Platform Trial in Stage 1 Diabetes: Comparing Golimumab vs Placebo

This is a double-masked, multicenter, randomized, placebo-controlled trial to determine whether treatment of participants with presymptomatic T1D (two or more diabetes autoantibodies or IA2 alone) and normal glycemia with golimumab results in delay or prevention of progression to confirmed dysglycemia or symptomatic diabetes. 225 participants with presymptomatic T1D will be randomly assigned to placebo or golimumab at a 1:2 randomization (75 placebo and 150 study drug). Golimumab or a saline placebo will be given as a subcutaneous injection. A loading dose regimen at 0 and 2 weeks will be followed by monthly doses for the duration of the participant's enrollment in the study. Study visits will occur every 6 months with some additional remote monitoring in between visits. Study visit procedures include OGTTs, physical exams, questionnaires, and other laboratory tests. The primary outcome is to determine if intervention with golimumab will prevent or delay the progression to confirmed dysglycemia or overt diabetes in persons less than 18 years of age with presymptomatic T1D. The study is expected to recruit for 3 years followed by an additional 3 years of follow-up for the last participant enrolled.

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.
• Weight ≥15 kg at the time of screening.
• Aged ≥2 to <45 years.
• A confirmed history of either IA2A alone or at least two or more diabetes-related biochemical autoantibodies (mIAA, GADA, ICA, IA-2A, ZnT8A) present on the same sample. Confirmed autoantibody result means that the presence of the antibody has been verified on more than one occasion. For multiple autoantibody positivity, the same autoantibodies do not need to be present on the different tests. Confirmation must occur within the six months prior to screening. In the absence of other antibodies, ICA and GADA positivity alone will not suffice for eligibility in this study.
• Oral glucose tolerance test (OGTT) results demonstrating normal glucose tolerance within 7 weeks (52 days) prior to randomization. If a participant has known previous abnormal glucose tolerance, the two most recent OGTTs must demonstrate normal glucose tolerance to be eligible.
• CMV and/or EBV seronegative participants must be CMV and EBV PCR negative within 60 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 60 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 live vaccines during treatment and for 3 months after study drug treatment period.
• Must meet TrialNet eligibility minimum immunization recommendations found in Appendix A of the manual of operations (MOO).
• Negative Coccidioides serology testing for those who have in the past resided in for at least 2 months, currently reside in, or within the past 2 months have visited an endemic area (as defined in Protocol MOO Appendix B).
• If a female participant with reproductive potential, willing to avoid pregnancy (abstinence or adequate contraceptive method) through up to 3 months after last study drug administration and undergo pregnancy testing at each study visit.

Exclusion criteria

• One or more screening laboratory values as stated:

• Leukocytes <3,500/μL or >14,000/μL
• Neutrophils <1,500/mL
• Platelet count <100,000 /μL
• Hemoglobin <6.2 mmol/L (10.0 g/dL)
• AST or ALT ≥ 2 times the upper limits of normal (2x ULN)
• Abnormal Glucose Tolerance or Diabetes

• Fasting plasma glucose ≥100 mg/dL (6.1 mmol/L), or
• 2 hour plasma glucose ≥140 mg/dL (7.8 mmol/L), or
• 30, 60, or 90 minute plasma glucose during OGTT ≥200 mg/dL (11.1 mmol/L)
• History of treatment with insulin except transient use during acute illness or hospitalization.
• Vaccination with a live vaccine within the last 4 weeks or killed/inactivated vaccine within the last 2 weeks prior to randomization.
• A history of confirmed infectious mononucleosis within the 3 months prior to randomization, as documented by EBV serology (EBV VCA-IgM and VCA-IgG; PCR would be confirmatory).
• Evidence of prior or current tuberculosis (TB) infection through any one or more of the following:

• A history of latent or active TB
• Signs and/or symptoms of TB
• Recent close contact with a person with known or suspected active TB unless appropriate prophylaxis for TB was given
• A history of a chest X-ray consistent with active TB or old, inactive TB
• 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).
• Prone to infections or has chronic, recurrent or opportunistic infectious disease, including but not limited to Pneumocystis carinii, aspergillosis, latent or active granulomatous infection, or an open, draining, or infected non-healing skin wound or ulcer.
• Known active infection or active signs or symptoms of acute or chronic infection at the time of randomization including SARS-Cov-2.
• Have or had a demyelinating disorder such as multiple sclerosis or Guillain-Barré syndrome.
• Current diagnosis of other autoimmune diseases except stable and/or adequately treated hypothyroidism and/or celiac disease (participants must be well controlled for the previous 6 months).
• Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 14 days of the screening visit.
• Has previously participated in a clinical trial for diabetes prevention and received active study agent within 6 months of treatment.
• History of blastomycosis, histoplasmosis, or coccidioidomycosis.
• A history of malignancies other than fully treated basal cell or squamous cell carcinoma of the skin.
• Have or had moderate to severe congestive heart failure.
• Ongoing or anticipated future use of any medications known to impact T1D progression.
• Evidence of current or past HIV or Hepatitis B or current Hepatitis C infection.
• Be pregnant or lactating or anticipate becoming pregnant during the study.
• Any condition, prior treatment, or laboratory abnormality that in the investigator's opinion may adversely affect study participation or confound study results.