Diabetes Mellitus, Type 1
Conditions
Keywords
Autoimmune, Diabetes Mellitus, Glucose Metabolism
Brief summary
The primary purpose of this study is to determine if giving the combination therapy consisting of Thymoglobulin® (ATG) and Neulasta® (GCSF) to patients with established Type 1 Diabetes (T1D) is safe and secondarily, if the ATG and GCSF will preserve insulin production.
Detailed description
This is a randomized, placebo controlled, phase I/II trial. Potential subjects will be screened via a 4 hour mixed meal tolerance test to assess residual beta cell (C-peptide) function. If the C-peptide level at any time is ≥ 0.1 pmol/ml, and the subject meets the additional inclusion and exclusion criteria, they will be eligible for randomization and enrollment. The study will be randomized 2:1 such that 17 subjects will receive active therapy and 8 will receive placebo. Subjects must receive Thymoglobulin®/ Neulasta® or placebo within 8 weeks of randomization. Thymoglobulin® (2.5mg/kg)/placebo will be given as 0.5 mg/kg IV on day 1 and 2 mg/kg on day 2. Six doses of Neulasta® (6mg/dose)/placebo will be given as standard of care every 2 weeks, with the first dose given prior to discharge after the Thymoglobulin® infusion. Complete metabolic panel (CMP) and complete blood count (CBC) will be done at the screening visit, just prior to study drug initiation, daily during the Thymoglobulin® infusion admission, and at follow up visits. Following discharge, daily phone calls will be made to the subjects during the first 5 days of therapy and weekly thereafter. In addition, weekly phone calls for the month following completion of therapy will be used to document adverse reactions. Thereafter calls will be made every two weeks.
Interventions
DRUGAnti-Thymocyte Globin (ATG)
Anti-Thymocyte Globin (ATG) will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2.
DRUGPlacebo
Saline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes
DRUGPegylated GCSF
6 doses of pegylated GCSF (6mg/dose) will be given subcutaneously every 2 weeks beginning after the ATG infusion.
Sponsors
The Leona M. and Harry B. Helmsley Charitable Trust
Genzyme, a Sanofi Company
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
12 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Must be \> 12 years \< 45 * Must have a diagnosis of T1D of greater than 4 months duration, with an upper limit of 2 years, Now only recruiting for those diagnosed greater than 1 year but less than 2 years. * Must have at least one diabetes-related autoantibody present (e.g., islet cell autoantigen (ICA), GAD, ZnT8, or islet antigen 2 (IA2) autoantibodies) * Must have stimulated C-peptide levels ≥ 0.1 pmol/ml (0.3ng/mL) when measured during a mixed meal tolerance test (MMTT), conducted at least 4 months from diagnosis of diabetes, and within 8 weeks of randomization * Must be EBV PCR negative within two weeks of randomization if EBV seronegative at screening * Be at least 6 weeks from last live immunization * Be willing to forgo live vaccines for 3 months following last dose of study drug * Be willing to comply with intensive diabetes management * Normal screening values for complete blood count (CBC), renal function and electrolytes (CMP).
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 (\<125,000 platelets/μL). * Have a chronic infection at time of randomization * Have a positive PPD * Be currently pregnant or lactating, or anticipate getting pregnant within the next two years * Require use of other immunosuppressive agents * Have serologic evidence of current or past HIV, Tuberculosis, Hepatitis B or Hepatitis C infection * Have any complicating medical issues or abnormal clinical laboratory results that 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 (e.g., lymphopenia, leukopenia, or thrombocytopenia) * Have a history of malignancies * Evidence of liver dysfunction with angiotensin sensitivity test (AST) or 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 use of non-insulin pharmaceuticals that affect glycemic control * Active participation in another T1D treatment study in the previous 30 days * Known allergy to G-CSF 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 Metabolic Function Baseline to 12 Months. | Baseline and 12 months | Area Under Curve (AUC) C-peptide production. Subjects underwent a 2 hour mixed meal tolerance test (MMTT) using a 6ml/kg load of boost to stimulate insulin production. Samples were collected at baseline, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. AUC was then calculated. Subjects repeated the MMTT at baseline, 3, 6, 9, and 12 months following ATG/GCSF or placebo. The primary outcome for the study was the change over 12 months in AUC C-peptide (1 year - baseline) for those who received ATG/GCSF versus the change in AUC C-peptide (1 year - baseline) for those who received placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| A1c | Change in baseline to 12 months | Change in A1c baseline to 12 months |
| Change in Insulin Requirements, Baseline to 12 Months | Change from baseline to 12 months | Change in Insulin Requirements, baseline to 12 months |
| Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months | Change from baseline to 12 months | Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months |
| Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months | Change from baseline to 12 months | Change in Insulin Autoantibodies (IAA) over 12 months |
| Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months | Change in Baseline to 12 months | Change in regulatory T cells (Treg) baseline to 12 months |
| Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months | Change from baseline to 12 months | Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months |
| Percentage of Neutrophils | Change from baseline to 12 months | Change in Neutrophil Count over 12 months |
| Change in White Blood Count (WBC) From Baseline to 12 Months | Change from baseline to 12 months | Change in WBC over 12 months |
| Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months | Change from baseline to 12 months | Change in Insulinoma Associated 2 Autoantibodies (IA-2A) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF Subjects will receive an infusion of Anti-Thymocyte Globin (ATG) followed by 6 doses of pegylated GCSF every 2 weeks for 10 weeks.
Anti-Thymocyte Globin plus pegylated GCSF: Anti-Thymocyte Globin (ATG)will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2, plus 6 doses of pegylated GCSF (6mg/dose)given subcutaneously every 2 weeks beginning after the ATG infusion | 17 |
| Placebo Saline infusion will be given on both Day 1 and Day 2 followed by placebo injection given in identical volumes in identical syringes in the identical subcutaneous manner
Placebo: Saline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes | 8 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Anti-Thymocyte Globin Plus Pegylated GCSF | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 3 Participants | 15 Participants |
| Age, Continuous | 23.64 years STANDARD_DEVIATION 10 | 23.55 years STANDARD_DEVIATION 10.6 | 23.61 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 17 participants | 8 participants | 25 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 12 Participants | 5 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 8 |
| other Total, other adverse events | 15 / 16 | 5 / 8 |
| serious Total, serious adverse events | 15 / 16 | 3 / 8 |
Outcome results
Primary
Change in Metabolic Function Baseline to 12 Months.
Area Under Curve (AUC) C-peptide production. Subjects underwent a 2 hour mixed meal tolerance test (MMTT) using a 6ml/kg load of boost to stimulate insulin production. Samples were collected at baseline, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. AUC was then calculated. Subjects repeated the MMTT at baseline, 3, 6, 9, and 12 months following ATG/GCSF or placebo. The primary outcome for the study was the change over 12 months in AUC C-peptide (1 year - baseline) for those who received ATG/GCSF versus the change in AUC C-peptide (1 year - baseline) for those who received placebo
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in Metabolic Function Baseline to 12 Months. | 0.74 nmol/L/min | Standard Deviation 0.47 |
| Placebo | Change in Metabolic Function Baseline to 12 Months. | 0.43 nmol/L/min | Standard Deviation 0.32 |
p-value: 0.01795% CI: [0.001, 0.552]t-test, 2 sided
Secondary
A1c
Change in A1c baseline to 12 months
Time frame: Change in baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | A1c | 0.47 % change | Standard Deviation 1.88 |
| Placebo | A1c | 0.98 % change | Standard Deviation 0.79 |
p-value: 0.3795% CI: [-1.64, 0.63]t-test, 2 sided
Secondary
Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months
Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months
Time frame: Change from baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months | -17.75 nmol/L | Standard Deviation 225.81 |
| Placebo | Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months | -29.5 nmol/L | Standard Deviation 38.96 |
p-value: 0.8995% CI: [-156.8, 180.3]t-test, 2 sided
Secondary
Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months
Change in Insulin Autoantibodies (IAA) over 12 months
Time frame: Change from baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months | 0.12 Units/mL | Standard Deviation 0.5 |
| Placebo | Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months | -0.15 Units/mL | Standard Deviation 0.43 |
p-value: 0.295% CI: [-0.15, 0.7]t-test, 2 sided
Secondary
Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months
Change in Insulinoma Associated 2 Autoantibodies (IA-2A)
Time frame: Change from baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months | -21.63 nmol/L | Standard Deviation 50.3 |
| Placebo | Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months | 2.5 nmol/L | Standard Deviation 31.47 |
p-value: 0.2395% CI: [-64.8, 16.7]t-test, 2 sided
Secondary
Change in Insulin Requirements, Baseline to 12 Months
Change in Insulin Requirements, baseline to 12 months
Time frame: Change from baseline to 12 months
Population: Insulin use data was not provided by all subjects resulting in sampling for analysis that was smaller than the cohort for the entire study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in Insulin Requirements, Baseline to 12 Months | -0.03 units/kg/day | Standard Deviation 0.4 |
| Placebo | Change in Insulin Requirements, Baseline to 12 Months | 0.08 units/kg/day | Standard Deviation 0.19 |
p-value: 0.6995% CI: [-0.4, 0.27]t-test, 2 sided
Secondary
Change in White Blood Count (WBC) From Baseline to 12 Months
Change in WBC over 12 months
Time frame: Change from baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in White Blood Count (WBC) From Baseline to 12 Months | -0.51 Change in percentage of WBC | Standard Deviation 0.81 |
| Placebo | Change in White Blood Count (WBC) From Baseline to 12 Months | 0.4 Change in percentage of WBC | Standard Deviation 1.25 |
Secondary
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months
Time frame: Change from baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months | -0.07 nmol/L | Standard Deviation 0.17 |
| Placebo | Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months | -0.10 nmol/L | Standard Deviation 0.32 |
p-value: 0.7995% CI: [-0.18, 0.23]t-test, 2 sided
Secondary
Percentage of Neutrophils
Change in Neutrophil Count over 12 months
Time frame: Change from baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Percentage of Neutrophils | 0.21 Percentage of neutrophils | Standard Deviation 0.69 |
| Placebo | Percentage of Neutrophils | 0.44 Percentage of neutrophils | Standard Deviation 1.19 |
p-value: 0.16395% CI: [-18.7, 3.35]t-test, 2 sided
Secondary
Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months
Change in regulatory T cells (Treg) baseline to 12 months
Time frame: Change in Baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anti-Thymocyte Globin Plus Pegylated GCSF | Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months | -0.46 percentage change | Standard Deviation 0.36 |
| Placebo | Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months | 0 percentage change | Standard Deviation 0.036 |
p-value: 0.4395% CI: [-0.3, 0.13]t-test, 2 sided