Omeprazole for Treatment of Term and preterm infants with gastro-oEsophageal Reflux (OTTER)

Research question: In preterm (<37 weeks gestation) and term-born (=37 weeks gestation) infants under 6 months of age clinically diagnosed with gastro-oesophageal reflux (Population), does pharmacological treatment with omeprazole for 4 weeks (Intervention) compared to placebo (Comparator) improve symptoms and severity of gastro-oesophageal reflux? (Outcome).

Background: NIHR HTA commissioning brief 23/100 requests proposals for evaluation of pharmacological therapies for the management of gastro-oesophageal reflux (GOR) in infants who have ongoing symptoms despite treatment with first line measures such as alginates or feed thickener. NICE guidance for GOR management in children recommends only considering pharmacological treatment if these first line treatments have been unsuccessful and GOR problematic.

The commonest pharmacological agents used in this situation are proton pump inhibitor drugs such as omeprazole. To date there is no robust evidence that proton pump inhibitors are effective or safe in infant GOR management, a recent Cochrane review concluded further studies are needed. Furthermore, the stomach acid reduction caused by these medicines has been associated with increased respiratory and gastrointestinal infections, impaired vitamin and mineral absorption and increased fracture risk.

Our study will focus on 2 patient groups identified to be of interest in the commissioning brief (preterm infants and term-born infants) and where GOR is most prevalent. Aims and objectives

1. To conduct a basket trial in two populations (preterm and term-born infants) to assess the clinical effectiveness of omeprazole compared to matched placebo, for treating symptomatic GOR

2. To monitor safety of omeprazole treatment, including infections, fractures and growth, up to 6 months after trial entry

3. To conduct a qualitative process evaluation of parental and healthcare professional experiences of the trial and medication use 4. To assess the cost-effectiveness of omeprazole use for symptomatic GOR

Methods: Randomised, multicentre, placebo-controlled, basket superiority trial in two patient populations: preterm-born infants (Population 1) and term-born infants (Population 2) with internal pilot, economic and process evaluations. Parents and healthcare professionals will be blinded to treatment allocation. Infants up to 6 months corrected gestational age (i.e. 6 months after their due date) and who have ongoing GOR symptoms despite first line measures, will be recruited from both primary and secondary care (hospital sites with in- and outpatient settings, including neonatal units).

Outcomes: The primary outcome is parent reported GOR symptom score at 4 weeks measured by validated questionnaire (I-GERQ-R). Secondary outcomes include growth, infections and fractures up to 6 months.

Timelines for delivery: Total 41 months. 1–9 set-up, 10–27 recruitment, 18 internal pilot stop-go decision, 35 end of follow-up and data cleaning, 35–41 data analyses and reporting.

Anticipated impact: OTTER will generate new knowledge on the efficacy, safety and cost effectiveness of omeprazole in term and preterm infant GOR management, informing revisions of NICE guidance on GOR.

Dissemination: Findings will be disseminated via published monograph, research papers in high-impact journals and conference presentations, and will be made available to study participants and the public via PPI partners, plain English summaries, infographics, animations and videos.