Clinical trial NCT02215200: ATG-GCSF in New Onset Type 1 Diabetes
Official title: Antithymocyte Globulin (ATG) and Pegylated Granulocyte Colony Stimulating Factor (GCSF) in New Onset Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: Type 1 Diabetes TrialNet
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Center for Research Resources (NCRR)
name: Juvenile Diabetes Research Foundation
name: American Diabetes Association
name: Sanofi
name: The Leona M. and Harry B. Helmsley Charitable Trust
name: Amgen
First posted: 2014-08-13
Enrollment: 89
Sex: ALL
Minimum age (years): 12
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months.
timeFrame: -10, 0 15, 30, 60, 90, and 120 minutes post-dose at baseline and 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Barbara Davis Center
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida Diabetes Center
state: Florida
city: Indianapolis
country: United States
facility: Indiana University-Riley Hospital for Children
state: Indiana
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University-Naomi Berrie Diabetes Center
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Eskind Diabetes Clinic
state: Tennessee
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
Study officials:
affiliation: University of Florida
name: Michael J Haller, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.