Immune Profile in Subjects With New Onset Type 1 Diabetes

Exploration of the Peripheral Immune System in Subjects With New Onset T1 Diabetes (NOT1D)

It is hypothesized that early changes in the immune system in New Onset Type 1 Diabetes Mellitus (NOT1D) subjects can be detected in immune cells from the inguinal lymph nodes (iLN), which will be distinct from changes observed in peripheral blood derived immune cells. Therefore this study will assess and compare the molecular immune profile of cells derived from the iLN in healthy and NOT1D subjects, to understand the immunological processes that may lead to beta cell destruction. It is a multi-center, non-drug treatment study. Up to 15 subjects in each group, namely healthy subjects and NOT1D subjects, will be evaluated in the study. A data look will be carried out after the recruitment of a cohort of up to 5 healthy subjects, to determine if the quality and quantity of cells derived from aspirate or core biopsy or from peripheral blood are likely to be sufficient to continue the study to meet its primary objective. An interim analysis will be carried out after the recruitment of 5 evaluable healthy subjects and 5 evaluable NOT1D subjects. The primary purpose of this interim analysis will be to facilitate decision making and study design for a potential follow-up interventional study.

Inclusion Criteria:

• Between 18 and 40 years of age inclusive, at the time of signing the informed consent.
• Healthy subjects will be as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination and laboratory tests.
• Subjects will be considered healthy if values for the following parameters: fasted glucose, glycated hemoglobin (HbA1c), International normalized ratio (INR), activated partial thromboplastin time (APTT), platelet count, red blood cells and total lymphocyte count are within the normal range at screening.
• NOT1D subject with documented diagnosis of diabetes mellitus according to American Diabetes Association (ADA) and World Health Organization (WHO) criteria and consistent with Type 1a (autoimmune) Diabetes Mellitus, with an interval of up to 8 weeks between the initial diagnosis and day 1 of the study (Day 1 = "iLN biopsy" day).
• NOT1D subject, who currently requires insulin treatment for type 1 diabetes (T1D) and has received insulin therapy for at least 7 days prior to screening.
• NOT1D subject positive, at screening, for at least one autoantibody associated with T1D: anti- Glutamic Acid Decarboxylase (GAD), anti-Islet antigen 2 (IA-2), anti- islet cell antibodies (ICA), anti-Indole 3 acetic acid (IAA), anti- Zinc transporter 8 (ZnT8).
• NOT1D subject with evidence, at screening, of residual functioning beta cells as measured by fasted C-peptide levels >=0.15 nanomole per liter (nmol/L).
• NOT1D subject having values for the following parameters: INR, APTT, platelet count, red blood cells and total lymphocyte count within the normal range at screening.
• Both, male or female subjects are eligible to participate in this study. A female subject is only eligible to participate if she is not pregnant [as confirmed by a negative urine human chorionic gonadotropin (hCG) test], not lactating at screening and study visit(s) or has documented evidence to not be of child bearing potential.
• Capable of giving signed informed consent which includes compliance with the study requirements and study restrictions.
• A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator, in consultation with the Medical Monitor if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

Exclusion Criteria:

• Healthy subjects having family history of T1D (that is, first degree relative has been diagnosed with T1D)
• Healthy subjects with presence of one or more of serum autoantibodies, such as anti-GAD, anti-IA2, anti-ICA, anti-IAA, anti-ZnT8, anti-thyroid peroxidase antibodies, anti-tissue transglutaminase antibodies and anti-nuclear antibodies.
• NOT1D subjects with history of autoimmune disease other than T1D
• NOT1D subjects with presence of one or more of serum autoantibodies of the following: anti-thyroid peroxidase antibodies, anti-tissue transglutaminase antibodies or anti-nuclear antibodies
• Allergy or intolerance to local anesthetic agents
• Any localized groin condition which would contraindicate biopsy procedure including but not limited to: Active infection/inflammation at the intended puncture site, previous surgery/scarring or any other anatomical abnormality as deemed relevant to the procedure by the investigator, in consultation with the Medical Monitor if required.
• History of bleeding disorders, current or anticipated continuous use of anticoagulant (including but not limited to warfarin, rivaroxaban) and antiplatelet agents (including but not limited to Nonsteroidal anti-inflammatory drugs [NSAIDS], clopidogrel, etc.)
• Active or unresolved bacterial infection, viral infection, fungal infection within 4 weeks prior to day 1.
• Known febrile episode over 38 degrees Celsius within 4 weeks prior to day 1.
• Active organ dysfunction or previous organ allograft.
• History of malignancy (with the exception of resected basal carcinoma of the skin or cervical carcinoma in situ).
• Has undergone any major surgical procedure within 30 days before screening, and/or is planning to undergo any such surgery during the period of the study (i.e. from screening until the last follow-up telephone call)
• Present or previous treatment with any cell depleting therapies or immune-modulating or suppressive agents (e.g., oral steroids), including investigational agents such as the following but not limited to e.g., Interleukin (IL)-2, alemtuzumab, anti- Cluster of Differentiation (CD) 4, anti-CD5, anti-CD3, anti-CD19, anti-CD20.
• Vaccination =<28 days before day 1 of the study or planned during the study period
• Current participation in an interventional clinical trial. Subjects, who participated in an interventional clinical trial previously, must wait for 3 months after completing the previous interventional clinical trial before participating in this study.
• Any medical history or clinically relevant abnormality that is deemed by the investigator and/or medical monitor to make the subject ineligible for inclusion because of a safety concern or any situation that, in the investigator's judgment, is likely to cause the subject to be unable or unwilling to participate in study procedures or to complete all scheduled assessments.
• A positive pre-study drug/alcohol screen (unless positive due to prescription medication). A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
• Inability to access the groin area to perform the biopsy procedure as judged by the investigator.