Investigating Re-Dosing With Otelixizumab in Adults With Newly-Diagnosed Type 1 Diabetes Mellitus

Evaluation of the Safety and Tolerability of Re-dosing With Intravenous (iv) Otelixizumab in Adult Subjects With Newly Diagnosed Type 1 Diabetes Mellitus

The purpose of this study to assess the safety and tolerability of re-dosing at 6 months with otelixizumab (given as an 8-day series of intravenous infusions) in adult subjects with newly diagnosed type 1 diabetes mellitus

The primary objective of this phase IIa, open-label, multi-centre study is to assess the safety, tolerability and immunogenicity of re-dosing at 6 months with an 8 consecutive day series of otelixizumab intravenous (IV) infusions in 8 adult subjects with newly diagnosed type 1 diabetes mellitus (T1DM). Although it is hoped that the β cell preserving effect of otelixizumab will be long-lasting, it is possible that the effect may decline over time and thus T1DM subjects may require re-treatment. Six months is the minimum time expected between treatments.

After baseline assessments, eligible subjects will receive 8 consecutive days of otelixizumab infusions, each given over a 30 minute period. Prophylaxis for cytokine release syndrome AEs will be given. At Month 6, following a review of any new medical conditions, concomitant medications, lymphocyte count, Epstein Barr Virus (EBV) viral load and other re-dosing eligibility criteria, subjects will be re-treated with the same dosing regimen. Subjects will be followed for 24 months in this study.

Inclusion Criteria:

• Male or female, aged 18 to 45 years. Women are allowed if they are of non-childbearing potential or agree to use one of the contraception methods listed in the protocol.
• Diagnosis of type 1 autoimmune diabetes mellitus according to ADA and WHO criteria
• No more than 90 days between diagnosis and the first dose of study drug.
• Currently requires insulin for T1DM treatment, or has required insulin at some time between diagnosis and the first dose of study drug.
• Positive for one or more of the autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti-GAD); antibody to protein tyrosine phosphatase-like protein (anti-IA-2); or insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will only be eligible if the subject has used insulin for less than 7 days total.
• Stimulated C-peptide level greater than 0.20 nmol/L and less than or equal to 3.50 nmol/L
• Body mass index not greater than 32 kg/m2.
• QTc <450 millisecond (msec) or <480msec for patients with Bundle Branch Block

Exclusion Criteria:

• Pregnant, breastfeeding, or planning to become pregnant from the beginning of the screening period or at least 14 days prior to initial dosing until at least 60 days after the last dose of the second treatment course of study drug.
• Current or prior malignancy, other than non-melanoma skin cancer (subject must have had fewer than 5 occurrences of non-melanoma skin cancer, and the last occurrence must not be within 3 months of study entry).
• Clinically significant abnormal laboratory values during the Screening period, other than those due to T1DM. Permitted ranges for selected laboratory values are shown in the protocol. A clinically significant abnormal value will not result in exclusion if, upon re test, the abnormality is resolved or becomes clinically insignificant.
• Significant and/or active disease in any body system likely to increase the risk to the subject or interfere with the subject's participation in or completion of the study. Examples of significant diseases include, but are not limited to, coronary artery disease, congestive heart failure, uncontrolled hypertension, renal failure, emphysema, history of bleeding peptic ulcers, history of seizure(s), addiction to illicit drugs, and alcohol abuse.
• Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), presence of hepatitis B surface antigen (HBsAg), positive hepatitis C test result within 3 months of screening
• Significant systemic infection during the 6 weeks before the first dose of study drug (e.g., infection requiring hospitalisation, major surgery, or IV antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localised cellulitis, candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant exclusion).
• History of current or past active tuberculosis infection and or latent tuberculosis infection. Further details are given in the protocol.
• A positive test for human immunodeficiency virus (HIV) antibody or risk factors which predispose subject to HIV infection.
• EBV viral load greater than or = to 10,000 copies per 10xe6 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR). If there is any clinical suspicion that a subject who is EBV seronegative and with EBV PCR <10,000 copies per 10xe6 PBMCs has symptoms consistent with infectious mononucleosis prior to administration of study drug, then a monospot test result must be negative before the subject can be dosed.
• A positive test for syphilis.
• Had a potent immunosuppressive agent (e.g., systemic high-dose corticosteroids on a chronic basis, methotrexate, cyclosporine, or anti-TNF agents) within the 30 days before the first dose of study drug, or expecting to require such treatment within 3 months after the last dose of study drug. (Intranasal, inhaled, and topical corticosteroid medications are permitted if used at recommended dosages.)
• Used an atypical antipsychotic drug (e.g., risperidone [Risperdal], quetiapine [Seroquel], or clozapine [Clozaril]) within the 30 days before first dose of study drug, or expecting to require such treatment during the study.
• Received a vaccine within the 30 days before the first dose of study drug, or expecting to require a vaccine during the dosing period or the 30 days after the last dose of study drug.
• Previously received otelixizumab or any other anti CD3 monoclonal antibody, e.g., OKT3 (muromonab or Orthoclone), ChAglyCD3, or hOKT3γ1 (ala ala), or not willing to refrain from using any such antibody for the planned duration of study participation (18 months after the last dose of study drug).
• Previously received an anti lymphocyte monoclonal antibody, such as anti-CD20, anti-thymocyte globulin (ATG), rituximab (Rituxan), or alemtuzumab (Campath), or planning to use any such antibody during the planned duration of study participation (18 months after the last dose of study drug).
• Had an investigational drug within the 3 months before the first dose of study drug or planning to take an investigational drug within18 months of the last dose of study drug.
• Have donated any plasma or blood within 45 days before the first dose of study drug.
• Prior allergic reaction, including anaphylaxis, to any human, humanised, chimeric, or rodent antibody.
• Undergone a major surgical procedure within 30 days before the first dose of study drug, or planning to undergo any such surgery within 3 months after the last dose of study drug.