclosporine and RAD maintenance immunosuppression
Biological: Allogeneic Islets of Langerhans
Up to 3 intraportal infusions of cadaveric pancreatic islets of Langerhans. First infusion to contain at least 5,000 islet equivalents/kg body weight. Subsequent infusions to contain at least 3,000 islet equivalents/kg body weight.
Other Name: Islets

Drug: Everolimus
Loading dose of 3 mg PO on day -2 relative to transplant, followed at least 12 hours later by dose of 1.5 mg PO BID. The daily dose will be adjusted according to the whole blood 12-hr trough to target 3-15 ng/ml for the first 3 months and 3-12 ng/ml thereafter.
Other Name: RAD

Drug: anti-thymocyte globulin
A total of 6 mg/kg IV over 12 hours on days -2, -1, 0, +1, and +2. The dose will be 0.5 mg/kg on day -2, 1.0 mg/kg on day -1, and 1.5 mg/kg on days 0, +1, and +2.
Other Names:
  • ATG
  • Thymogloblin

Drug: Cyclosporine
Cyclosporine started on day +1 relative to the first islet transplant. Initial dose of 3 mg/kg/day administered in 2 divided doses; then adjusted to maintain target levels of 400 (350-500) ng/mL for the first three months following islet transplant and 300 (200-350) ng/mL thereafter.
Other Name: Neoral

Primary Outcome Measures :
  1. • The incidence, timing, and severity of adverse events during one year after the first and any subsequent islet transplants. [ Time Frame: 1 year ]
  2. • Incidence and severity of hypoglycemia during the first year after the first and any subsequent islet transplants. [ Time Frame: 1 yr ]
  3. • The proportion of recipients who develop alloantibodies directed at islet donor alloantigens during the first year after the first and any subsequent islet transplants. [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. • The proportion of subjects who achieve insulin independence in the first year after single-donor or sequential transplantation. [ Time Frame: 1 year ]
  2. • The proportion of islet allograft recipients with full and partial islet graft function at one year after the most recent islet transplant. [ Time Frame: 1 year ]
  3. • Glycemic control and insulin secretory responses during the first year after the first and any subsequent transplants. [ Time Frame: 1 year ]
  4. • The effect of donor age, pretransplant islet insulin secretory response in vitro, number of transplanted islet equivalents (IEQ), number of transplanted beta cells, pretransplant recipient insulin requirements and action, recipient body mass index (BM [ Time Frame: Day of transplant ]
  5. • The impact of islet transplantation on the quality of life of transplant recipients. [ Time Frame: 1 year ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Primary islet allotransplant
  • Patients with type 1 diabetes mellitus under intensive insulin management
  • Age 18 or older
  • Ability to give written informed consent

Exclusion Criteria:

  • Age less than 18 years.
  • BMI >26 kg/m2.
  • Insulin requirement of > 50 IU per day.
  • Positive C-peptide response to intravenous arginine stimulation.
  • Untreated proliferative retinopathy.
  • Creatinine clearance < 60 ml/min/1.73 m2 for females and 70 ml/min/1.73 m2 for males.
  • Serum creatinine >1.3 mg/dl for females, >1.5 mg/dl for males.
  • Previous pancreas or islet transplant.
  • Presence of history of panel-reactive anti-HLA antibodies >10%.
  • Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures.
  • Active infection including hepatitis C, hepatitis B, HIV, or TB (or under treatment for suspected TB).
  • Negative screen for Epstein-Barr Virus (EBV).
  • Invasive aspergillus infection within year prior to study entry.
  • History of malignancy.
  • Active alcohol or substance abuse
  • History of non-adherence to prescribed regimens.
  • Psychiatric disorder making the subject not a suitable candidate for transplantation.
  • Inability to provide informed consent.
  • Baseline Hgb < 11.7 g/dl in females, or < 13 g/dl in males; lymphopenia (<1,000/microL), or leukopenia (<3,000 total leukocytes/microL), or an absolute CD4+ count <500/microL., or platelets <150,000/microL
  • History of coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or patient with INR >1.5.
  • Severe co-existing cardiac disease.
  • Baseline liver function tests outside of normal range or history of significant liver disease.
  • Active peptic ulcer disease.
  • Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
  • Presence of severe allergy requiring acute or chronic treatment, or hypersensitivity to drugs similar to RAD (e.g., macrolides).
  • Known hypersensitivity to rabbit proteins.
  • Hyperlipidemia (fasting LDL cholesterol > 130 mg/dl, treated or untreated; and/or fasting triglycerides > 200 mg/dl).
  • Addison's disease.
  • Under treatment requiring chronic use of systemic steroids.
  • Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial.

Information from the National Library of Medicine

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 identifier (NCT number): NCT00286624

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United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota
Juvenile Diabetes Research Foundation
National Institutes of Health (NIH)
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Principal Investigator: Bernhard J. Hering, M.D. University of Minnesota
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Responsible Party: Bernhard J. Hering, M.D., University of Minnesota Identifier: NCT00286624    
Other Study ID Numbers: 0207M29841
First Posted: February 3, 2006    Key Record Dates
Last Update Posted: May 8, 2008
Last Verified: May 2008
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Antilymphocyte Serum
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors
Antineoplastic Agents