Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes (AbATE)

• Diabetes-related endpoints, including insulin use, time to undetectable C-peptide response, and HbA1C level [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• pharmacokinetic measures, including drug levels, adverse events, Epstein-Barr virus (EBV)/cytomegalovirus (CMV) viral loads [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• mechanistic assessments, including T cell depletion/repopulation, alterations to cytokine levels, and T cell activation measures [ Time Frame: 24 months ] [ Designated as safety issue: No ]

• - Diabetes related endpoints including Insulin use, time to undetectable C-peptide response, HbA1C level
• - pharmacokinetic measures, including drug levels, adverse events, EMV/CMV viral loads
• - mechanistic assessments, including T-cell depletion/repopulation, alterations to cytokine levels, T-cell activation measures

hOKT3gamma1 (Ala-Ala) is a man-made antibody that is commonly used to prevent organ rejection. The purpose of this study is determine whether hOKT3gamma1 (Ala-Ala) can halt the progression of newly diagnosed type 1 diabetes.

Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks insulin-producing beta cells in the pancreas. Without these cells, the body cannot maintain proper blood glucose levels in response to daily activities, such as eating or exercise. Generally, at the time of type 1 diabetes diagnosis, 60% to 85% of the diabetic person's beta cells have already been destroyed. However, between 15% and 40% of these cells remain and are able to produce insulin. Treatment that slows the destruction of additional beta cells may be able to decrease a patient's reliance on insulin and improve their quality of life.

hOKT3gamma1 (Ala-Ala) is a genetically engineered monoclonal antibody directed against the CD3 antigen on T cells; this antibody selectively attacks the immune cells responsible for beta cell destruction. In a small exploratory clinical trial, patients with newly diagnosed type 1 diabetes who received a single, 2-week treatment with hOKT3gamma1 (Ala-Ala) had preserved beta cell function and significantly lower insulin requirements than untreated patients for up to two years after therapy. This study will investigate whether a second course of hOKT3gamma1 (Ala-Ala) administered one year after the first administration is able to prolong or improve the effects of the drug in people who have recently diagnosed type 1 diabetes mellitus.

Participants will be randomly assigned to one of two groups. Group 1 will receive hOKT3gamma1 (Ala-Ala) antibody treatment plus standard diabetes management; Group 2 will receive standard diabetes management alone. Group 1 will be treated with the antibody for the first 14 days of the study and again one year later. Group 1 participants will be admitted to the hospital for the first 5 days of a treatment cycle. Participants who live within 1 hour of the hospital may receive the remainder of a treatment cycle as an outpatient, but those who live farther away will be hospitalized for 14 days. For the first treatment cycle, there will be study visits on the 3 consecutive days after the treatment cycle and at Months 1, 2, 3, 6, 9, and 12. For the second treatment cycle, there will be study visits on the 3 consecutive days after the treatment cycle and at Months 13, 16, 19, 21, and 24. Group 2 will have 12 study visits over two years.

At study entry, all participants will receive daily iron supplementation, either as ferrous sulfate or a multivitamin with iron. Participants will be followed for up to 2 years to assess their overall diabetes health and to capture laboratory measures of beta cell and immune system function. Medication history and adverse event assessment will occur at all visits. A physical exam, vital signs measurement, and blood collection will occur at most visits. Medical history and urine collection will occur at selected visits.

• Drug: hOKT3gamma1 (Ala-Ala)
  daily 14-day dose escalation course (from 51 ug/m2 IV on day 1, to 826 ug/m2 on days 5-14) at study entry, with possible second course after 12-month interval
  Other Name: teplizumab
• Other: Intensive diabetes management
  Dietary counselling, insulin dosing and scheduling, multiple consultations with clinical diabetes management team

• Experimental: 1
  Interventions:

  • Drug: hOKT3gamma1 (Ala-Ala)
  • Other: Intensive diabetes management
• Active Comparator: 2
  Intervention: Other: Intensive diabetes management

• Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005 Jun;54(6):1763-9.
• Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002 May 30;346(22):1692-8.

Inclusion Criteria:

• Diagnosis of type 1 diabetes (according to American Diabetes Association [ADA] criteria) within the 8 weeks prior to study entry
• Weigh at least 25 kg (55 lbs)
• Insulin autoantibodies assessed within 10 days of any insulin use OR anti-glutamic acid decarboxylase (GAD) autoantibodies OR anti-ICA512/IA-2 autoantibodies
• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Prior participation in a clinical trial that could potentially affect diabetes condition or immunologic status
• Participation in another investigational clinical trial within the 6 weeks prior to study entry
• Pregnancy or breastfeeding