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Hematopoietic Stem Cell Support Versus Insulin in T1D

Primary Purpose

Diabetes Mellitus, Type 1

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

Autologous Hematopoietic Stem Cell Transplantation

intensive insulin therapy

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1

Eligibility Criteria

16 Years - 35 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Hematopoietic Stem Cell Transplantation

control arm of intensive insulin therapy

Arm Description

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

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)

Outcomes

Primary Outcome Measures

C-peptide

C-peptide (fasting and every 30 minutes during 2 hour mixed meal tolerance test

Secondary Outcome Measures

Insulin dose

Insulin dose, recorded as daily insulin dose in IU/Kg/day

Serum levels of hemoglobin A1c

Stimulated C-peptide levels during mixed meal tolerance test

Full Information

NCT ID

NCT01285934

First Posted

January 27, 2011

Last Updated

August 19, 2015

Sponsor

Northwestern University

Collaborators

University of Sao Paulo General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT01285934

Brief Title

Hematopoietic Stem Cell Support Versus Insulin in T1D

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2015

Overall Recruitment Status

Withdrawn

Why Stopped

No participant enrolled

Study Start Date

January 2009 (undefined)

Primary Completion Date

August 2015 (Actual)

Study Completion Date

August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Northwestern University

Collaborators

University of Sao Paulo General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 1

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hematopoietic Stem Cell Transplantation

Arm Type

Experimental

Arm Description

Arm Title

control arm of intensive insulin therapy

Arm Type

Other

Arm Description

Intervention Type

Biological

Intervention Name(s)

Autologous Hematopoietic Stem Cell Transplantation

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

intensive insulin therapy

Other Intervention Name(s)

IIT

Intervention Description

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.

Primary Outcome Measure Information:

Title

C-peptide

Description

C-peptide (fasting and every 30 minutes during 2 hour mixed meal tolerance test

Time Frame

Every 6 months for 5 years

Secondary Outcome Measure Information:

Title

Insulin dose

Description

Insulin dose, recorded as daily insulin dose in IU/Kg/day

Time Frame

5 years

Title

Serum levels of hemoglobin A1c

Time Frame

5 years

Title

Stimulated C-peptide levels during mixed meal tolerance test

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Richard Burt, MD

Organizational Affiliation

Northwestern University

Official's Role

Principal Investigator

12. IPD Sharing Statement

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Hematopoietic Stem Cell Support Versus Insulin in T1D

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