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
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring Autoimmune, Diabetes Mellitus, Glucose Metabolism
Eligibility Criteria
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
No
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
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
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
Change from baseline to 12 months
Title
Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months
Description
Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months
Time Frame
Change from baseline to 12 months
Title
Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months
Description
Change in Insulin Autoantibodies (IAA) over 12 months
Time Frame
Change from baseline to 12 months
Title
Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months
Description
Change in Insulinoma Associated 2 Autoantibodies (IA-2A)
Time Frame
Change from baseline to 12 months
Title
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months
Description
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months
Time Frame
Change from baseline to 12 months
Title
Percentage of Neutrophils
Description
Change in Neutrophil Count over 12 months
Time Frame
Change from baseline to 12 months
Title
Change in White Blood Count (WBC) From Baseline to 12 Months
Description
Change in WBC over 12 months
Time Frame
Change from baseline to 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael J. Haller, MD
Organizational Affiliation
University of Florida Pediatric Endocrinology
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143-0748
Country
United States
Facility Name
Barbara Davis Center for Childhood Diabetes
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045-6511
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0296
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
19628781
Citation
Parker MJ, Xue S, Alexander JJ, Wasserfall CH, Campbell-Thompson ML, Battaglia M, Gregori S, Mathews CE, Song S, Troutt M, Eisenbeis S, Williams J, Schatz DA, Haller MJ, Atkinson MA. Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes. 2009 Oct;58(10):2277-84. doi: 10.2337/db09-0557. Epub 2009 Jul 23.
Results Reference
background
PubMed Identifier
25500887
Citation
Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, Zou B, Brusko TM, Hulme MA, Wasserfall CH, Mathews CE, Atkinson MA, Schatz DA. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015 Jan;125(1):448-55. doi: 10.1172/JCI78492. Epub 2014 Dec 15.
Results Reference
derived
Links:
URL
http://diabetes.ufl.edu
Description
University of Florida Diabetes Center of Excellence
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Reversing Type 1 Diabetes After it is Established
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