Efficacy of Extracorporeal Photopheresis (ECP) in the Treatment of Type 1 Diabetes Mellitus

The standard of care is defined as per the "DOH Standards for diagnosis, management and data reporting for diabetes" in combination with the DOH recommended NICE (UK National Institute for Health and Care Excellence) guidelines "Type 1 diabetes in adults: diagnosis and management (NG17)". OPERA Study will be fully conducted in ADSCC, including the patient assessment and inclusion, randomization, ECP procedures, and follow-up consultations, according to this Protocol and GCP principles. All patients will receive T1DM standard of care, plus additional ECP protocols on two regimens of investigational interventions. The primary objective is the safety assessment of ECP, to be assessed by the tolerability to the ECP procedures, incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) assessed by the CTCAE v5.0, and the WHO-UMC causality assessment system. The other primary objective is the preliminary efficacy assessment of the ECP as an add-on treatment to the standard of care for T1DM patients, assessed by the exogenous insulin use, HbA1c levels, C-peptide levels, and clinically important hypoglycemic episodes. The secondary objective is the assessment of the immune response profile in T1DM patients receiving standard of care and additional ECP procedures. The trial is approved by the institutional ADSCC Research Ethics Committee (REC) and written informed consent will be obtained from all patients. OPERA Study will be conducted following the principles of the Declaration of Helsinki and ICH-GCP guidelines.

• Inclusion Criteria

• Confirmed and documented diagnosis of T1DM. Patients must have:
• A documented history of T1DM within the first 3 years of onset.
• Should be on a multiple dose injection (MDI) therapy.
• C-Peptide levels of ˂ 0.7 ng/mL.
• HbA1C ≥ 6.5% to ≤ 10%.
• Evidence of pancreatic autoimmunity, if available (positive anti-glutamic acid decarboxylase [GAD]; Islet antigen 2 [anti-IA2]; and/or zinc transporter 8 [ZnT8] antibodies).
• Male or female aged ≥ 18 to ≤ 50 years.
• Weight > 40 kg.
• Hematocrit ≥ 32%.
• Platelet count ≥ 100 x10^9/L (with or without transfusion support).
• Willingness to participate in all OPERA Study tests, visits, and ECP procedures, as outlined in the informed consent.
• Willingness to use at least one reliable method of birth control (e.g. abstinence, oral contraceptives, intrauterine devices, barrier method with spermicide, or surgical sterilization) throughout the study for all men and women of childbearing potential.
• The patient agrees to participate in the trial, and signs the OPERA Study informed consent form.
• Exclusion Criteria

• Pediatric aged < 18 or ˃ 50 years.
• Clinical diagnosis of type 2 diabetes mellitus (T2DM).
• Inability to tolerate fluid changes associated with ECP (e.g. inadequate renal, hepatic, pulmonary and cardiac function leading to enable patient to tolerate extracorporeal volume shifts associated with ECP).
• Hypersensitivity or allergy to citrate products.
• Hypersensitivity or allergy to psoralen compounds such as Methoxsalen (8-Methoxypsoralen, 8-MOP).
• Aphakia (8-MOP is contraindicated because of the significantly increased risk of retinal damage due to the absence of lenses).
• Presence of comorbidities that may result in photosensitivity (systemic lupus erythematosus, porphyries, albinism, etc.).
• Suspected or diagnosed Diabetic Ketoacidosis (DKA) at the moment of the screening visit.
• Uncontrolled infection requiring treatment at study entry.
• Laboratory evidence of any of the following:
• White Blood Cell (WBC) count < 3.00 x10^9/L.
• Serum transaminase levels > x2 upper normal limit (UNL).
• Hematocrit < 32%.
• Platelet count < 100 x10^9/L (with or without transfusion support).
• Diagnostic of Hepatitis B Virus (HBV) infection.
• Diagnostic of Human Immunodeficiency Virus (HIV) infection or Acquired Immunodeficiency Syndrome (AIDS).
• Pregnant or lactating women.
• Have participated in other clinical trial in the past 3 months.
• Organ transplants in the past 3 months.
• Current diagnosis of cancer.
• Inability to comply with all OPERA Study tests, visits, and procedures (including ECP).
• Inability to provide informed consent.