Anti-CD3 Mab (Teplizumab) for Prevention of Diabetes in Relatives At-Risk for Type 1 Diabetes Mellitus (TN10)

General Description

Up to ten percent of all diagnosed diabetics have type 1 diabetes. Type 1 diabetes is a condition that develops due to an autoimmune attack against beta cells in the pancreas, which causes the body to stop producing insulin. Occurring most often in children and young adults, this type of diabetes appears suddenly and can lead to lifelong health complications. Relatives of people with type 1 diabetes have a greater risk of developing the disease. Type 1 Diabetes TrialNet is an international clinical trials network that conducts studies to find ways to prevent or delay the development of the disease and to enhance treatment for the newly diagnosed.

Teplizumab (Anti-CD3) is a monoclonal antibody that interferes in the autoimmune attack of pancreatic beta cells. Previous studies have shown that teplizumab reduces the loss of insulin production in type 1 diabetics during the first year after diagnosis. TrialNet 10 (TN10) was a phase 2 prevention trial of TrialNet, studying the effect of teplizumab on insulin production in the relatives of type 1 diabetics who were at high risk of developing the disease. Participants were randomly assigned to either the active or placebo group of the study, and monitored and tested over time until diagnosed with diabetes.

Objectives

The primary objective of TN10 was to determine whether intervention with teplizumab prevents or delays the development of type 1 diabetes (T1D) in high-risk autoantibody positive non-diabetic relatives of individuals with T1D.

Outcome Measure

TN10 compared the elapsed time from random treatment to development of diabetes for participants given teplizumab and those given the placebo. Criteria for diabetes onset were defined by the American Diabetes Association based on glucose testing or the presence of unequivocal hyperglycemia with acute metabolic decompensation. In addition, the association of demographic, genetic, immunologic, metabolic, and lifestyle factors were analyzed over time until the diagnosis of diabetes.

Criteria

Inclusion criteria:

• Between ages of 8-45 years
• Have a relative with type 1 diabetes
• If first degree relative, must be 8-45 years old (brother, sister, parent, offspring)
• If second degree relative, must be between 8-20 years old (niece, nephew, aunt, uncle, grandchild, cousin)
• Abnormal glucose tolerance by OGTT confirmed within 7 weeks of the baseline visit
• Presence of at least two confirmed diabetes autoantibodies

Exclusion criteria:

• Type 1 diabetes previously diagnosed or detected at screening
• Abnormalities in blood counts, liver enzymes, or international normalized ratio (INR)
• Positive purified protein derivative (PPD) test
• Vaccination with live virus within 6 weeks of randomization
• Evidence of acute infection based on laboratory testing or clinical evidence
• Serological evidence of HIV, hepatitis B, or hepatitis C infection
• Currently pregnant or lactating
• Prior treatment with study drug or other monoclonal antibody

Detailed inclusion and exclusion criteria can be found in the study protocol.

Outcome

In this phase 2 trial, a single course of teplizumab significantly slowed progression to clinical type 1 diabetes in high-risk, non-diabetic relatives of participants with diabetes who had at least two autoantibodies and abnormal results of an oral glucose-tolerance test at trial entry. The median delay in the diagnosis of diabetes was 2 years; at the conclusion of the trial, the percentage of diabetes-free persons in the teplizumab group (57%) was double that in the placebo group (28%).