Islet Cell Transplantation Alone and CD34+ Donor Bone Marrow Cell Infusion in Type 1 Diabetes Mellitus

Phase 2

Terminated

Conditions: Type 1 Diabetes Mellitus

Interventions: Biological: Islet Transplantation and Bone Marrow

Registration Number: NCT00315614

Lead Sponsor: University of Miami

Brief Summary: SPECIFIC AIMS:

* To reverse hyperglycemia and insulin dependency in patients with Type 1 diabetes mellitus by islet cell transplantation.

* To induce a state of donor specific tolerance and eliminate the need for continuous immunosuppressive therapy by simultaneous transplantation of donor bone marrow cells with islets and utilization of the monoclonal antibody Campath-1H for induction of Immunosuppression.

* To assess long-term function of successful islet cell transplants in patients with Type 1 diabetes mellitus.

* To determine whether the natural history of the microvascular, macrovascular and neuropathic complications are altered following successful transplantation of islet

Detailed Description: In our current protocol (IRB #2000/0024) the immunosuppressive regimen, comprised of induction with daclizumab and maintenance therapy with sirolimus and tacrolimus, has been combined with the infusion of CD34+ enriched donor bone marrow stem cells in an attempt to create a chimeric state and hence induce donor tolerance. This strategy was tested by evaluating graft survival following the removal of all immunosuppressive medication after one year.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

Inclusion Criteria

Patients between 18 and 65 years of age
Patients with type 1 diabetes mellitus for more than 5 years duration
One or more of the following:
- Hypoglycemia unawareness - judged by history of blood sugars <54 on glucometer without symptoms and/or hypoglycemic episodes requiring assistance from either family, glucagon administration or emergency services
- Poor diabetes control (HbA1c>8% or >2 visits/yr to hospital for treatment of ketoacidosis) despite intensive insulin therapy
- Progressive complications of type 1 diabetes mellitus
Body Mass Index (BMI) ≤26

Exclusion Criteria

Untreated proliferative diabetic retinopathy;
HbA1C > 12%;
Insulin requirement > 1.0u/kg/d
Stimulated or basal C-peptide > 0.3 ng/ml
Creatinine clearance < 60 and/or serum creatinine consistently > 1.5mg/dl;
Macroalbuminuria > 300mg albumin in 24 hours
Presence of panel reactive antibodies > 20%;
Previous/concurrent organ transplantation (except failed islet cell transplantation);
Any medical condition requiring chronic use of steroids;
Malignancy or previous malignancy (except non-melanomatous skin cancer);
X-ray evidence of pulmonary infection;
Active infections;
Positive tuberculin test (unless proof of adequate treatment for latent tuberculosis can be provided)
Active peptic ulcer disease,
Gall stones and/or portal hypertension and/or hemangioma on liver ultrasound;
Serological evidence of HIV, HBV (HBsAg+ and/or HBcAb+ and/or HBsAb+ without evidence of vaccination), HTLV-1 or HCV;
Negative serology for Epstein Barr virus (EBV) or evidence of acute infection (IgM>IgG);
Abnormal liver function test;
Anemia (hemoglobin <12.0 g/dl);
Hyperlipidemia (fasting total cholesterol >240mg/dl and/or fasting triglycerides >200mg/dl and/or fasting LDL cholesterol>140mg/dl);
Body Mass Index above 26 and/or weight >80kg;
Prostate specific antigen (PSA) > 4 ng/ml;
Unstable cardiovascular status (including positive stress echocardiography if >age 35);
Active alcohol or substance abuse;
Sexually active females who are not: a) post-menopausal, b) surgically sterile, or c) not using an acceptable method of contraception (oral contraceptives, Norplant, Depo-Provera, and barrier devices are acceptable; condoms used alone are not acceptable);
Positive pregnancy test or intent for future pregnancy, or male subject's intent to procreate.
Any condition or any circumstances that makes it unsafe to undergo an islet cell transplant.
History of previous transplant or previous bone marrow infusion.
Persistent leucopenia (white blood cell count <3,000/mm3

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Islet Transplantation and Bone Marrow	Islet Transplantation and Bone Marrow	Administration of islets and infusion of CD34 enriched Bone Marrow cells in subjects with type 1 diabetes, impaired awareness of hypoglycemia and severe hypoglycemia.

Primary Outcome Measures

Name	Time	Method
The Achievement of Persistent Islet Function Following Cessation of Immunosuppression.	for the duration of islet graft function	Immunosuppression was never discontinued. Patients elected to move to other trials to receive additional islet infusions. Since immunosuppression was never discontinued we were not able to evaluate the primary endpoint.
A Reduction or Absence of Rejection Episodes	for the duration of islet graft function	Number of rejection episodes after transplantation. Immunosuppression was never discontinued. Patients elected to move to other trials to receive additional islet infusions. Since immunosuppression was never discontinued we were not able to evaluate the primary endpoint.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects With Basal C-peptide Greater Than 0.5 ng/ml	for the duration of islet graft function	Number of subjects with basal C-peptide greater than 0.5 ng/ml prior to weaning of immunosuppression;
Number of Subjects With Reduction of Severe Hypoglycemia and Improvement in Hypoglycemia Awareness	for the duration of islet graft function	Number of subjects with reduction of episodes of severe hypoglycemia and the presence of awareness of hypoglycemia