Safety and Efficacy Study of Autologous Stem Cell Transplantation for Early Onset Type I Diabetes Mellitus

Autologous Hematopoietic Stem Cell Transplantation for Early Onset Type 1 Diabetes Mellitus- a Phase I/II Study

The study evaluates the effect of inactivation of the immune system with chemotherapy and immunotherapy and infusion of bone marrow stem cells in early onset type 1 diabetes mellitus. We hypothesize that reprograming the immune system will stop immune aggression to the insulin producing cells allowing their regeneration and thus decreasing or eliminating the need of exogenous insulin.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Procedure: Immunosuppression and autologous stem cell transplantation

Detailed Description

Patients from 12 to 35 years old with type I diabetes mellitus proved by anti-pancreatic beta cell antibodies and recently diagnosed (less than 6 weeks) will be included in this study. Peripheral blood hematopoietic stem cells will be mobilized from bone marrow of the patient with cyclophosphamide plus G-CSF (granulocyte-colony stimulating factor), collected by leukapheresis and cryopreserved. After 2-3 weeks, high dose immunosuppression is given (cyclophosphamide 200 mg/kg plus rabbit antithymocyte globulin 4.5 mg/kg) and stem cells are thawed and injected intravenously. This procedure is performed in isolated rooms at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto, University of São Paulo, Brazil. Patients are discharged from the hospital after engraftment and closely followed up to 2 months after transplantation (with at least weekly outpatient visits) and continue the followup for 5 years after transplantation. Clinical, hematological, metabolical and immunological evaluations are performed to analyse the effect of the transplant in the disease and in the hematopoetic and immunologic systems of the body. Patients fitting the inclusion criteria but not agreeing to perform the transplantation are the control group and they will be followed in parallel with transplanted patients.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Ribeirão Preto, Brazil, 14048-900
    • Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 1 diabetes mellitus diagnosed by clinical/metabolic parameters and positive anti-GAD antibodies
• Less than 12 weeks from diagnosis

Exclusion Criteria:

• Previous diabetic ketoacidosis
• Pregnancy
• Severe psychiatric disorder
• Severe organic impairment (renal, hepatic, cardiac, pulmonary)
• Active infectious disease
• Previous or present neoplastic disease

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: Transplant arm; This is a single arm study. The intervention is immunosuppression and autologous stem cell transplantation.

Procedure: Immunosuppression and autologous stem cell transplantation; Immunosuppression and autologous stem cell transplantation: Mobilization of hematopoietic stem cells (HSC) with cyclophosphamide (2 g/m2) and granulocyte-colony stimulating factor (G-CSF, 10 ug/kg/d), followed by collection and cryopreservation of unselected HSC and conditioning with cyclophosphamide (200 mg/kg) plus rabbit anti-thymocyte globulin (ATG 4.5 mg/kg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C-peptide levels	Stimulated C-peptide levels will be measured.	Every 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-GAD titres		Every 6 months
Transplant-related toxicity		Every 6 months or when reported
Exogenous insulin dose	Number of international insulin units per kilogram per day in use will be registered.	Every 6 months
Hemoglobin A1C	Hb A1C will be measured.	Every 6 months
Immunologic reconstitution parameters		Yearly
Quality of Life	SF-36 questionnaire	Every year

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Northwestern University; Genzyme, a Sanofi Company
• Investigators: Principal Investigator: Julio C Voltarelli, MD PhD, University Hospital, School of Medicine of Ribeirão Preto, Brazil; Study Chair: Maria C Oliveira, MD PhD, University Hospital, Ribeirão Preto Medical School, Brazil

Publications and helpful links

General Publications

• Burt RK, Oyama Y, Traynor A, Kenyon NS. Hematopoietic stem cell therapy for type 1 diabetes: induction of tolerance and islet cell neogenesis. Autoimmun Rev. 2002 May;1(3):133-8. doi: 10.1016/s1568-9972(02)00033-2.
• Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KC, Foss-Freitas MC, Simoes BP, Foss MC, Squiers E, Burt RK. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007 Apr 11;297(14):1568-76. doi: 10.1001/jama.297.14.1568.
• Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1573-9. doi: 10.1001/jama.2009.470.

Helpful Links

• General information about the blood and research center where stem cells are collected and where immunologic studies are performed

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: April 13, 2006
• First Submitted That Met QC Criteria: April 13, 2006
• First Posted (Estimate): April 17, 2006

Study Record Updates

• Last Update Posted (Estimate): January 18, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Stem cells; Diabetes mellitus; Autologous stem cell transplantation; Autoimmune diseases
• 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: HCFMRPUSP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD may be shared if the responsible investigators feel it may increase understanding, reliability and reproducibility of the present study.