Efficacy and Safety of Once-Daily Esomeprazole for the Treatment of Gastroesophageal Reflux Disease in Neonatal Patients Geoffrey Davidson, MBBS, MD 1,2 , Tobias G. Wenzl, MD, PhD 3 , Michael Thomson, MB ChB, MD 4 , Taher Omari, PhD 1,2 , Peter Barker, PhD 5 , Per Lundborg, MD, PhD 6 , and Marta Illueca, MD 5 Objective To evaluate the efficacy and safety of proton pump inhibitors in infants aged <1 year with gastroesoph- ageal reflux disease (GERD). Study design In this randomized, double-blind, placebo-controlled multicenter study, neonates (premature to 1 month corrected age; n = 52) with signs and symptoms of GERD received esomeprazole 0.5 mg/kg or placebo once daily for up to 14 days. Change from baseline in the total number of GERD symptoms (from video monitoring) and GERD-related signs (from cardiorespiratory monitoring) was assessed with simultaneous esophageal pH, impedance, cardiorespiratory, and 8-hour video monitoring. Results There were no significant differences between the esomeprazole and placebo groups in the percentage change from baseline in the total number of GERD-related signs and symptoms (14.7% vs 14.1%, respectively). Mean change from baseline in total number of reflux episodes was not significantly different between esomeprazole and placebo (7.43 vs 0.2, respectively); however, the percentage of time pH was <4.0 and the number of acidic reflux episodes >5 minutes in duration was significantly decreased with esomeprazole vs placebo (10.7 vs 2.2 and 5.5 vs 1.0, respectively; P # .0017). The number of patients with adverse events was similar between treatment groups. Conclusions Signs and symptoms of GERD traditionally attributed to acidic reflux in neonates were not significantly altered by esomeprazole treatment. Esomeprazole was well tolerated and reduced esophageal acid exposure and the number of acidic reflux events in neonates. (J Pediatr 2013;163:692-8). See related articles, p 627 and p 699 G astroesophageal reflux (GER) is common in preterm infants, healthy infants, and children. 1 Episodes of reflux can be asymptomatic or manifest as regurgitation or vomiting. 1,2 Uncomplicated GER in pediatric patients does not typically require medical therapy, but may be managed through dietary changes and other lifestyle modifications. 2 However, reflux may evolve into gastroesophageal reflux disease (GERD) and manifest as bothersome symptoms, 2,3 such as recurrent vomiting, regurgitation, back arching, crying, irritability, and food refusal. 1-3 More serious signs and symptoms can include failure to thrive, cardiorespiratory symptoms, esophagitis, apnea, and recurrent pneumonia. 1,2,4 Oral proton pump inhibitors (PPIs), such as esomeprazole, are approved for the treatment of GERD in children aged 1-17 years. 1,5,6 Esomeprazole is a PPI approved for treatment of GERD with esophagitis due to acid reflux in infants from 1 month to 11 months of age. However, PPIs often are prescribed off-label to treat non-specific symptoms in infants. 7 A systematic review suggested that PPIs are not effective in reducing these symptoms 8 ; this is either because the symptoms are not caused by GER or, if due to GER, because the symptoms are caused by volume reflux, rather than acidity. Results from available studies differ greatly in terms of study design, treatment regimens, and diagnostic criteria, and most outcomes are subjectively based on pa- rental questionnaires. 9 Studies that measure both reflux episodes and symptoms using less subjective methods are limited. In the present study, we used novel simultaneous and integrated pH/impedance, and cardiorespiratory and video monitoring to investigate the efficacy and safety of the PPI esomeprazole in preterm and full- term neonates. The use of combined pH/impedance monitoring allows evalua- tion of the effect of acid suppression therapy on all types of reflux (including acidic [pH < 4.0], weakly acidic [pH 4.0-6.9], and nonacidic [pH $ 7.0]), and From the 1 Women’s and Children’s Hospital, Children, Youth and Women’s Health Service, North Adelaide, Australia; 2 School of Pediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia; 3 Clinic for Child and Adolescent Medicine, University Hospital RWTH, Aachen, Germany; 4 Sheffield Children’s Hospital, Sheffield, United Kingdom; 5 AstraZeneca LP, Wilmington, DE; and 6 Formerly with AstraZeneca R&D, M€ olndal, Sweden Funding and conflict of interest information is available at www.jpeds.com (Appendix). Registered with ClinicalTrials.gov: NCT00427635 (As- traZeneca Study code: D9614C00004). 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.05.007 AE Adverse event GER Gastroesophageal reflux GERD Gastroesophageal reflux disease LSM Least square mean ITT Intent-to-treat PPI Proton pump inhibitor SAE Serious adverse event 692