Clinical trial NCT00315614: Islet Cell Transplantation Alone and CD34+ Donor Bone Marrow Cell Infusion in Type 1 Diabetes Mellitus
Official title: Islet Cell Transplantation Alone and CD34+ Enriched Donor Bone Marrow Cell Infusion in Patients With Type 1 Diabetes Mellitus; Steroid Free Regimen
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
Keywords: Islet Transplantation
Lead sponsor: University of Miami
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Diabetes Research Institute Foundation
First posted: 2006-04-18
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: The Achievement of Persistent Islet Function Following Cessation of Immunosuppression.
timeFrame: for the duration of islet graft function
measure: A Reduction or Absence of Rejection Episodes
timeFrame: for the duration of islet graft function
Secondary outcomes:
measure: Number of Subjects With Basal C-peptide Greater Than 0.5 ng/ml
timeFrame: for the duration of islet graft function
measure: Number of Subjects With Reduction of Severe Hypoglycemia and Improvement in Hypoglycemia Awareness
timeFrame: for the duration of islet graft function
Other outcomes:
Locations:
city: Miami
country: United States
facility: Diabetes Research Institute
state: Florida
Study officials:
affiliation: Diabetes Research Institute University of Miami
name: Rodolfo Alejandro, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tharavanij T, Betancourt A, Messinger S, Cure P, Leitao CB, Baidal DA, Froud T, Ricordi C, Alejandro R. Improved long-term health-related quality of life after islet transplantation. Transplantation. 2008 Nov 15;86(9):1161-7. doi: 10.1097/TP.0b013e31818a7f45.