ATG-GCSF in New Onset Type 1 Diabetes

NCT02215200 | Completed Phase 2 Results DMC FDA Drug

• 5 other identifiers: ATG-GCSF (IND)Type 1 Diabetes TrialNetTN19UC4DK106993UC4DK117009
• Study Type: interventional
• Target: 89
• Locations: 1 country
• Sites: 13

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.

Conditions

Diabetes Mellitus, Type 1

Keywords

Type 1 Diabetes TrialNet

Outcome Measures

Primary Outcomes (1)

• 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").

  -10, 0 15, 30, 60, 90, and 120 minutes post-dose at baseline and 12 months

Study Arms (3)

Anti-Thymocyte Globulin (ATG) and Placebo

EXPERIMENTAL

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); Drug: Placebo (for GCSF)

ATG plus Granulocyte colony stimulating factor (GCSF)

EXPERIMENTAL

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); Drug: Granulocyte colony stimulating factor (GCSF)

Placebo

PLACEBO COMPARATOR

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); Drug: Placebo (for GCSF)

Interventions

Anti-Thymocyte Globulin (ATG) DRUG

Thymoglobulin

Also known as: Thymoglobulin

ATG plus Granulocyte colony stimulating factor (GCSF); Anti-Thymocyte Globulin (ATG) and Placebo

Granulocyte colony stimulating factor (GCSF) DRUG

Granulocyte colony stimulating factor (GCSF)

Also known as: Neulasta

ATG plus Granulocyte colony stimulating factor (GCSF)

Placebo (for ATG) DRUG

Normal saline administered by IV infusion to mimic ATG

Placebo

Placebo (for GCSF) DRUG

Placebo prepared to mimic 6mg subcutaneous injection of GCSF

Anti-Thymocyte Globulin (ATG) and Placebo; Placebo

Eligibility Criteria

• Age: 12 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Center for Research Resources (NCRR): collaborator
• Juvenile Diabetes Research Foundation: collaborator
• American Diabetes Association: collaborator
• Sanofi: collaborator
• The Leona M. and Harry B. Helmsley Charitable Trust: collaborator
• Amgen: collaborator

Study Sites (13)

University of California - San Francisco

San Francisco, California, 94158-2549, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Barbara Davis Center

Aurora, Colorado, 80045, United States

Location

Yale University

New Haven, Connecticut, 06519, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

University of South Florida Diabetes Center

Tampa, Florida, 33612, United States

Location

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Columbia University-Naomi Berrie Diabetes Center

New York, New York, 10032, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Vanderbilt Eskind Diabetes Clinic

Nashville, Tennessee, 37232, United States

Location

Benaroya Research Institute

Seattle, Washington, 98101, United States

Location

Related Publications (3)

• Jacobsen LM, Diggins K, Blanchfield L, McNichols J, Perry DJ, Brant J, Dong X, Bacher R, Gersuk VH, Schatz DA, Atkinson MA, Mathews CE, Haller MJ, Long SA, Linsley PS, Brusko TM. Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes. JCI Insight. 2023 Aug 22;8(16):e161812. doi: 10.1172/jci.insight.161812.

  PMID: 37432736 DERIVED

• 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.

  PMID: 30967424 DERIVED

• 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.

  PMID: 30012675 DERIVED

Related Links

• Type 1 Diabetes TrialNet

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Antilymphocyte Serum; thymoglobulin; Granulocyte Colony-Stimulating Factor; pegfilgrastim

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors

Results Point of Contact

• Title: Carla Greenbaum, MD
• Organization: Benaroya Research Institute

cjgreen@benaroyaresearch.org

1-800-425-8361

Study Officials

• Michael J Haller, M.D.

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2014
• First Posted: August 13, 2014
• Study Start: December 1, 2014
• Primary Completion: August 1, 2017
• Study Completion: August 1, 2018
• Last Updated: March 2, 2020
• Results First Posted: March 2, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR, ANALYTIC CODE

Locations

US (13)