Protege Encore Study- Clinical Trial of Teplizumab (MGA031) in Children and Adults With Recent-Onset Type 1 Diabetes Mellitus

• Successful versus unsuccessful clinical responses. A successful response requires that both components of a composite endpoint are met. The composite endpoint includes both the subject's total daily insulin usage and his/her HbA1c levels [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
• C-peptide secretory responses, as defined by the total area under the curve of the C-peptide response to a mixed meal [ Time Frame: 12 and up to 24 months ] [ Designated as safety issue: No ]

• Successful versus unsuccessful clinical responses. A successful response requires that both components of a composite endpoint are met. The composite endpoint includes both the subject's total daily insulin usage and his/her HbA1c levels [ Time Frame: at 24 Months ] [ Designated as safety issue: No ]
• C-peptide secretory responses, as defined by the total area under the curve of the C-peptide response to a mixed meal [ Time Frame: at 24 months ] [ Designated as safety issue: No ]

The primary purpose of this study is to determine whether teplizumab (MGA031) infusions lead to greater reductions in insulin requirements in conjunction with near normal blood sugar control compared to placebo in patients recently diagnosed with type 1 diabetes.

• Drug: Teplizumab (MGA031)
  IV dosing daily for 14 days times 2 courses
  Other Name: MGA031
• Drug: Placebo
  IV dosing daily for 14 days times 2 courses

• Experimental: 1
  Intervention: Drug: Teplizumab (MGA031)
• Experimental: 2
  Intervention: Drug: Teplizumab (MGA031)
• Experimental: 3
  Intervention: Drug: Teplizumab (MGA031)
• Placebo Comparator: 4
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Subjects 8-35 years old
2. Body weight > 36 Kg
3. Diagnosis of diabetes mellitus according to the American Diabetes Association (ADA) criteria
4. Randomization on Study Day 0 within 12 weeks of first visit to any physician for symptoms or signs of diabetes
5. Requires insulin for T1DM or has required insulin at some time between diagnosis and administration of study drug
6. Detectable fasting or stimulated C-peptide level (above the lower limit of the reportable range of the assay) at screening

7. Diagnosis of T1DM as evidenced by one positive result on testing for any of the following antibodies at screening:

   • Islet-cell autoantibodies 512 (ICA512)/islet antigen-2 (IA-2),
   • Glutamic acid decarboxylase (GAD) autoantibodies, or
   • Insulin autoantibodies (in subjects on insulin for more than 2 weeks, ICA512/IA-2 or GAD must be positive).

Exclusion Criteria:

1. Prior administration of a monoclonal antibody—within the 1 year before randomization
2. Participation in any type of therapeutic drug or vaccine clinical trial within the last 12 weeks before randomization at Study Day 0
3. Any medical condition that, in the opinion of the investigator, would interfere with safe completion of the trial
4. Pregnant females or lactating females who intend to provide their own breast milk to the baby during the study
5. Current therapy with GLP-1 receptor agonists (e.g., exenatide or pramlintide), or any other agents that might stimulate pancreatic beta cell regeneration or insulin secretion
6. Current treatment with oral antidiabetic agents
7. Evidence of active or latent tuberculosis

8. Vaccination with a live virus or organism within the 8 weeks before randomization continuing through Week 52 of the study.

   • Influenza vaccination with a killed virus, including booster vaccinations, within 4 weeks before or after each dosing cycle.
   • Vaccination with other antigens or killed organisms within 8 weeks before or after each dosing cycle
9. Any infectious mononucleosis-like illness within the 6 months before randomization