Optimal Dosing of Omeprazole in Neonates (OMEPRAZOLE-1)

Optimal Dose and Population Pharmacokinetics of Omeprazole in Neonates With Gastroesophageal Reflux Disease (GERD)

"The principal aim of this trial is to determine the minimum effective dose of omeprazole in neonates with GERD objectively diagnosed by a 24-h intra-oesophageal pH monitoring (pHmetry), to obtain a short-term efficacy in the pHmetry of control performed 72 hrs ± 24 after initiation of omeprazole. The secondary objectives of the study were: (1) to assess the efficacy of omeprazole upon other pHmetry parameters, (2) to characterize the population pharmacokinetics and pharmacogenetics of omeprazole, (3) to evaluate the effect of omeprazole upon oro-pharyngeal pH monitoring and (4) to assess the short-term safety of use of omeprazole in neonates."

"Omeprazole is a proton pump inhibitor increasingly prescribed in the neonatal population for gastroesophageal reflux disease (GERD) complicated or not by the presence of esophagitis. Although extensively evaluated in adults, optimal dosing schemas, efficacy and safety have not been determined in the neonatal population where its prescription remains off-label. The study is a double blind trial that was designed using a Bayesian sequential analysis approach. The principle of this approach is to identify the adequate drug dosage to obtain a level of efficacy as close as possible to a predetermined target level of efficacy in the population. In this study, five different dosages of omeprazole are tested (1, 1,5, 2, 2,5, 3 mg/kg/day) and a target probability of successful treatment of 95% has been chosen. To assess the influence of gestational age on omeprazole's efficacy, analysis was stratified on 3 groups: (1) neonates of less than 32 weeks gestational age (GA), (2) neonates born between 32 and 35 weeks of GA, (3) neonates of more than 36 weeks of GA. A total maximum number of 90 neonates is expected to be included (30 neonates per group). Patients' participation in the study ends after completion of the pHmetry of control that is 72 ±24 hours after omeprazole initiation. Patients in the study will all benefit for the management of their GERD from non-pharmacological therapies such as adequate positioning and use of available thickening agents for formula The only pharmacologic agent authorised during study for treating GERD is omeprazole. All other available GERD treatments will not be prescribed."

Presence of a normalised control pHmetry Presence of a normalised control pHmetry Presence of a normalised control pHmetry

Normalised control pHmetry is defined by a reflux index (duration that the recorded intra-oesophageal pH is less than 4.0, expressed as a percentage of the total duration of pH monitoring) of less than 5%

Plasma concentrations of omeprazole and its metabolite, hydroxyl-omeprazole, After the first administration of omeprazole, blood will be collected either between H0.5 and H4 or between H4 and H12 or both

changes in salivary pH monitoring Without treatment period: just before and 3 hours after a meal Under treatment period: just before and just after the insertion of the pHmetry catheter

INCLUSION CRITERIA: Full-term neonates or preterm neonates with a postmenstrual age >/= 35 weeks Presenting abnormal pHmetry (= percentage of the entire record that intra-oesophageal pH is <4 is superior or equal to 5%) Patient must receive discontinuous oral feedings If proton pump inhibitors or other pharmacologic antireflux therapies had already commenced, these had to be withdrawn 7 days before baseline recordings In-patient in Neonatal Intensive Care Unit or Neonatology Unit of the Robert Debré University Hospital Both parents sign written informed consent form Affiliated to social security EXCLUSION CRITERIA: Patients under proton pump inhibitors (PPI) treatment or that have discontinued PPI treatment less than 7 days before inclusion Patients with acute gastrointestinal disease (diarrhoea) Patients than present leucopenia or thrombocytopenia (value half the normal value for age) Patients that present aspartate and alanine aminotransferase values twice the upper limit of normal Patients that present renal and hepatic failure Newborns presenting galactosemia, glucose-galactose malabsorption, deficiency in lactase enzymes Co-administration of atazanavir and ritonavir Patients allergic to omeprazole or to any other ingredients in the medicine