E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067584 |
E.1.2 | Term | Type 1 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To determine the changes in stimulated C-peptide response over the first two hours of a mixed meal tolerance test (MMTT) at 12 months for 2.5mg/kg ATG arm versus the placebo.
• Conditional on finding a statistical difference between the 2.5mg/kg ATG arm and placebo, to identify the minimally effective dose (lowest dose significantly different to placebo) amongst the doses studied in the trial using change in stimulated C-peptide response over the first two hours of a MMTT at 12 months versus placebo.
|
|
E.2.2 | Secondary objectives of the trial |
• To determine the effects of ATG treatment on: - MMTT-stimulated C-peptide (at baseline, 3, 6 and 12 months) - HbA1c (at baseline, 3, 6, 12 months) - Fasting/stimulated dried blood spot (DBS) C-peptide measurements (monthly) - CGM measures over 14 days at 3, 6 and 12 months
• To determine whether ATG treatment mediates a reduction in CD4 positive T-cells but relative preservation of CD8 positive T-cells
• Descriptive analysis of the safety profile of different doses of ATG in different age groups
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has given written informed consent to participate; or have a parent or legal guardian provide written informed consent. Individuals under the age of consent will be asked to assent to trial participation.
2. Be aged ≥5 years to ≤25 years at written informed consent/assent
3. Have been diagnosed with T1D within 3–9 weeks of planned treatment day 1
4. Have random C-peptide levels ≥200 pmol/L measured at screening, as tested centrally
5. Have 1 or more diabetes-related autoantibody (GADA, IA-2A or ZnT8A) present at screening, as tested centrally
6. Will be ≥6 weeks from last live immunisation at planned treatment day 1 and be willing to forgo live vaccines during the trial until 6 months post treatment
7. Be willing to comply with intensive diabetes management |
|
E.4 | Principal exclusion criteria |
1. Type 2 diabetes
2. Evidence of prior or current tuberculosis (TB) infection
3. Clinically significant abnormal full blood count (FBC), renal function or liver function at screening, including: - Immunodeficient or clinically significant chronic leucopenia, neutropenia, lymphopenia or thrombocytopenia at the screening visit, according to local reference ranges - Evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limit of normal (ULN), at screening - Evidence of renal dysfunction with creatinine greater than 1.5 times the ULN at screening
4. Requiring use of other immunosuppressive or immunomodulation agents, including chronic use of systemic steroids
5. Any active chronic infections at screening, or any active acute or chronic infections at baseline or on treatment day, which would contraindicate any additional immunosuppression
6. Seropositive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection at screening
7. Positive for SARS-CoV-2 based on local testing regimen
8. Unwilling to use appropriate contraception if sexually active during the trial, from date of written informed consent until completion of the 12-month follow up visit
9. Any history of malignancies, other than skin
10. Current or ongoing use of non-insulin pharmaceuticals that affect glycaemic control
11. Active participation in another T1D treatment interventional trial in the previous 30 days prior to screening (excluding treatment with insulin)
12. Any prior treatment with ATG, Abatacept or anti-CD3
13. Known allergy to ATG or to similar products
14. Any condition, complicating medical issues, or abnormal clinical laboratory results that the investigator judges may adversely affect trial conduct, cause increased risk to the participant, or compromise the trial results |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The area under the stimulated C-peptide response curve. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Measured over the first 2 hours of a MMTT at 12 months after treatment follow up |
|
E.5.2 | Secondary end point(s) |
1. The area under the stimulated C-peptide response curve over the first 2 hours of a mixed meal tolerance test (MMTT) 2. Dried blood spot (DBS) C-peptide measurements 3. CD4-positive T cells and CD8-positive T cells 4. HbA1c 5. Insulin requirements 6. T1D-associated autoantibodies (GADA, IAA, IA-2A and ZnT8A) 7. CGM measures (time in range, time above, time below) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At baseline, 3, 6 and 12 months 2. At all observation times 3/4/5/6/7. Over 12 months |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Adaptive design, in which treatment doses will be decided by interim analyses |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The trial ends when the last patient has completed the trial.
Translational endpoints will be investigated, and the data cleaned for the primary analysis and reported within 6 months from end of trial.
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |