Hematopoietic Stem Cell Support Versus Insulin in T1D
| Status: | Recruiting |
|---|---|
| Conditions: | Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 16 - 35 |
| Updated: | 8/15/2015 |
| Start Date: | January 2009 |
| End Date: | December 2017 |
| Contact: | Dzemila Spahovic, MD |
| Email: | d-spahovic@northwestern.edu |
| Phone: | 312-695-4960 |
A Trial of High Dose Immunosuppression and Autologous Hematopoietic Stem Cell Support Versus Intensive Insulin Therapy in Adults With Early Onset Type I Diabetes Mellitus
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.
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.
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.
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.
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
We found this trial at
1
site
Northwestern University Northwestern is recognized both nationally and internationally for the quality of its educational...
Click here to add this to my saved trials
