Anti-IL-1 Treatment in Children Diabetic Keto-Acidosis (DKA) at Diagnosis of Type 1 Diabetes

This is a randomized, double-blind, placebo-controlled phase 2 study. Specific aim is to evaluate feasibility and safety of anti-IL-1 (interleukin 1) treatment in the course of standard therapy for diabetic ketoacidosis in children and its effect on intracranial pressure.

Anakinra is a fully human IL-1ra (interleukin 1 receptor agonist) licensed in 2001 by FDA for the treatment of rheumatoid arthritis. It competitively binds to the IL-1 receptor, thus blocking IL-1 signaling. It is a short-acting agent that requires daily subcutaneous administration at 1-2 mg/kg, maximum 100 mg/dose. It has been effective in lowering HbA1c (glycated haemoglobin) in T2D (type 2 diabetes) and a randomized trial of anakinra in recent onset T1D (type 1 diabetes) is underway in Europe. Overall, anakinra has been used in adults and children with a good safety record, for more than 10 years. Infrequent side effects include infections, neutropenia, nausea, diarrhea, cardiopulmonary arrest, influenza-like symptoms, and production of anti-anakinra antibodies.

Study Design: A double-blinded placebo-controlled RCT (randomized controlled trial) with 2:1 allocation (14 active treatment vs. 7 placebo). Anakinra treatment will be given as a bolus of 2 mg/kg infused intravenously over 30 minutes followed by infusion of 2 mg/kg/hour for 4 hours immediately after confirmation of the diagnosis of DKA (diabetic keto-acidosis) and when laboratory safety parameters are available (CBC (complete blood count) and pregnancy test) and after a consent is obtained. Primary outcomes: Safety and tolerability of anti-IL-1 treatment (anakinra) during the initial 24 hr period of DKA treatment. Secondary outcomes: Optic nerve sheath diameter (cut-off to define cerebral edema: 4.5 mm); Changes in cytokines levels during the treatment with anakinra.

Eligibility Criteria:
Inclusion Criteria:

* Age 8-18 years at diagnosis of type 1 diabetes
* Diabetic ketoacidosis with:

  * plasma glucose concentration \>300 mg/dl,
  * venous pH \<7.30 or
  * serum bicarbonate concentration \<15 mmol/L, and
  * ketones in urine or serum
* Hematology:

  * WBC \>3000 x 109/L;
  * platelets \>100,000 x 109/L;
  * hemoglobin \>10.0 g/dL
* Negative blood pregnancy test in females.

Exclusion Criteria:

* Children with underlying disorders, including:

  * active autoimmune or immune deficiency disorder other than type 1 diabetes,
  * malignancy,
  * organ transplant,
  * any condition requiring chronic corticosteroid use
* Previous immunotherapy to prevent type 1 diabetes
* Current or prior infection with HIV, hepatitis B or hepatitis C assessed by history
* Patients who present with DKA concomitant with alcohol or drug use,
* Head trauma,
* Meningitis or other conditions which might affect neurological function
* Renal failure
* Any condition, medical or otherwise that would, in the opinion of the investigator, prevent complete participation in the study, or that would pose a significant hazard to the subject's participation
* Patients with a history of known hypersensitivity to:

  * E coli-derived proteins,
  * anakinra, or
  * any components of the investigational drug product