Type 1 Diabetes Mellitus
Conditions
Keywords
Islet cells, hypoglycemia, hypoglycemia unawareness, islet after kidney transplantation, islet transplant, insulin independence, insulin dependence, labile diabetes
Brief summary
City of Hope National Medical Center, located in Duarte, CA, is hosting a clinical study on islet cell transplantation, an experimental procedure being evaluated as a treatment for patients with type 1 diabetes. Islet cell transplantation involves taking insulin-producing cells from organ donors and transplanting them into the liver of a patient with diabetes. Once transplanted, the islets produce insulin, which can improve blood sugar control and eliminate the need to inject insulin or use an insulin pump. Anti-thymocyte globulin (ATG) and alemtuzumab (Campath) are anti-rejection medications that work by decreasing a patient's T-cells. T-cells are special white blood cells that recognize and destroy unwanted things like infections but can also attack transplanted cells and organs. Reducing the number of T-cells at the time of transplant may protect islets and improve long-term transplant success. In previous research studies, islet transplantation has been successful in reducing low blood sugar episodes, improving overall blood sugar control, and in some cases, allowing patients with type 1 diabetes to stop taking insulin. The purpose of this study is to determine if islet cell transplantation using ATG or alemtuzumab, along with additional medications to prevent the body from rejecting the transplanted cells, is a safe and effective treatment for type 1 diabetes. Study participants may receive up to three islet transplants and will be followed for five years to monitor blood sugar control, islet transplant function, and changes in quality of life.
Interventions
BIOLOGICALAllogenic Human Islet Cells
Intraportal (into the liver) infusion of islet cells, with a maximum of three islet transplants.
DRUGImmunosuppressive Agents
Anti-rejection medications (to prevent the body from rejecting the islet cells) and other medications to guard against infection and support participant health and/or the health of the transplanted islets.
DRUGGastrin 17
Gastrin-17 (or GAST-17) - a gut hormone injected under the skin for 30 days (optional treatment for islet dysfunction).
Sponsors
University of California, Los Angeles
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 68 Years
Healthy volunteers
No
Inclusion criteria
Three different categories of patients with Type 1 Diabetes will be considered for study participation: * Naïve islet transplant alone (nITA) candidates: T1D patients complicated by frequent/severe hypoglycemia, hypoglycemia unawareness, AND/OR otherwise unstable blood glucose control who have not received a previous transplant (except for a failed pancreas more than 6 months prior to screening) * Repeat transplant (RT) candidates: T1D patients who have received two or fewer previous islet transplants \> 1 month prior to screening, but continue to require exogenous insulin treatment or have an HbA1c \> 6.5% * Islet after kidney transplant (IAK) candidates: T1D patients with a history of successful renal transplant \> 3 months prior to screening Inclusion criteria for all candidates: 1. Age 18-68 years 2. Type 1 diabetes mellitus for at least 5 years 3. Ability and willingness to comply with post-transplant regimen, including taking anti-rejection medications, use of reliable contraception, frequent clinic visits, lab tests, careful recording of blood glucose values, insulin doses and medications, and completing detailed follow-up studies Additional Inclusion Criteria nITA Candidates Only 4. Unstable blood sugar control characterized by: Frequent hypoglycemia (blood glucose ≤ 54 mg/dl more than once per week) -AND/OR- Hypoglycemia unawareness (Clarke score of 4 or more) -AND/OR- One or more severe hypoglycemic episodes in 12 months preceding enrollment. -AND/OR- Erratic blood glucose levels that interfere with daily activities -AND/OR- One or more hospital visits for diabetic ketoacidosis in the 12 months preceding enrollment Additional Inclusion Criteria for RT Candidates Only 5. One or two or previous islet transplants \> 1 month prior to screening with continuing insulin requirements and/or HbA1c \> 6.5% Additional Inclusion Criteria for IAK Candidates Only 6. Successful kidney transplant \> 3 months prior to screening 7. Stable maintenance immunosuppression consisting of tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic or azathoprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic +/- ≤ 10 mg/day corticosteroids 8. No history of acute rejection related to kidney graft in last 12 months and low risk of rejection 9. Under continuing care of physician for kidney graft, who has provided letter in support of candidate's consideration for study participation
Exclusion criteria
