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."

Study Overview

• Status: Completed
• Conditions: Gastroesophageal Reflux Disease (GERD)
• Intervention / Treatment: Drug: Omeprazole

Detailed Description

"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."

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75019
    • Hospital Robert Debre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: neonates of less than 32 weeks gestational age; omeprazole	Drug: Omeprazole; administration of Omeprazole; Other Names: administration of Omeprazole
Experimental: neonates born between 32 and 35 weeks of GA; omeprazole	Drug: Omeprazole; administration of Omeprazole; Other Names: administration of Omeprazole
Experimental: neonates of more than 36 weeks of GA; omeprazole	Drug: Omeprazole; administration of Omeprazole; Other Names: administration of Omeprazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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%	72±24 hours after initiation of omeprazole treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean number of reflux episodes per hour	mean number of reflux episodes per hour	72±24 hours after initiation of omeprazole treatment
duration of the longest reflux episode	duration of the longest reflux episode	72±24 hours after initiation of omeprazole treatment
plasma concentrations of omeprazole and its metabolite, hydroxyl-omeprazole	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	H0.5 and H4 or between H4 and H12 after the first administration of omeprazole
changes in salivary pH monitoring	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	just before and 3 hours after a meal Under treatment period
changes in biological parameters	changes in biological parameters	96±24 hours after initiation of omeprazole treatment

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Evelyne Jacqz-Aigrain, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: August 2, 2012
• First Submitted That Met QC Criteria: August 3, 2012
• First Posted (Estimate): August 6, 2012

Study Record Updates

• Last Update Posted (Estimate): October 11, 2012
• Last Update Submitted That Met QC Criteria: October 10, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: neonates; reflux disease; population pharmacokinetics, omeprazole
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastroesophageal Reflux; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole
• Other Study ID Numbers: P 051043; 2006-005335-16 (EudraCT Number)