This is a 2-arm, multi-center, open label study to learn if ATG works the same or better than teplizumab in delaying or preventing Stage 3 Type 1 diabetes. Participants will be administered either 2 infusions of ATG or 14 infusions of teplizumab and will then be followed for at least 12-48 months after administration, depending on timepoint enrolled into the study. If the primary endpoint demonstrates a positive signal and as decided by TrialNet, there is potential for a study extention. This would extend follow-up visits for a possible study duration of about 9 years among the earliest enrollees of the initial study.

This protocol will enroll 60 participants between the ages of 4 and 34 with Stage 2 Type 1 diabetes. Oral glucose tolerance testing will be done at the screening, baseline visit (V0) and at 3, 6 and 12 months in the first year after study drug administration. Eligible study participants will be randomized to recieve either 2 doses of ATG over 2-3 days or 14 doses of teplizumab given once daily over 14 consecutive days. Safety labs will also be done during select study visits to monitor the participant's health. Once the treatment phase has been completed, participants will have 3 in-person study visits in year one of the study with interim contact to assess adverse events and symptoms of diabetes. After year one of the study, participants will continue in-person follow-up visits every 6 months until the last enrolled participant completes the 12-month visit or develops Stage 3 Type 1 diabetes, whichever occurs first. The total initial study duration is expected to last 3-4 years. There is a possibility the study will be extended after the initial study duration, dependent upon the primary outcome (DPTRS at the month 6 visit) and as determined by TrialNet. If the study extension is done, participants would be presented an additional consent form to opt into additional follow-up visits which would increase total time in study to about 9 years.

Inclusion Criteria:

• Willing to provide informed consent or have a parent or legal guardians provide informed consent when the participant is <18 years of age.

• Aged ≥4 to <35 years

• A history of at least two or more diabetes-related biochemical autoantibodies (mIAA, GADA, ICA, IA-2A, ZnT8A) present on the same sample. In the absence of other antibodies, ICA and GADA positivity alone will not suffice for eligibility in this trial.

• Participants must meet ADA stage 2 T1D glycemic criteria* by TrialNet testing within 100 days of the baseline visit.

  *The ADA definition of stage 2 T1D is characterized by glucose intolerance or dysglycemia in the presence of two or more islet autoantibodies, impaired fasting glucose (≥ 100mg/dL), impaired glucose tolerance (2-hour post 75g glucose load ≥ 140mg/dL), high glucose levels at intermediate time points on OGTT (30, 60, 90 min timepoints of ≥ 200 mg/dL), and/or HbA1c between 5.7% and 6.4% or ≥ 10% increase in HbA1c within a two year window, with the most recent HbA1c value obtained within 100 days of the baseline visit.

• CMV and/or EBV seronegative participants must be CMV and EBV PCR negative within 30 days prior to randomization and may not have had signs or symptoms of a CMV or EBV-compatible illness lasting longer than 7 days within 30 days of the baseline visit.

• CMV seropositive participants must be CMV PCR negative and all EBV seropositive participants must have EBV PCR < 2,000 IU/mL within 30 days prior to randomization and may not have had signs or symptoms of a CMV or EBV-compatible illness lasting longer than 7 days within 30 days prior to the baseline visit.

• Be at least 8 weeks from last live immunization at the time of the baseline visit.

• Be willing to forgo vaccines (other than non-live influenza and COVID-19) during the 3 months after study drug treatment period and forgo live vaccines for 12 months after study drug treatment period.

• Must meet TrialNet eligibility minimum immunization recommendations found in Appendix A of the manual of operations (MOO).

• With the exception of stage 2 T1D, participants must be healthy, as defined by absence of any other untreated diagnoses that the investigator deems to be a potential confounder.

• If a female participant with reproductive potential, willing to avoid pregnancy (abstinence or adequate contraceptive method) through the completion of the study infusions and up to 3 months after study drug administration and undergo pregnancy testing prior to each study visit.

• Must be residing or have accommodations within 1 hour of the infusion site during study drug infusions and must be within 1 hour of a medical care facility for 1 day after completion of infusions.

• Participants must live in a location with rapid access to emergency medical services.

Exclusion Criteria:

• Immunodeficiency or clinically significant chronic lymphopenia: (Leukopenia (<3,000 leukocytes/μL), neutropenia (<1,500 neutrophils/μL), lymphopenia (<800 lymphocytes/μL), thrombocytopenia (<100,000 platelets/μL).

• Hemoglobin less than 13 g/dL for adult men and less than 11.5g/dL for adult females and less than 11 g/dL for participants under age 18.

• Active signs or symptoms of acute or chronic infection at the time of the baseline visit including SARS-Cov-2.

• Uncontrolled autoimmune thyroid disease and/or celiac disease (participants must be well controlled for the previous 6 months).

• Evidence of prior or current tuberculosis infection through any one or more of the following:

  1. A history of latent or active TB
  2. Signs and/or symptoms of TB
  3. Recent close contact with a person with known or suspected active TB unless appropriate prophylaxis for TB was given
  4. A history of a chest X-ray consistent with active TB or old, inactive TB, or interferon gamma release assay IGRA (QuantiFERON) test
  5. A history of a positive purified protein derivative (PPD) skin test result (>10 mm induration), or positive/repeatedly indeterminate on an interferon-gamma release assay (IGRA; e.g., QuantiFERON-TB test).

• Currently pregnant or lactating or anticipate getting pregnant within the study period.

• Require use of other immunosuppressive agents including chronic use of oral or intravenous injectable steroids.

• Evidence of current or past HIV or Hepatitis B or current Hepatitis C infection.

• 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, COPD, sickle cell disease, neurological disease, or blood count abnormalities.

• A history of malignancies other than of skin.

• Evidence of liver dysfunction with AST or ALT ≥ 2 times the upper limit of the reference range.

• Evidence of renal dysfunction with creatinine ≥ 1.5 times the upper limit of the reference range.

• Increased bilirubin ≥ 2 times (total) or ≥ 1.5 times (direct) the normal limit (Participants with documentation of Gilbert's Disease permitted).

• Vaccination with a live vaccine within the last 8 weeks or killed/inactivated vaccine within the last 2 weeks of the baseline visit.

• Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 14 days of screening.

• Prior treatment with Teplizumab or ATG (either in a previous clinical trial or clinically).

• Has previously participated in a clinical trial for diabetes prevention and received active study agent within 6 months of treatment.

• Known allergy to rabbits or rabbit derived products.

• Prior adverse reactions to heparin.

• Any condition that in the investigator's opinion may adversely affect study participation.

• Any screening/baseline laboratory result not otherwise stated out of normal reference range and/or medical history that may increase the risk of the participant's participation in this trial.

• Previously diagnosed with Stage 3 TID according to ADA criteria.

Data will be available at the NIDDK Central Repository

Final datasets will be available at the NIDDK Central Repository 12 months from the last participant's follow-up visit

IPD can be requested through the NIDDK Central Repository once submitted.