MELD-ATG: Phase II, Dose Ranging, Efficacy Study of Anti-thymocyte Globulin (ATG) Within 6 Weeks of Diagnosis of Type 1 Diabetes (T1D)

A phase II, Multi-centre, randomised, double-blind, placebo-controlled, Multi-arm parallel cohort trial.

Randomisation wil be stratified by age. The trial consist of seven cohorts. The first cohort of 30 participants will be randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg.

ATG total dose in a 1:1:1:1 allocation ratio. There will be an initial age step down selection of this cohort with recruitment starting with dose aged 12-25 years and, providing no new safety concerns are raised in the first 10 participants to receive active dose, progressing to all ages (5-25 years) The next two cohorts of 12 participants will be randomised to placebo, 2.5 mg/kg, and 2 specified middle ATG total doses in a 1:1:1:1 allocation ratio.

The next four cohorts of 15 participants will be randomised to placebo, 2.5 mg/kg, and a single selected middle ATG total doses in a 1:1:1 allocation ratio.

This design allows sequential adjustment of the middle doses to be explored following review of all safety and early efficacy data by the Independent Data Monitoring Committee ( IDMC) and Dose Determine Committee (DDC) to seek the minimum effective dose

Inclusion criteria

• has given written informed consent to participate; or have a parent or legal guardian provide written informed consent. Individual under the age of consent will be asked to assent to trial participation
• be aged > 5 years to < 25 years at written informed consent/assent
• have been diagnosed with T1d within 3-9 weeks of planned treatment day 1
• have random C-peptide levels > 200 pmol/L measured at screening, as tested centrally
• have 1 or more diabetes-related autoantibody (GADA, IA-2A or ZnT8A) present at screening, as tested centrally
• will be > 6 weeks form last live immunisation at planned treatment day 1 and be willing to forgo live vaccines during the trial until 6 months post treatment
• be willing to comply with intensive diabetes management

Exclusion criteria

• Type 2 diabetes
• Evidence of prior or current tuberculosis (TB) infection
• Clinically significant abnormal full blood count (FBC), renal function or liver function at screening
• Requiring use of other immunosuppressive or immunomodulation agents, including chronic use of systemic steroids
• 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
• seropositive for human immunodeficiency virus (HIV),hepatitis B of hepatitis C infection at screening
• positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) based on local testing regimen
• 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
• any history of malignancies, other than skin
• current or ongoing use of non-insulin pharmaceuticals that effect glycaemic control
• active participation in another T1D treatment interventional trial in the previous 30 days prior to screening ( excluding treatment with insulin)
• any prior treatment with ATG, Abatacept or Anti-CD3 monoclonal antibody (Anti-CD3)
• known allergy to ATG or to similar products
• 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