Objectives | Outcome measures | Time point(s) of evaluation of this outcome measure |
Primary objectives | ||
1. To determine the changes in stimulated C-peptide response over the first 2 hours of an MMTT for 2.5 mg/kg ATG arm vs the placebo. | 1. The area under the stimulated C-peptide response curve over the first 2 hours of an MMTT for the 2.5 mg/kg ATG and placebo arms | 1. 12 months |
2. Conditional on finding a statistical difference between the 2.5 mg/kg ATG arm and placebo, to identify the minimally effective dose significantly different to placebo among the doses studied in the trial using change in stimulated C-peptide response over the first 2 hours of an MMTT vs placebo | 2. The area under the stimulated C-peptide response curve over the first 2 hours of an MMTT for the 0.1 mg/kg ATG, 0.5 mg/kg ATG, 1.5 mg/kg ATG, 2.5 mg/kg ATG and placebo arms | 2. 12 months |
Secondary objectives | ||
1. To determine the effects of ATG treatment on stimulated C-peptide | 1. The area under the stimulated C-peptide response curve over the first 2 hours of an MMTT measured throughout the study in different ATG dosage groups | 1. Baseline, 3, 6, 12 months |
2. To determine the effects of ATG treatment on HbA1c | 2. HbA1c measurements measured throughout the study in different ATG dosage groups in mmol/mol | 2. Baseline, 3, 6, 12 months |
3. To determine the effects of ATG treatment on intermittent CGM measures | 3. CGM measures (time in range, time above, time below) measured throughout the study in all different ATG dosage groups and placebo | 3. For 14 days at 3, 6, 12 months |
4. To determine the effects of ATG treatment on fasting and stimulated DBS C-peptide measurements | 4. DBS C-peptide measurements measured throughout the study in all different ATG dosage groups and placebo in pmol/L at 0 min and 60 min | 4. Baseline, monthly |
5. To determine whether ATG treatment mediates a reduction in CD4-positive T cells but relative preservation of CD8-positive T cells | 5. CD4-positive T cells and CD8-positive T cells measured throughout the study in different dosage groups | 5. Baseline, 1, 2, 4 weeks and 3, 6, 12 months |
6. Descriptive analysis of the safety profile of different doses of ATG in different age groups | 6. Safety will be assessed at each visit by physical examination, including assessment of the most commonly reported reactions to ATG, namely serum sickness, CD4 + lymphocyte decrease, cytokine release syndrome, fever, influenza-like symptoms and rash; vital signs (temperature, blood pressure, heart rate); weight, abnormal laboratory parameters (liver, kidney function, full blood count); reporting of adverse events in different dosage groups | 6. Baseline, treatment day 1 and 2, 1, 2, 4 weeks and 3, 6, 12 months |
7. To determine the effects of ATG treatment on T1D-associated autoantibodies (GADA, IAA, IA-2A and ZnT8A) | 7. T1D-associated autoantibodies (GADA, IAA, IA-2A and ZnT8A) at the start and end of the study | 7. Screening, 12 months |
8. To determine the effects of ATG treatment on insulin requirements | 8. Insulin requirements measured throughout the study in all different ATG dosage groups | 8. Baseline, 1, 2, 4 weeks and 3, 6, 12 months |
Exploratory objectives | ||
1 and 2 To study the effects of treatment on other biomarkers related to immunological changes and β-cell death or survival in this population | 1. The effects of ATG treatment on other biomarkers related to immunological changes and β-cell death or survival in this population | 1. Baseline, 1, 2, 4 weeks and 3, 6, 12 months |
2. Multidimensional analyses of changes in T1D phenotypes by immunological, transcript and mi/small RNA profiling, proteomic, metabolomic and lipidomic studies and the relation of these to clinical outcomes and progression, with the intention of facilitating biomarker discovery, surrogate marker development and potentially participant stratification in future trials | 2. Baseline, 1, 2, 4 weeks and 3, 6, 12 months |
ATG, antithymocyte globulin; CGM, continuous glucose monitoring; DBS, dried blood spot; GADA, Glutamic acid decarboxylase antibodies; HbA1c, glycated haemoglobin; IAA, Insulin auto-antibodies; MMTT, Mixed-Meal Tolerance Test; T1D, type 1 diabetes.