1. Body Mass Index (BMI) \> 33 2. Insulin requirements \> 1.2 units/kg/day 3. Known sensitization to both rATG -and- alemtuzumab 4. Significant kidney dysfunction 5. Significant liver/gall bladder disease 6. Significant cardiovascular disease 7. Active proliferative retinopathy 8. High blood pressure despite appropriate treatment 9. High cholesterol/triglycerides despite appropriate treatment 10. Anemia or other blood disorders that require medical treatment 11. WBC \<3,000/ul 12. Increased risk of bleeding, other chronic hemostasis disorders, or treatment with chronic anticoagulant therapy 13. Recent unresolved acute infection (except for mild skin infection or nail fungal infection), or chronic infection 14. Epstein-Barr Virus (EBV) IgG negative 15. Any history of malignancy, except for completely resected squamous or basal cell carcinoma of the skin or in situ cancer of the cervix 16. Recent history of non-adherence to medical treatment, or inability to demonstrate capacity to comply with strict blood glycemic control and insulin therapy 17. Psychiatric illness that is untreated, or likely to interfere significantly with study compliance despite treatment 18. Previous organ/tissue transplant, except as noted above 19. Administration of live attenuated vaccines within 2 months of enrollment 20. Presence of a chronic disease that must be chronically treated with a contraindicated agent 21. Use of investigational agents within four weeks of enrollment 22. Active alcohol or substance abuse, including cigarette smoking 23. Pregnant women, women intending future pregnancy, women of reproductive potential who are unable or unwilling to follow effective contraceptive measures prior to study entry and for as long as they are on immunosuppression medication, and women presently breast feeding are excluded 24. Individuals without health insurance 25. History of gastric bypass 26. Any medical condition that in the opinion of the investigator will interfere with safe participation in the trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of subjects who are insulin independent, hypoglycemia free, AND with hemoglobin A1c < or = 6.5% at 1 year post-transplant | 1 year post-transplant |
| Proportion of subjects who are insulin independent, hypoglycemia free, AND with hemoglobin A1c < or = 6.5% at 2 years post-transplant | 2 years post-transplant |
| Proportion of subjects who are insulin independent, hypoglycemia free, AND with hemoglobin A1c < or = 6.5% at 5 years post-transplant | 5 years post-transplant |
Secondary
| Measure | Time frame |
|---|---|
| Proportion of subjects who are free of severe hypoglycemic episodes AND have a hemoglobin A1c < or = 7.0% | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
Other
| Measure | Time frame |
|---|---|
| Decline in insulin intake/100,000 IEQ infused | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Insulin secretion during Intravenous Glucose Tolerance Test (IVGTT), IVGTT+arginine stimulation (IVGTT+AST), Maximum Stimulated Insulin Secretion test (MSIS), and/or Mixed Meal Tolerance Test (MMTT) | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Rate of alloimmune rejection | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Rate of autoimmune reactivation | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Incidence and severity of adverse events related to islet transplant procedure | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Incidence and severity of adverse events related to immunosuppression | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Proportion of subjects experiencing reduction/elimination of hypoglycemic episodes | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Incidence of immune sensitization defined by presence of anti-HLA antibodies post-transplant that were absent pre-transplant | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Incidence of discontinuation of immunosuppression | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Improvement in glucose time within range during continuous glucose monitoring | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Improvement in Personal Glycemic State (PGS) score calculated from continuous glucose monitoring | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Incidence of Gastrin-17 use for treatment of islet graft dysfunction AND incidence of change or early discontinuation of Gastrin-17 treatment | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Incidence of change in immunosuppression drug regimen | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Duration of insulin independence | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Proportion of subjects who maintain a positive c-peptide secretion response to glucose/glucagon stimulation | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
| Change in average daily insulin use compared to baseline | +75 days, +6 months, +12 months, and +2, +3, +4 and +5 years post islet transplant |
Countries
United States
Outcome results
None listed