Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study – a randomised controlled trial

Abstract

IntroductionInfants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that target the underlying pathophysiology. Diazoxide is one such treatment that acts on the pancreatic β-cell in a dose-dependent manner to decrease insulin secretion.Methods and analysisPhase IIB, double-blind, two-arm, parallel, randomised trial of diazoxide versus placebo in neonates ≥35 weeks’ gestation for treatment of severe (blood glucose concentration (BGC)<1.2 mmol/L or BGC 1.2 to <2.0 mmol/L despite two doses of buccal dextrose gel and feeding in a single episode) or recurrent (≥3 episodes <2.6 mmol/L in 48 hours) transitional hypoglycaemia. Infants are loaded with diazoxide 5 mg/kg orally and then commenced on a maintenance dose of 1.5 mg/kg every 12 hours, or an equal volume of placebo. The intervention is titrated from the third maintenance dose by protocol to target BGC in the range of 2.6–5.4 mmol/L. The primary outcome is time to resolution of hypoglycaemia, defined as the first point at which the following criteria are met concurrently for ≥24 hours: no intravenous fluids, enteral bolus feeding and normoglycaemia. Groups will be compared for the primary outcome using Cox’s proportional hazard regression analysis, expressed as adjusted HR with a 95% CI.Ethics and disseminationThis trial has been approved by the Health and Disability Ethics Committees of New Zealand (19CEN189). Findings will be disseminated in peer-reviewed journals, to clinicians and researchers at local and international conferences and to the public.Trial registration numberACTRN12620000129987.

Diazoxide for Severe or Recurrent Neonatal Hypoglycemia

“…The NeoGluCO Study (ACTRN12620000129987) was a double-blinded, 2-arm, parallel randomized clinical trial of diazoxide vs placebo (trial protocol in Supplement 1) 8…”

“…Blinding was maintained by using opaque bottles labeled with a 4-digit random number and by adding a small amount of cornstarch to the placebo (4 g per 50 mL), making it visibly identical to the diazoxide suspension . Tetrad testing among hospital staff showed that the interventions had sensory equivalence and could not be distinguished …”

“…13 Tetrad testing among hospital staff showed that the interventions had sensory equivalence and could not be distinguished. 8 The interventions were titrated using a bedside algorithm, 8 commencing before the third maintenance dose, to a target blood glucose concentration of 47 to 98 mg/dL, representing the 10th and 90th centiles for healthy breastfed newborns in the first week. 14 Once the primary outcome was reached, 1 further intervention dose was given unless the intervention had already been discontinued according to the algorithm.…”

“…7 We undertook the Neonatal Glucose Care Optimisation (NeoGluCO) Study to investigate use of low-dose oral diazoxide in the early management of severe or recurrent hypoglycemia in late preterm through full-term newborns. 8 In pancreatic β cells, insulin exocytosis is controlled by adenosine triphosphate (ATP)-sensitive potassium channels (K ATP ), which close as glucose-generated ATP increases, triggering cell membrane depolarization. Diazoxide binds to the K ATP sulfonylurea receptor, causing hyperpolarization and attenuation of glucose-stimulated insulin secretion.…”

“…Diazoxide binds to the K ATP sulfonylurea receptor, causing hyperpolarization and attenuation of glucose-stimulated insulin secretion . We hypothesized that diazoxide therapy, by modulating β-cell responsiveness to glucose, would improve glycemic stability, allowing earlier weaning from intravenous fluids and establishment of enteral feeding …”