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

• ClinicalTrials.gov Identifier: NCT02215200
• Recruitment Status: Completed
• First Posted: August 13, 2014
• Results First Posted: March 2, 2020
• Last Update Posted: March 2, 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
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: Anti-Thymocyte Globulin (ATG); Drug: Granulocyte colony stimulating factor (GCSF); Drug: Placebo (for ATG); Drug: Placebo (for GCSF)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Antithymocyte Globulin (ATG) and Pegylated Granulocyte Colony Stimulating Factor (GCSF) in New Onset Type 1 Diabetes
• Study Start Date: December 2014
• Actual Primary Completion Date: August 2017
• Actual Study Completion Date: August 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Anti-Thymocyte Globulin (ATG) and Placebo; 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	Drug: Anti-Thymocyte Globulin (ATG); Thymoglobulin; Other Name: Thymoglobulin; Drug: Placebo (for GCSF); Placebo prepared to mimic 6mg subcutaneous injection of GCSF
Experimental: ATG plus Granulocyte colony stimulating factor (GCSF); 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	Drug: Anti-Thymocyte Globulin (ATG); Thymoglobulin; Other Name: Thymoglobulin; Drug: Granulocyte colony stimulating factor (GCSF); Granulocyte colony stimulating factor (GCSF); Other Name: Neulasta
Placebo Comparator: Placebo; 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	Drug: Placebo (for ATG); Normal saline administered by IV infusion to mimic ATG; Drug: Placebo (for GCSF); Placebo prepared to mimic 6mg subcutaneous injection of GCSF

Outcome Measures

Primary Outcome Measures :

1. Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months. [ Time Frame: -10, 0 15, 30, 60, 90, and 120 minutes post-dose at baseline and 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").

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 45 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

University of California - San Francisco

San Francisco, California, United States, 94158-2549

Stanford University

Stanford, California, United States, 94305

United States, Colorado

Barbara Davis Center

Aurora, Colorado, United States, 80045

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06519

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

University of Miami

Miami, Florida, United States, 33136

University of South Florida Diabetes Center

Tampa, Florida, United States, 33612

United States, Indiana

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, United States, 46202

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, New York

Columbia University-Naomi Berrie Diabetes Center

New York, New York, United States, 10032

United States, Pennsylvania

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Vanderbilt Eskind Diabetes Clinic

Nashville, Tennessee, United States, 37232

United States, Washington

Benaroya Research Institute

Seattle, Washington, United States, 98101

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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

Investigators

• Principal Investigator: Michael J Haller, M.D.; University of Florida

  Study Documents (Full-Text)

Documents provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Study Protocol  [PDF] March 30, 2016

Informed Consent Form  [PDF] March 30, 2016

Statistical Analysis Plan  [PDF] August 30, 2017

More Information

Additional Information:

Type 1 Diabetes TrialNet 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT02215200
• Other Study ID Numbers: ATG-GCSF (IND); Type 1 Diabetes TrialNet ( Other Identifier: Type 1 Diabetes TrialNet ); TN19 ( Other Identifier: Type 1 Diabetes TrialNet ); UC4DK106993 ( U.S. NIH Grant/Contract ); UC4DK117009 ( U.S. NIH Grant/Contract )
• First Posted: August 13, 2014
• Results First Posted: March 2, 2020
• Last Update Posted: March 2, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data are available at the NIDDK Central Repository
• Supporting Materials: Study Protocol; Clinical Study Report (CSR); Analytic Code
• URL: https://repository.niddk.nih.gov/studies/TN19_ATG_GCSF/?query=tn19

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Type 1 Diabetes TrialNet

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Lenograstim; Thymoglobulin; Antilymphocyte Serum; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Immunosuppressive Agents