Hematopoietic Stem Cell Support Versus Insulin in T1D

NCT ID: NCT01285934

Last Updated: 2015-08-21

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-01-31
• Study Completion Date: 2015-08-31

Brief Summary

Type 1 diabetes mellitus (T1D) results from immune-mediated destruction of insulin-producing islet cells. The loss of islet cells is traditionally treated with insulin therapy and in some cases pancreas or islet cell transplantation. Another approach would be to preserve islet cell mass before it is irreversibly lost. Previous trials using immune suppression within 6 weeks of T1D onset have demonstrated diminished exogenous insulin requirements compared to untreated controls. In our prior phase I non-randomized study, by extending immune suppression to the point of immune ablation / immune reset with autologous HSC support, several patients with new onset T1D have maintained an insulin-free, drug free remissions for more than 4 years. Although these results appear highly promising, it may be argued that our results are mitigated by the documented honeymoon effect following T1D, that is by a normal transient insulin free interval occurring after disease onset in some patients. The goal of this trial is to extend this phase I study of new onset T1D to clarify whether our post transplant insulin free interval is due to treatment intervention (transplant) or a result of a normally occurring "insulin free honeymoon period". Both groups will receive identical change of life style (i.e. diet, exercise) education.

Detailed Description

Eligible patients will have type 1 diabetes (aged ≥ 18 years old) within five months of disease diagnosis, and a positive antibody to an islet cell autoantigen, and fasting C-peptide > 0.2 nmol/l. Hematopoietic stem cells will be mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (10 g/kg/day) collected from peripheral blood by leukoapheresis and cryopreserved. HSC will injected IV after conditioning with cyclophosphamide (200 mg/kg) divided 50 mg/kg on day -5, -4, -3, -2, and rabbit antithymocyte globulin (4.5 mg/kg) divided 0.5 mg/kg day-5, and 1.0 mg/kg day -4, -3-, -2, -1. Rituxan (500mg) IV will be given on days -6 and +1. The control arm will receive either continuous subcutaneous insulin infusion (CSII) or intensive subcutaneous insulin therapy with multiple insulin injections (at least 4/day) utilizing a long acting background insulin and pre-meal rapid acting insulin. The main outcome measure will be: fasting C-peptide. Other outcome measures will include: daily exogenous insulin requirements, serum levels of hemoglobin A1c, area under the curve (AUC) C-peptide levels during mixed meal tolerance test, islet cell autoantigen antibody titers, and quality of life (QOL) short form 36 (SF-36) questionnaire.

Conditions

Diabetes Mellitus, Type 1

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hematopoietic Stem Cell Transplantation

Patients who meet eligibility and have completed pre-HSCT testing in section 7.0 (study parameters) may be enrolled in the transplant arm and will undergo an Autologous Hematopoietic Stem Cell Transplantation

Group Type: EXPERIMENTAL

Autologous Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

All participants randomized to the transplant arm wil undergo Autologous Hematopoietic Stem Cell Transplantation

control arm of intensive insulin therapy

The control arm of intensive insulin therapy (IIT) will enroll all patients who meet eligibility but decline HSCT or whose insurance does not approve payment for HSCT before expiration of eligibility (within 5 months of disease onset)

Group Type: OTHER

intensive insulin therapy

Intervention Type: DRUG

The control arm will be either CSII via an insulin pump or intensive subcutaneous insulin therapy with multiple insulin injections (at least 4/day) utilizing a long acting background insulin and pre-meal rapid acting insulin.

Interventions

Autologous Hematopoietic Stem Cell Transplantation

All participants randomized to the transplant arm wil undergo Autologous Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

intensive insulin therapy

The control arm will be either CSII via an insulin pump or intensive subcutaneous insulin therapy with multiple insulin injections (at least 4/day) utilizing a long acting background insulin and pre-meal rapid acting insulin.

Intervention Type: DRUG

Other Intervention Names

IIT

Eligibility Criteria

Inclusion Criteria

• Ages 16 to 35 years old
• A diagnosis of type 1 diabetes by hyperglycemia and at least 1 antibody to islet cell autoantigen: GAD, IAA, ICA, IA-2, or Slc30A8
• Fasting C-peptide > 0.20 nmol / liter
• Enrollment within 5 months of T1D diagnosis
• Eligible patients must be referred to a fertility / reproductive endocrinologist and have written documentation of medical counseling advising patients about the risk of infertility and the possible options of sperm and oocyte banking before enrollment.

Exclusion Criteria

• HIV positive
• Patients in the honeymoon phase not taking insulin
• Hepatitis A, B, or C positive
• On corticosteroids or other immune suppressive medications
• History of diabetic ketoacidosis
• Ongoing malignancy except localized treated basal cell or squamous skin cancer.
• History of cardiac disease or congestive heart failure or ventricular tachycardia or abnormal dobutamine cardiac echocardiogram
• Positive pregnancy test, inability or unwillingness to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a potential side effect of therapy.
• Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
• DLCO < 60% of predicted
• Resting LVEF < 45%
• Creatinine > 1.5 mg/dl
• Known hypersensitivity to E Coli derived proteins.
• Transaminases greater than 2 times normal
• Positive tuberculosis skin test
• Any active infection
• Any co-morbid illness that in the opinion of the investigator would jeopardize the ability of the subject to tolerate the study.
• Failure to collect at least 2.0 x 106 CD34+ cells/kg
• History of alcohol or illicit drug abuse
• Unwilling to be compliant with change in life-style-diet and exercise

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Sao Paulo General Hospital

OTHER

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Richard Burt, MD

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard Burt, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Other Identifiers

Diabetes2008

Identifier Type: -

Identifier Source: org_study_id