Diabetes Mellitus, Type 1
Conditions
Keywords
Type 1 Diabetes TrialNet
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.
Interventions
Thymoglobulin
Granulocyte colony stimulating factor (GCSF)
Normal saline administered by IV infusion to mimic ATG
DRUGPlacebo (for GCSF)
Placebo prepared to mimic 6mg subcutaneous injection of GCSF
Sponsors
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
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 45 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months. | -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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Anti-Thymocyte Globulin (ATG): Thymoglobulin
Placebo (for GCSF): Placebo prepared to mimic 6mg subcutaneous injection of GCSF | 29 |
| 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
Anti-Thymocyte Globulin (ATG): Thymoglobulin
Granulocyte colony stimulating factor (GCSF): Granulocyte colony stimulating factor (GCSF) | 29 |
| 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
Placebo (for ATG): Normal saline administered by IV infusion to mimic ATG
Placebo (for GCSF): Placebo prepared to mimic 6mg subcutaneous injection of GCSF | 31 |
| Total | 89 |
Baseline characteristics
| Characteristic | Anti-Thymocyte Globulin (ATG) and Placebo | Total | Placebo | ATG Plus Granulocyte Colony Stimulating Factor (GCSF) |
|---|---|---|---|---|
| Age, Continuous | 17.2 Years STANDARD_DEVIATION 5 | 17.4 Years STANDARD_DEVIATION 5.56 | 16.9 Years STANDARD_DEVIATION 4.6 | 18.1 Years STANDARD_DEVIATION 6.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 85 Participants | 30 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 86 Participants | 29 Participants | 29 Participants |
| Region of Enrollment United States | 29 participants | 89 participants | 31 participants | 29 participants |
| Sex: Female, Male Female | 13 Participants | 39 Participants | 14 Participants | 12 Participants |
| Sex: Female, Male Male | 16 Participants | 50 Participants | 17 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 | 0 / 31 |
| other Total, other adverse events | 28 / 29 | 29 / 29 | 31 / 31 |
| serious Total, serious adverse events | 28 / 29 | 29 / 29 | 8 / 31 |
Outcome results
Primary
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).
Time frame: -10, 0 15, 30, 60, 90, and 120 minutes post-dose at baseline and 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Anti-Thymocyte Globulin (ATG) and Placebo | Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months. | 0.528 nmol/L |
| ATG Plus Granulocyte Colony Stimulating Factor (GCSF) | Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months. | 0.646 nmol/L |
| Placebo | Change in Area Under the Stimulated C-peptide Curve From Baseline to 12 Months. | 0.406 nmol/L |