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Reversing Type 1 Diabetes After it is Established

Primary Purpose

Diabetes Mellitus, Type 1

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Anti-Thymocyte Globin (ATG)

Placebo

Pegylated GCSF

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring Autoimmune, Diabetes Mellitus, Glucose Metabolism

Eligibility Criteria

12 Years - 45 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Must be > 12 years < 45
Must have a diagnosis of T1D of greater than 4 months duration, with an upper limit of 2 years, Now only recruiting for those diagnosed greater than 1 year but less than 2 years.
Must have at least one diabetes-related autoantibody present (e.g., islet cell autoantigen (ICA), GAD, ZnT8, or islet antigen 2 (IA2) autoantibodies)
Must have stimulated C-peptide levels ≥ 0.1 pmol/ml (0.3ng/mL) when measured during a mixed meal tolerance test (MMTT), conducted at least 4 months from diagnosis of diabetes, and within 8 weeks of randomization
Must be EBV PCR negative within two weeks of randomization if EBV seronegative at screening
Be at least 6 weeks from last live immunization
Be willing to forgo live vaccines for 3 months following last dose of study drug
Be willing to comply with intensive diabetes management
Normal screening values for complete blood count (CBC), renal function and electrolytes (CMP).

Exclusion Criteria:

Be immunodeficient or have clinically significant chronic lymphopenia: (Leukopenia (< 3,000 leukocytes /μL), neutropenia (<1,500 neutrophils/μL), lymphopenia (<800 lymphocytes/μL), or thrombocytopenia (<125,000 platelets/μL).
Have a chronic infection at time of randomization
Have a positive PPD
Be currently pregnant or lactating, or anticipate getting pregnant within the next two years
Require use of other immunosuppressive agents
Have serologic evidence of current or past HIV, Tuberculosis, Hepatitis B or Hepatitis C infection
Have any complicating medical issues or abnormal clinical laboratory results that interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, chronic obstructive pulmonary disease (COPD), sickle cell disease, neurological, or blood count abnormalities (e.g., lymphopenia, leukopenia, or thrombocytopenia)
Have a history of malignancies
Evidence of liver dysfunction with angiotensin sensitivity test (AST) or ALT greater than 3 times the upper limits of normal
Evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal
Vaccination with a live virus within the last 6 weeks
Current use of non-insulin pharmaceuticals that affect glycemic control
Active participation in another T1D treatment study in the previous 30 days
Known allergy to G-CSF or ATG
Prior treatment with ATG or known allergy to rabbit derived products
Any condition that in the investigator's opinion, may adversely affect study participation or may compromise the study results

Sites / Locations

University of California, San Francisco
Barbara Davis Center for Childhood Diabetes
University of Florida

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Anti-Thymocyte Globin plus pegylated GCSF

Placebo

Arm Description

Subjects will receive an infusion of Anti-Thymocyte Globin (ATG) followed by 6 doses of pegylated GCSF every 2 weeks for 10 weeks.

Saline infusion will be given on both Day 1 and Day 2 followed by placebo injection given in identical volumes in identical syringes in the identical subcutaneous manner

Outcomes

Primary Outcome Measures

Change in Metabolic Function Baseline to 12 Months.

Area Under Curve (AUC) C-peptide production. Subjects underwent a 2 hour mixed meal tolerance test (MMTT) using a 6ml/kg load of boost to stimulate insulin production. Samples were collected at baseline, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. AUC was then calculated. Subjects repeated the MMTT at baseline, 3, 6, 9, and 12 months following ATG/GCSF or placebo. The primary outcome for the study was the change over 12 months in AUC C-peptide (1 year - baseline) for those who received ATG/GCSF versus the change in AUC C-peptide (1 year - baseline) for those who received placebo

Secondary Outcome Measures

Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months

Change in regulatory T cells (Treg) baseline to 12 months

A1c

Change in A1c baseline to 12 months

Change in Insulin Requirements, Baseline to 12 Months

Change in Insulin Requirements, baseline to 12 months

Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months

Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months

Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months

Change in Insulin Autoantibodies (IAA) over 12 months

Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months

Change in Insulinoma Associated 2 Autoantibodies (IA-2A)

Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months

Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months

Percentage of Neutrophils

Change in Neutrophil Count over 12 months

Change in White Blood Count (WBC) From Baseline to 12 Months

Change in WBC over 12 months

Full Information

NCT ID

NCT01106157

First Posted

April 15, 2010

Last Updated

July 16, 2019

Sponsor

University of Florida

Collaborators

The Leona M. and Harry B. Helmsley Charitable Trust, Genzyme, a Sanofi Company

1. Study Identification

Unique Protocol Identification Number

NCT01106157

Brief Title

Reversing Type 1 Diabetes After it is Established

Official Title

Reversing Type 1 Diabetes After it is Established: A Pilot Safety and Feasibility Study of Anti-Thymocyte Globulin (Thymoglobulin®)and Pegylated GCSF (Neulasta®) in Established Type 1 Diabetes

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

April 2010 (Actual)

Primary Completion Date

January 2015 (Actual)

Study Completion Date

July 16, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

Collaborators

The Leona M. and Harry B. Helmsley Charitable Trust, Genzyme, a Sanofi Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The primary purpose of this study is to determine if giving the combination therapy consisting of Thymoglobulin® (ATG) and Neulasta® (GCSF) to patients with established Type 1 Diabetes (T1D) is safe and secondarily, if the ATG and GCSF will preserve insulin production.

Detailed Description

This is a randomized, placebo controlled, phase I/II trial. Potential subjects will be screened via a 4 hour mixed meal tolerance test to assess residual beta cell (C-peptide) function. If the C-peptide level at any time is ≥ 0.1 pmol/ml, and the subject meets the additional inclusion and exclusion criteria, they will be eligible for randomization and enrollment. The study will be randomized 2:1 such that 17 subjects will receive active therapy and 8 will receive placebo. Subjects must receive Thymoglobulin®/ Neulasta® or placebo within 8 weeks of randomization. Thymoglobulin® (2.5mg/kg)/placebo will be given as 0.5 mg/kg IV on day 1 and 2 mg/kg on day 2. Six doses of Neulasta® (6mg/dose)/placebo will be given as standard of care every 2 weeks, with the first dose given prior to discharge after the Thymoglobulin® infusion. Complete metabolic panel (CMP) and complete blood count (CBC) will be done at the screening visit, just prior to study drug initiation, daily during the Thymoglobulin® infusion admission, and at follow up visits. Following discharge, daily phone calls will be made to the subjects during the first 5 days of therapy and weekly thereafter. In addition, weekly phone calls for the month following completion of therapy will be used to document adverse reactions. Thereafter calls will be made every two weeks.

6. Conditions and Keywords

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

Diabetes Mellitus, Type 1

Keywords

Autoimmune, Diabetes Mellitus, Glucose Metabolism

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Anti-Thymocyte Globin plus pegylated GCSF

Arm Type

Experimental

Arm Description

Subjects will receive an infusion of Anti-Thymocyte Globin (ATG) followed by 6 doses of pegylated GCSF every 2 weeks for 10 weeks.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Saline infusion will be given on both Day 1 and Day 2 followed by placebo injection given in identical volumes in identical syringes in the identical subcutaneous manner

Intervention Type

Drug

Intervention Name(s)

Anti-Thymocyte Globin (ATG)

Other Intervention Name(s)

Thymoglobulin

Intervention Description

Anti-Thymocyte Globin (ATG) will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Saline infusion

Intervention Description

Saline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes

Intervention Type

Drug

Intervention Name(s)

Pegylated GCSF

Other Intervention Name(s)

Neulasta

Intervention Description

6 doses of pegylated GCSF (6mg/dose) will be given subcutaneously every 2 weeks beginning after the ATG infusion.

Primary Outcome Measure Information:

Title

Change in Metabolic Function Baseline to 12 Months.

Description

Time Frame

Baseline and 12 months

Secondary Outcome Measure Information:

Title

Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months

Description

Change in regulatory T cells (Treg) baseline to 12 months

Time Frame

Change in Baseline to 12 months

Title

A1c

Description

Change in A1c baseline to 12 months

Time Frame

Change in baseline to 12 months

Title

Change in Insulin Requirements, Baseline to 12 Months

Description

Change in Insulin Requirements, baseline to 12 months

Time Frame