title: Dose-Finding Study of Omeprazole on Gastric pH in Neonates with Gastro-Esophageal Acid Reflux Using a Bayesian Sequential Approach.
abstract: OBJECTIVE
  Proton pump inhibitors are frequently administered on clinical symptoms in neonates but benefit remains controversial. Clinical trials validating omeprazole dosage in neonates are limited. The objective of this trial was to determine the minimum effective dose (MED) of omeprazole to treat pathological acid reflux in neonates using reflux index as surrogate marker.
  
  
  METHODS
  Double blind dose-finding trial with continual reassessment method of individual dose administration using a Bayesian approach, aiming to select drug dose as close as possible to the predefined target level of efficacy (with a credibility interval of 95%).
  
  
  METHODS
  Neonatal Intensive Care unit of the Robert Debré University Hospital in Paris, France.
  
  
  METHODS
  Neonates with a postmenstrual age ≥ 35 weeks and a pathologic 24-hour intra-esophageal pH monitoring defined by a reflux index ≥ 5% over 24 hours were considered for participation. Recruitment was stratified to 3 groups according to gestational age at birth.
  
  
  METHODS
  Five preselected doses of oral omeprazole from 1 to 3 mg/kg/day.
  
  
  METHODS
  Primary outcome, measured at 35 weeks postmenstrual age or more, was a reflux index <5% during the 24-h pH monitoring registered 72±24 hours after omeprazole initiation.
  
  
  RESULTS
  Fifty-four neonates with a reflux index ranging from 5.06 to 27.7% were included. Median age was 37.5 days and median postmenstrual age was 36 weeks. In neonates born at less than 32 weeks of GA (n = 30), the MED was 2.5mg/kg/day with an estimated mean posterior probability of success of 97.7% (95% credibility interval: 90.3-99.7%). The MED was 1mg/kg/day for neonates born at more than 32 GA (n = 24).
  
  
  CONCLUSIONS
  Omeprazole is extensively prescribed on clinical symptoms but efficacy is not demonstrated while safety concerns do exist. When treatment is required, the daily dose needs to be validated in preterm and term neonates. Optimal doses of omeprazole to increase gastric pH and decrease reflux index below 5% over 24 hours, determined using an adaptive Bayesian design differ among neonates. Both gestational and postnatal ages account for these differences but their differential impact on omeprazole doses remains to be determined.
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Pediatric Pharmacology and Pharmacogenetics and INSERM CIC1426, Hôpital Robert Debré, Paris, France.|Univ Paris 7-Diderot, Sorbonne Paris Cité, ED 563-EA7323, Paris, France.
authors.forename: Florentia
authors.initials: F
authors.lastname: Kaguelidou
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Clinical Epidemiology and INSERM CIC1426 Hôpital Robert Debré, Paris, France.|Univ Paris 7-Diderot, Sorbonne Paris Cité, France UMR-S 1123 and ECEVE, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Alberti
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Neonatology Hôpital Robert Debré, Paris, France.|Univ Paris 7-Diderot, Sorbonne Paris Cité, France UMR-S 1123, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Biran
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Pharmacy Hôpital Robert Debré, Paris, France.|Univ Paris 5-Descartes and Univ Paris 13 Sorbonne Paris Cité Laboratoire Educations et Pratiques de Santé, EA 3412, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bourdon
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Neonatology Hôpital Robert Debré, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Farnoux
authors.affiliation: Univ Paris 6 - Pierre et Marie Curie, Paris, France.|INSERM, Paris France U1138 Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Zohar
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Pediatric Pharmacology and Pharmacogenetics and INSERM CIC1426, Hôpital Robert Debré, Paris, France.|Univ Paris 7-Diderot, Sorbonne Paris Cité, ED 563-EA7323, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000284:Administration, Oral; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D004305:Dose-Response Relationship, Drug; D050782:Esophageal pH Monitoring; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D005865:Gestational Age; D006785:Hospitals, University; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D007902:Length of Stay; D008297:Male; D009853:Omeprazole / Q000627:therapeutic use*; D014839:Vomiting / Q000209:etiology
chemical_list: D000897:Anti-Ulcer Agents; D009853:Omeprazole