Type 1 Diabetes Mellitus
Conditions
Keywords
Islet Transplantation
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.
Interventions
BIOLOGICALIslet Transplantation and Bone Marrow
Islet transplantation and CD34 Bone Marrow infusion in subjects with type 1 diabetes.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Diabetes Research Institute Foundation
University of Miami
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Patients between 18 and 65 years of age 2. Patients with type 1 diabetes mellitus for more than 5 years duration 3. 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 4. Body Mass Index (BMI) ≤26
Exclusion criteria
1. Untreated proliferative diabetic retinopathy; 2. HbA1C \> 12%; 3. Insulin requirement \> 1.0u/kg/d 4. Stimulated or basal C-peptide \> 0.3 ng/ml 5. Creatinine clearance \< 60 and/or serum creatinine consistently \> 1.5mg/dl; 6. Macroalbuminuria \> 300mg albumin in 24 hours 7. Presence of panel reactive antibodies \> 20%; 8. Previous/concurrent organ transplantation (except failed islet cell transplantation); 9. Any medical condition requiring chronic use of steroids; 10. Malignancy or previous malignancy (except non-melanomatous skin cancer); 11. X-ray evidence of pulmonary infection; 12. Active infections; 13. Positive tuberculin test (unless proof of adequate treatment for latent tuberculosis can be provided) 14. Active peptic ulcer disease, 15. Gall stones and/or portal hypertension and/or hemangioma on liver ultrasound; 16. Serological evidence of HIV, HBV (HBsAg+ and/or HBcAb+ and/or HBsAb+ without evidence of vaccination), HTLV-1 or HCV; 17. Negative serology for Epstein Barr virus (EBV) or evidence of acute infection (IgM\>IgG); 18. Abnormal liver function test; 19. Anemia (hemoglobin \<12.0 g/dl); 20. Hyperlipidemia (fasting total cholesterol \>240mg/dl and/or fasting triglycerides \>200mg/dl and/or fasting LDL cholesterol\>140mg/dl); 21. Body Mass Index above 26 and/or weight \>80kg; 22. Prostate specific antigen (PSA) \> 4 ng/ml; 23. Unstable cardiovascular status (including positive stress echocardiography if \>age 35); 24. Active alcohol or substance abuse; 25. 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); 26. Positive pregnancy test or intent for future pregnancy, or male subject's intent to procreate. 27. Any condition or any circumstances that makes it unsafe to undergo an islet cell transplant. 28. History of previous transplant or previous bone marrow infusion. 29. Persistent leucopenia (white blood cell count \<3,000/mm3
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Islet Transplantation and CD34 Bone Marrow Islet Transplantation: Islet transplantation | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Islet Transplantation and CD34 Bone Marrow |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
A Reduction or Absence of Rejection Episodes
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.
Time frame: for the duration of islet graft function
Population: IImmunosuppression 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. No data available to analyze.
Primary
The Achievement of Persistent Islet Function Following Cessation of Immunosuppression.
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.
Time frame: for the duration of islet graft function
Population: IImmunosuppression 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. No data available to analyze.
| Arm | Measure | Value |
|---|---|---|
| Islet Transplantation and CD34 Bone Marrow | The Achievement of Persistent Islet Function Following Cessation of Immunosuppression. | 0 |
Secondary
Number of Subjects With Basal C-peptide Greater Than 0.5 ng/ml
Number of subjects with basal C-peptide greater than 0.5 ng/ml prior to weaning of immunosuppression;
Time frame: for the duration of islet graft function
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Islet Transplantation and CD34 Bone Marrow | Number of Subjects With Basal C-peptide Greater Than 0.5 ng/ml | 3 Participants |
Secondary
Number of Subjects With Reduction of Severe Hypoglycemia and Improvement in Hypoglycemia Awareness
Number of subjects with reduction of episodes of severe hypoglycemia and the presence of awareness of hypoglycemia
Time frame: for the duration of islet graft function
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Islet Transplantation and CD34 Bone Marrow | Number of Subjects With Reduction of Severe Hypoglycemia and Improvement in Hypoglycemia Awareness | 3 Participants |