Platform Trial to Delay Stage 3 Diabetes: Comparing Teplizumab With ATG (TN40A)

National Institutes of Health (NIH)

Status and phase: Not yet enrolling; Phase 2

Conditions: Type 1 Diabetes Mellitus

Treatments: Drug: Teplizumab; Drug: Antithymocyte Globulin (ATG)

Study type: Interventional

Funder types: NIH

Identifiers

NCT07216391

TN40A

Details and patient eligibility

About

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 be followed for 12 months after administration.

Full description

This protocol will enroll 60 participants with Stage 2 diabetes. Oral glucose tolerance testing will be done at the screening, baseline visit (V0) and at 3, 6 and 12 months after study drug administration. Participants will continue follow-up visits until 12 months from the baseline visit.

Enrollment: 60 estimated patients

Sex: All

Ages: 4 to 34 years old

Volunteers: No Healthy Volunteers

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 randomization.

  *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 randomization.

• CMV and/or EBV seronegative participants 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.

• CMV seropositive participants must be CMV PCR negative and all EBV seropositive participants must have EBV PCR < 2,000 IU/mL 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.

• Be at least 4 weeks from last live immunization.

• Be willing to forgo vaccines (other than non-live influenza and COVID-19) during the 3 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.

  • 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 randomization.

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).
• Active signs or symptoms of acute or chronic infection at the time of randomization including SARS-Cov-2.
• Uncontrolled autoimmune thyroid disease and/or celiac disease (participants must be well controlled for the previous 6 months).
• Evidence of a history of prior or current tuberculosis infection as assessed interferon gamma release assay (QuantiFERON) with the exception of post-exposure prophylaxis.
• 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 4 weeks or killed/inactivated vaccine within the last 2 weeks.
• 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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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60 participants in 2 patient groups

ATG

Experimental group

Description:

Antithymocyte globulin (ATG) will be intravenously administered over two days, with a total of 2 infusion periods. The first dose (0.5mg/kg) will be infused over a minimum of 6 hours, and the second dose (2mg/kg) over a minimum of 4 hours with a maximum infusion time for each infusion of 10 hours. Infusions may be administered either in a hospital or outpatient setting at the investigator's or institutions discretion.

Treatment:

Drug: Antithymocyte Globulin (ATG)

Teplizumab

Active Comparator group

Description:

Intravenous infusions of teplizumab will be given for 14 consecutive days. Each infusion takes about 30 minutes. Vital signs will be monitoring for at least 30 minutes after each infusion. If reactions to the infusion occur participants may be monitored for at least 2 hours after the study drug infusion. The total dose for the 14-day course is approximately 11,240 µg/m².

Treatment:

Drug: Teplizumab