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ATG-GCSF in New Onset Type 1 Diabetes (ATG-GCSF)

Primary Purpose

Diabetes Mellitus, Type 1

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Anti-Thymocyte Globulin (ATG)
Granulocyte colony stimulating factor (GCSF)
Placebo (for ATG)
Placebo (for GCSF)
Sponsored by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring Type 1 Diabetes TrialNet

Eligibility Criteria

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

Inclusion Criteria:

  • Must be > 12 years < 46
  • Must have a diagnosis of T1D for less than 100 days at randomization
  • Willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the subject is <18 years of age
  • Positive for at least one islet cell autoantibody; glutamic acid decarboxylase 65 (GAD65A), Insulin micro IAA (mIAA), if obtained within 10 days of the onset of insulin therapy, islet antigen 2 (IA-2A), Islet Cell Antigen (ICA), or zinc transporter 8 (ZnT8A)
  • Must have stimulated C-peptide levels = 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) conducted at least 21 days from diagnosis of diabetes and within one month (37 days) of randomization
  • Must be Epstein-Barr virus (EBV PCR) negative within two weeks of randomization if EBV seronegative at screening
  • Be at least 6 weeks from last live immunization
  • Participants are required to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available
  • Be willing to forgo vaccines during the treatment period and for 3 months following last dose of study drug
  • Be willing to comply with intensive diabetes management

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 (<100,000 platelets/µL).
  • Have active signs or symptoms of acute infection at the time of randomization
  • Have evidence of prior or current tuberculosis infection as assessed by purified protein derivative (PPD), interferon gamma release assay (IGRA) or by history
  • Be currently pregnant or lactating, or anticipate getting pregnant within the two year study period
  • Require use of other immunosuppressive agents including chronic use of systemic steroids
  • Have evidence of current or past human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection
  • Have any complicating medical issues or abnormal clinical laboratory results that may 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
  • Have a history of malignancies other than skin
  • Evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (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 or ongoing use of non-insulin pharmaceuticals that affect glycemic control within prior 7 days of screening
  • Active participation in another T1D treatment study in the previous 30 days
  • Prior treatment with abatacept or anti-cd3
  • Known allergy to GCSF 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
  • Stanford University
  • Barbara Davis Center
  • Yale University
  • University of Florida
  • University of Miami
  • University of South Florida Diabetes Center
  • Indiana University-Riley Hospital for Children
  • University of Minnesota
  • Columbia University-Naomi Berrie Diabetes Center
  • University of Pittsburgh
  • Vanderbilt Eskind Diabetes Clinic
  • Benaroya Research Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Anti-Thymocyte Globulin (ATG) and Placebo

ATG plus Granulocyte colony stimulating factor (GCSF)

Placebo

Arm Description

Anti-Thymocyte Globulin (ATG)/Placebo: Anti-Thymocyte Globulin (ATG) will be administered at a dose of 2.5mg/kg as two divided IV infusions of 0.5mg/kg and 2mg/kg. First dose (0.5mg/kg) will be infused over a minimum of 12 hours, and the second dose (2mg/kg) over a minimum of 8 hours. The second dose should be given no less than 12 and no more than 24 hours after the previous dose. Placebo(for GCSF) treatment will begin 6 hours after completion of the ATG. Placebo will be given subcutaneously every 2 weeks for a total of 6 doses

Granulocyte colony stimulating factor (GCSF) is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 6 mg GCSF (based on protein weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in water for injection, U.S. Pharmacopeial Convention (USP). The standard 6mg dose will be given with the exception of subjects who weigh less than 45 kg. GCSF treatment will begin 6 hours after completion of the ATG / Placebo. GCSF will be given subcutaneously every 2 weeks for a total of 6 doses

Placebo for ATG will be administered by IV infusion in 2 doses. Placebo for GCSF will be administered subcutaneously every 2 weeks for a total of 6 doses

Outcomes

Primary Outcome Measures

Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months.
The C-peptide 2 hour area under the curve (AUC) mean is calculated at baseline and 12 months and measured in nmol/L. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the "AUC mean" and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis").

Secondary Outcome Measures

Full Information

First Posted
August 11, 2014
Last Updated
February 28, 2020
Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), Juvenile Diabetes Research Foundation, American Diabetes Association, Sanofi, The Leona M. and Harry B. Helmsley Charitable Trust, Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT02215200
Brief Title
ATG-GCSF in New Onset Type 1 Diabetes
Acronym
ATG-GCSF
Official Title
Antithymocyte Globulin (ATG) and Pegylated Granulocyte Colony Stimulating Factor (GCSF) in New Onset Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
December 2014 (undefined)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
August 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), Juvenile Diabetes Research Foundation, American Diabetes Association, Sanofi, The Leona M. and Harry B. Helmsley Charitable Trust, Amgen

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
This is a three-arm, 1:1:1 randomized, placebo controlled, double- blinded trial in which at least 28 subjects will receive active Anti-Thymocyte Globulin and Granulocyte colony-stimulating factor (ATG-GCSF), at least 28 subjects will receive ATG alone and at least 28 subjects will receive placebo alone within 100 days from diagnosis of Type 1 Diabetes (T1D). The primary objective of the study will be to determine the safety and ability of low dose ATG plus GCSF and low dose ATG alone to retain/enhance C-peptide production in new onset T1D patients demonstrating residual beta cell function.
Detailed Description
The primary statistical hypothesis to be assessed in the study is whether the 2 hour area under the curve (change in baseline to 12 months) in residual beta cell function (C-peptide) will differ between those treated with ATG and GCSF or ATG alone as compared with placebo. The study will also examine the effect of the proposed treatments on surrogate markers for immunologic and metabolic outcomes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
Keywords
Type 1 Diabetes TrialNet

