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

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.

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