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

Islet Cell Transplantation Alone and CD34+ Enriched Donor Bone Marrow Cell Infusion in Patients With Type 1 Diabetes Mellitus; Steroid Free Regimen

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

Study Overview

• Status: Terminated
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Biological: Islet Transplantation and Bone Marrow

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Diabetes Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Biological: Islet Transplantation and Bone Marrow; Islet transplantation and CD34 Bone Marrow infusion in subjects with type 1 diabetes.; Other Names: Islet; type 1 DM; Bone marrow

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	for the duration of islet graft function
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.	for the duration of islet graft function

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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;	for the duration of islet graft function
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	for the duration of islet graft function

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Diabetes Research Institute Foundation
• Investigators: Principal Investigator: Rodolfo Alejandro, MD, Diabetes Research Institute University of Miami

Publications and helpful links

General Publications

• 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.

Helpful Links

• Diabetes Research Institute web site

Study record dates

Study Major Dates

• Study Start: December 1, 2000
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: April 14, 2006
• First Submitted That Met QC Criteria: April 14, 2006
• First Posted (Estimate): April 18, 2006

Study Record Updates

• Last Update Posted (Actual): April 4, 2017
• Last Update Submitted That Met QC Criteria: March 29, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Islet Transplantation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 2000/0024; R01DK056953 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Single arm few subjects.