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
89 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Anti-Thymocyte Globulin (ATG) and Placebo
Arm Type
Experimental
Arm Description
Anti-Thymocyte Globulin (ATG)/Placebo: Anti-Thymocyte Globulin (ATG) will be administered at a dose of 2.5mg/kg as two divided IV infusions of 0.5mg/kg and 2mg/kg. First dose (0.5mg/kg) will be infused over a minimum of 12 hours, and the second dose (2mg/kg) over a minimum of 8 hours. The second dose should be given no less than 12 and no more than 24 hours after the previous dose. Placebo(for GCSF) treatment will begin 6 hours after completion of the ATG. Placebo will be given subcutaneously every 2 weeks for a total of 6 doses
Arm Title
ATG plus Granulocyte colony stimulating factor (GCSF)
Arm Type
Experimental
Arm Description
Granulocyte colony stimulating factor (GCSF) is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 6 mg GCSF (based on protein weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in water for injection, U.S. Pharmacopeial Convention (USP). The standard 6mg dose will be given with the exception of subjects who weigh less than 45 kg. GCSF treatment will begin 6 hours after completion of the ATG / Placebo. GCSF will be given subcutaneously every 2 weeks for a total of 6 doses
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo for ATG will be administered by IV infusion in 2 doses. Placebo for GCSF will be administered subcutaneously every 2 weeks for a total of 6 doses
Intervention Type
Drug
Intervention Name(s)
Anti-Thymocyte Globulin (ATG)
Other Intervention Name(s)
Thymoglobulin
Intervention Description
Thymoglobulin
Intervention Type
Drug
Intervention Name(s)
Granulocyte colony stimulating factor (GCSF)
Other Intervention Name(s)
Neulasta
Intervention Description
Granulocyte colony stimulating factor (GCSF)
Intervention Type
Drug
Intervention Name(s)
Placebo (for ATG)
Intervention Description
Normal saline administered by IV infusion to mimic ATG
Intervention Type
Drug
Intervention Name(s)
Placebo (for GCSF)
Intervention Description
Placebo prepared to mimic 6mg subcutaneous injection of GCSF
Primary Outcome Measure Information:
Title
Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months.
Description
The C-peptide 2 hour area under the curve (AUC) mean is calculated at baseline and 12 months and measured in nmol/L. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the "AUC mean" and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis").
Time Frame
-10, 0 15, 30, 60, 90, and 120 minutes post-dose at baseline and 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 < 46 Must have a diagnosis of T1D for less than 100 days at randomization Willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the subject is <18 years of age Positive for at least one islet cell autoantibody; glutamic acid decarboxylase 65 (GAD65A), Insulin micro IAA (mIAA), if obtained within 10 days of the onset of insulin therapy, islet antigen 2 (IA-2A), Islet Cell Antigen (ICA), or zinc transporter 8 (ZnT8A) Must have stimulated C-peptide levels = 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) conducted at least 21 days from diagnosis of diabetes and within one month (37 days) of randomization Must be Epstein-Barr virus (EBV PCR) negative within two weeks of randomization if EBV seronegative at screening Be at least 6 weeks from last live immunization Participants are required to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available Be willing to forgo vaccines during the treatment period and for 3 months following last dose of study drug Be willing to comply with intensive diabetes management 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 (<100,000 platelets/µL). Have active signs or symptoms of acute infection at the time of randomization Have evidence of prior or current tuberculosis infection as assessed by purified protein derivative (PPD), interferon gamma release assay (IGRA) or by history Be currently pregnant or lactating, or anticipate getting pregnant within the two year study period Require use of other immunosuppressive agents including chronic use of systemic steroids Have evidence of current or past human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection Have any complicating medical issues or abnormal clinical laboratory results that may 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 Have a history of malignancies other than skin Evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (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 or ongoing use of non-insulin pharmaceuticals that affect glycemic control within prior 7 days of screening Active participation in another T1D treatment study in the previous 30 days Prior treatment with abatacept or anti-cd3 Known allergy to GCSF 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, M.D.
Organizational Affiliation
University of Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California - San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158-2549
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Barbara Davis Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
University of South Florida Diabetes Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Indiana University-Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Columbia University-Naomi Berrie Diabetes Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Vanderbilt Eskind Diabetes Clinic
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Benaroya Research Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data are available at the NIDDK Central Repository
IPD Sharing URL
https://repository.niddk.nih.gov/studies/TN19_ATG_GCSF/?query=tn19
Citations:
PubMed Identifier
30967424
Citation
Haller MJ, Long SA, Blanchfield JL, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Geyer SM, Warnock MV, Miller JL, Atkinson MA, Becker DJ, Baidal DA, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell WE, Wilson DM, Greenbaum CJ; Type 1 Diabetes TrialNet ATG-GCSF Study Group. Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data. Diabetes. 2019 Jun;68(6):1267-1276. doi: 10.2337/db19-0057. Epub 2019 Apr 9.
Results Reference
derived
PubMed Identifier
30012675
Citation
Haller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, Atkinson MA, Becker DJ, Baidal D, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell W, Wilson DM, Greenbaum CJ; Type 1 Diabetes TrialNet ATG-GCSF Study Group. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves beta-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care. 2018 Sep;41(9):1917-1925. doi: 10.2337/dc18-0494. Epub 2018 Jul 16.
Results Reference
derived
Links:
URL
http://www.diabetestrialnet.org
Description
Type 1 Diabetes TrialNet

Learn more about this trial

ATG-GCSF in New Onset Type 1 Diabetes

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