Efficacy and Safety of Teplizumab Versus Placebo in Stage 3 Type 1 Diabetes Patients Aged 1-25: A Randomized, Double-Blind, Phase 3 Trial

Primary objective: To demonstrate superiority of teplizumab versus placebo on glycemic control or prandial insulin independency over 52 weeks, addressing the clinical need to improve metabolic outcomes in participants with recently diagnosed Stage 3 Type 1 Diabetes.

• Evaluate efficacy of teplizumab versus placebo on endogenous insulin secretion in participants ≥5 years of age.
• Assess efficacy of teplizumab versus placebo on glycemic control in the overall study population.
• Determine whether teplizumab reduces hypoglycemia compared with placebo.
• Characterize the safety and tolerability of teplizumab versus placebo.
• Characterize the pharmacokinetics of teplizumab.
• Evaluate the potential for immunogenicity of teplizumab.

The trial enrolled 566 participants ranging from 1 to 25 years of age, inclusive of both male and female subjects, with inclusion of vulnerable minors. All individuals were required to have a diagnosis of Stage 3 type 1 diabetes according to the American Diabetes Association 2025 criteria, confirmed by a positive test for at least one disease‑specific autoantibody and a random C‑peptide level of ≥0.2 nmol/L at screening. Eligibility mandated initiation of the study drug within eight weeks of diagnosis and the ability to give informed consent (or assent with legal guardian consent for minors). Female participants of childbearing potential needed to use a highly effective contraceptive method and provide negative pregnancy tests. No specific dietary or physical‑activity requirements were stipulated. The study population was selected based on these criteria to evaluate the superiority of teplizumab versus placebo on glycemic control and prandial insulin independence over a 52‑week period.

In this Phase 3 investigation, participants aged 1–25 years with a recent diagnosis of Stage 3 Type 1 Diabetes are allocated in a randomized, double‑blind, placebo‑controlled parallel design to receive either intravenous teplizumab (850 µg/m²) or a matched placebo. After informed consent, a screening visit confirms eligibility, including autoantibody positivity, a C‑peptide level ≥0.2 nmol/L, and a negative pregnancy test when required. Eligible subjects are randomized within 8 weeks of diagnosis and receive the assigned infusion(s) according to the protocol; follow‑up visits occur at weeks 4, 12, 24, 36, and 52 to assess safety, pharmacokinetics, and efficacy endpoints such as change in HbA1c and preservation of C‑peptide secretion. The end‑of‑study visit at week 52 concludes participant involvement, which therefore spans approximately one year plus the initial screening period. Early termination may be initiated for serious adverse events, pregnancy, protocol non‑compliance, or other safety concerns determined by the investigator.

The investigational product Teplizumab is supplied as a concentrate for solution for infusion and is administered intravenously at a dose of 850 µg/m². The preparation is intended for infusion according to the protocol‑specified schedule, and the dosing is calculated based on each participant’s body surface area.

The comparator arm receives a matched placebo that contains no active substance. The placebo is administered in the same infusion format and schedule as the active product to preserve blinding.

Both study treatments are delivered by intravenous infusion at the designated time points, and dosing records are captured in the electronic case report form. Compliance with the infusion schedule is monitored through site‑reported administration logs and verification of infusion completion prior to the next scheduled visit.

Efficacy will be evaluated using both primary and secondary endpoints. Primary endpoints differ by region: in the United States and non‑European Union countries, the change from baseline in Glycated hemoglobin (HbA1c) and the total number of days without prandial insulin use will be assessed; in European Union countries, the change from baseline in mean 2‑hour mixed meal tolerance test (MMTT) stimulated C‑peptide concentration (calculated from the area under the curve) and HbA1c change from baseline, together with the total number of days without prandial insulin use, will be evaluated.

Secondary efficacy assessments include the change from baseline in mean 2‑hour MMTT stimulated C‑peptide AUC, the proportion of participants remaining C‑peptide positive (peak ≥0.2 nmol/L), the incidence of participants achieving HbA1c ≤6.5 % while requiring ≤0.25 IU/kg/day of insulin, and the change from baseline in time‑in‑range (70–180 mg/dL) as measured by continuous glucose monitoring (CGM). Additional secondary measures comprise the rate of level 2 and level 3 hypoglycemic events per participant‑year, pharmacokinetic parameters of teplizumab (Cmax, AUC, AUClast), and the incidence of antidrug antibodies (ADAs). All efficacy parameters will be collected using validated laboratory assays for HbA1c and C‑peptide, standardized MMTT procedures, and CGM devices, with analyses performed by comparing the teplizumab and placebo arms over the 52‑week treatment period.