ATG-GCSF in New Onset Type 1 Diabetes

NCT ID: NCT02215200

Last Updated: 2020-03-02

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

89 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-12-31

Study Completion Date

2018-08-31

Brief Summary

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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

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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.

Conditions

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Diabetes Mellitus, Type 1

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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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

Group Type EXPERIMENTAL

Anti-Thymocyte Globulin (ATG)

Intervention Type DRUG

Thymoglobulin

Placebo (for GCSF)

Intervention Type DRUG

Placebo prepared to mimic 6mg subcutaneous injection of GCSF

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

Group Type EXPERIMENTAL

Anti-Thymocyte Globulin (ATG)

Intervention Type DRUG

Thymoglobulin

Granulocyte colony stimulating factor (GCSF)

Intervention Type DRUG

Granulocyte colony stimulating factor (GCSF)

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

Group Type PLACEBO_COMPARATOR

Placebo (for ATG)

Intervention Type DRUG

Normal saline administered by IV infusion to mimic ATG

Placebo (for GCSF)

Intervention Type DRUG

Placebo prepared to mimic 6mg subcutaneous injection of GCSF

Interventions

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Anti-Thymocyte Globulin (ATG)

Thymoglobulin

Intervention Type DRUG

Granulocyte colony stimulating factor (GCSF)

Granulocyte colony stimulating factor (GCSF)

Intervention Type DRUG

Placebo (for ATG)

Normal saline administered by IV infusion to mimic ATG

Intervention Type DRUG

Placebo (for GCSF)

Placebo prepared to mimic 6mg subcutaneous injection of GCSF

Intervention Type DRUG

Other Intervention Names

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Thymoglobulin Neulasta

Eligibility Criteria

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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
Minimum Eligible Age

12 Years

Maximum Eligible Age

45 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role collaborator

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role collaborator

American Diabetes Association

OTHER

Sponsor Role collaborator

Sanofi

INDUSTRY

Sponsor Role collaborator

The Leona M. and Harry B. Helmsley Charitable Trust

OTHER

Sponsor Role collaborator

Amgen

INDUSTRY

Sponsor Role collaborator

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

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Michael J Haller, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

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University of California - San Francisco

San Francisco, California, United States

Site Status

Stanford University

Stanford, California, United States

Site Status

Barbara Davis Center

Aurora, Colorado, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

University of Florida

Gainesville, Florida, United States

Site Status

University of Miami

Miami, Florida, United States

Site Status

University of South Florida Diabetes Center

Tampa, Florida, United States

Site Status

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, United States

Site Status

University of Minnesota

Minneapolis, Minnesota, United States

Site Status

Columbia University-Naomi Berrie Diabetes Center

New York, New York, United States

Site Status

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Site Status

Vanderbilt Eskind Diabetes Clinic

Nashville, Tennessee, United States

Site Status

Benaroya Research Institute

Seattle, Washington, United States

Site Status

Countries

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United States

References

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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.

Reference Type DERIVED
PMID: 37432736 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30967424 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30012675 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Informed Consent Form

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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http://www.diabetestrialnet.org

Type 1 Diabetes TrialNet

Other Identifiers

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Type 1 Diabetes TrialNet

Identifier Type: OTHER

Identifier Source: secondary_id

TN19

Identifier Type: OTHER

Identifier Source: secondary_id

UC4DK106993

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UC4DK117009

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ATG-GCSF (IND)

Identifier Type: -

Identifier Source: org_study_id

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