Rituximab in New Onset Type 1 Diabetes

• -Area under stimulated C-peptide curve over the first 2 hours of a 4-hour MMTT administered at 2 years
• Insulin dose (units/kg) and number of injections
• Glycosylated hemoglobin (HbA1c)

Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Without these beta cells, the body cannot maintain proper blood glucose levels in response to daily activities such as eating or exercise. With fewer insulin producing cells blood glucose increases, causing hunger, thirst, and unexplained weight loss. By the time these symptoms develop, 80-90% of a person's beta cells have already been destroyed. However, this also means that between 10-20% of these cells remain that continue to produce insulin.

Scientists have learned that two types of immune cells, B cells and T cells, are involved in causing type 1 diabetes. T cells are responsible for attacking and destroying the beta cells that make insulin. Although they don't attack insulin producing cells, B cells may be what trigger the T cells to attack.

This study will investigate the use of rituximab to see if it can help lower the number of immune B cells thereby preventing the destruction of any remaining insulin producing beta cells that remain at diagnosis. Rituximab is approved by the Food and Drug Administration (FDA) for the treatment of a condition called B-lymphocyte lymphoma. Its effects on the immune system are well understood through its use in organ transplantation. Research has shown that rituximab might be helpful in treating other conditions caused by T cells and B cells, including type 1 diabetes. The goal of this study is to find out if rituximab can preserve residual insulin secretion and prevent further beta cell destruction in type 1 diabetes.

The study is a randomized, two-arm, trial in which 2/3 of participants will receive the study drug, while the remaining 1/3 will receive a placebo (a pretend medicine that does nothing). The group you are assigned to is decided by chance (as by the toss of a coin or drawing straws). Neither you nor your doctor will be able to choose which group you are in. Also, neither you nor the researchers will know which group you are in. Participants will take rituximab, or the placebo, once a week during the first 4 weeks in the study. It will be given as an intravenous infusion at a clinical center.

Participants will need to return to the clinical center for a visit about every 3 months for two years; those participants that continue to secrete insulin will have further follow-up for an additional two years.

• Drug: Anti-CD20 (rituximab)
• Drug: Placebo Comparator
  Placebo intravenous infusion

• Experimental: Rituximab Intravenous Infusion
  Participants will receive active rituximab (anti-CD20 monoclonal antibody) as an intravenous infusion, with 4 administrations at weeks 0, 1, 2, and 3 at a dose of 375mg/m2
  Intervention: Drug: Anti-CD20 (rituximab)
• Placebo Comparator: Placebo Intravenous Infusion
  Participants will receive placebo given as an intravenous infusion with 4 administrations at weeks 0, 1, 2, and 3.
  Intervention: Drug: Placebo Comparator

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Inclusion Criteria:

• Between the ages of 8 and 45 years
• Within 3 months of diagnosis of type 1 diabetes
• Have presence of at least one diabetes-related autoantibody
• Must have stimulated C-peptide levels of at least 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) within one month of randomization
• If female with reproductive potential, willing to avoid pregnancy and undergo pregnancy testing while participating in the study
• Have not received an immunization for at least one month
• Must be willing to comply with intensive diabetes management
• Must weigh at least 25 kg at study entry

Exclusion Criteria:

• Are immunodeficient or have clinically significant chronic lymphopenia
• Have an active infection or positive purified protein derivative (PPD) test result
• Currently pregnant or lactating; or anticipate becoming pregnant.
• Require chronic use of steroids
• Have current or past HIV, hepatitis B, or hepatitis C infection
• Have any complicating medical issues that interfere with study conduct or cause increased risk
• Have a history of malignancies
• Currently using non-insulin pharmaceuticals that effect glycemic control
• Currently participating in another type 1 diabetes treatment study

• National Institute of Allergy and Infectious Diseases (NIAID)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• American Diabetes Association
• Juvenile Diabetes Research Foundation