STOP-T1D Low-Dose (ATG)

Open to people ages 12-34

1. Willing to provide informed consent or have a parent or legal guardian provide informed consent when the subject is <18 years of age.
2. Age greater than or equal to 12 and < 35 years
3. 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.
4. Weight greater than the 5th percentile for age and sex.
5. BMI < 95th and > 5th percentile for age for those under age 18 years and < 30 and > 15 for adults (≥ 18)
6. ADA Stage 2 criteria* AND at least one of the following high-risk markers (occurring at the same visit) within 7 weeks (52 days) of randomization, defined below (for defining a 2-year 50% risk for progression to Stage 3 T1D):
   1. HbA1c ≥ 5.7 and <6.5% b. Index60 ≥ 1.4 i. Index60 = 0.3695 × (log fasting C-peptide [ng/mL]) + 0.0165 × 60-min glucose (mg/dL) - 0.3644 × 60-min C-peptide (ng/mL) c. DPTRS ≥ 7.4 DPTRS = (1.57 x log BMI) - (0.06 x age) + (0.81 x glucose sum from 30 to 120 min/100) - (0.85 x C-peptide sum from 30 to 120 min/10) + (0.48 x log fasting C-peptide)

   *Dysglycemia is defined as 2-hr glucose ≥ 140 and <200 mg/dL or fasting glucose ≥ 110 and <126

7. All subjects must be CMV and EBV PCR negative within 30 days of 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 randomization
8. Seated blood pressure less than 130/80 mmHg for participants ≥ 18 years. For participants < 18 years seated blood pressure less than 95th percentile for age, sex and height.

9. Be at least 4 weeks from last live immunization

   10. Participants are required to receive non-live influenza vaccination at least 2 weeks

   prior to randomization when vaccine for the current or upcoming flu season is available.

   11. Participants are required to receive an authorized non-live COVID-19 vaccination and

   be fully vaccinated, including eligible boosters at least two weeks prior to randomization. Participants must also have a negative COVID-19 PCR test within 3 days of the first day of treatment.

   12. Willingness to comply with study directed social distancing and protection from

   SARS-Cov-2 infection.

   13. Be willing to forgo vaccines (other than killed influenza) during the 3 months after

   study drug treatment period (Days 0 and 1)

   14. Be up to date on all recommended vaccinations based on age of subject* 15. With the exception of stage 2 T1D, subjects must be healthy, as defined by absence of

   any other untreated diagnoses that the protocol committee deems to be a potential confounder.

   16. 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.

   17. Must be residing or have accommodations within 1 hour of the infusion site during the

   two days of study drug infusions and must be within 1 hour of a medical care facility for 1 day after completion of infusion 2.

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

   • Adult subjects must be fully immunized. Pediatric subjects who have not completed their primary vaccination schedule must receive all vaccinations allowable per the AAP immunization guidelines for their current age prior to study drug delivery. Any remaining vaccinations should be given and continue per the schedule at least 3 months after study drug is administered.

1. 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).
2. Hemoglobin less than 13.5 g/dL for adult men and less than 12 g/dL for adult females and less than 11 g/dL for participants under age 18
3. Active signs or symptoms of acute infection at the time of randomization including SARS-Cov-2.
4. Uncontrolled autoimmune thyroid disease and/or celiac disease (participants must be well controlled for the previous 6 months).
5. Evidence of prior or current tuberculosis infection as assessed interferon gamma release assay (QuantiFERON).
6. Currently pregnant or lactating or anticipate getting pregnant within the study period.
7. Require use of other immunosuppressive agents including chronic use of systemic steroids.
8. Evidence of current or past HIV or Hepatitis B or current Hepatitis C infection.

9. 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.

   10. A history of malignancies other than of skin. 11. Evidence of liver dysfunction with AST or ALT outside of the reference range. 12. Evidence of renal dysfunction with creatinine outside of the reference range. 13. Increased bilirubin (total and direct) outside of the normal limit (Participants with

   documentation of Gilbert's Disease permitted).

   14. Vaccination with a live virus within the last 4 weeks. 15. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control

   within 7 days of screening

   16. Prior treatment with Teplizumab (either in a previous clinical trial or clinically). 17. Has participated in a clinical trial for diabetes prevention previously and received

   active study agent within 3 months of randomization.

   18. Known allergy to ATG 19. Prior treatment with ATG or known allergy to rabbit-derived products 20. Prior adverse reactions to heparin. 21. Any condition that in the investigator's opinion may adversely affect study

   participation will be reviewed by the Study Chair to ensure consistency and adjudicate whether or not the subject may compromise the study results

   22. Any screening/baseline laboratory result not otherwise stated out of normal reference

   range and/or medical history that may increase the risk of the subject's participation in this trial.

   23. Previously diagnosed with Stage 3 TID according to ADA criteria76 (see Appendix 3 for

   Criteria for diagnosis of diabetes)