ORIGINALLY APPEARED IN JPGN 2008;46:524.

ORIGINAL ARTICLE: GASTROENTEROLOGY

Safety and Tolerability of Esomeprazole in Children With Gastroesophageal Reflux Disease 

Mark A. Gilger, yVasundhara Tolia, zYvan Vandenplas, §Nader N. Youssef, jjBarry Traxler, and jjMarta Illueca

ABSTRACT Objectives: To evaluate safety, tolerability, and symptom improvement with once-daily esomeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). Patients and Methods: In this 8-week, multicenter, randomized, uncontrolled, double-blind study, children ages 1 to 11 years were stratified by weight to receive esomeprazole 5 or 10 mg (children < 20 kg) or 10 or 20 mg (children  20 kg) once daily. Safety and tolerability was assessed by evaluating adverse events (AEs; both treatment- and non-treatment-related AEs) and changes from baseline in medical history, physical examinations, and clinical laboratory tests. Investigators scored symptom severity every 2 weeks using the Physician’s Global Assessment (PGA). Patients’ parents rated GERD symptoms of heartburn, acid regurgitation, and epigastric pain (none to severe, 0–3) at baseline (based on past 72 hours) and daily (from past 24 hours). Results: Of 109 patients randomized, 108 had safety data. AEs were experienced by 68.0% and 65.2% of children < 20 kg receiving esomeprazole 5 and 10 mg, respectively, and 83.9% and 82.8% of children  20 kg receiving esomeprazole 10 and 20 mg, respectively, regardless of causality. Overall, only 9.3% of patients reported 13 treatment-related AEs; the most common were diarrhea (2.8% [3/108]), headache (1.9% [2/108]), and somnolence (1.9% [2/108]). Vomiting, a serious AE in 2 patients, was not judged by the investigator to be related to treatment. At the final visit, PGA scores improved significantly from baseline (P < 0.001). Of 58 patients with moderate to severe baseline PGA symptom scores, 91.4% had lower scores by the final visit. GERD symptom scores were significantly improved from baseline to the final week of the study in all of the treatment groups (P < 0.01) Conclusions: In children ages 1 to 11 years with endoscopically proven GERD, esomeprazole (at daily doses of 5, 10, or 20 mg) was generally well Received August 27, 2007; accepted March 24, 2008. From the Baylor College of Medicine, Houston, TX, the yWayne State University, Detroit, MI, the zVrije Universiteit Brussels, Brussels, Belgium, the §Goryeb Children’s Hospital at Atlantic Health, Morristown, NJ, and jjAstraZeneca LP, Wilmington, DE. Address correspondence and reprint requests to Mark A. Gilger, MD, Texas Children’s Hospital, Clinical Care Center, Suite 10.10, 6621 Fannin St, Houston, TX 77030-2399 (e-mail: [email protected]). Dr Tolia’s current affiliation is Providence Hospital, Southfield, MI. The study was supported by AstraZeneca LP, Wilmington, DE. Medical writing services provided by Scientific Connexions, Newtown, PA, funded by AstraZeneca LP. M.A.G. is a speaker for and consultant to TAP and AstraZeneca LP, a speaker for Nestle, and a recipient of NIH support (1-R03-DK068148–01). V.T. and N.N.Y. receive grant/research support from AstraZeneca LP, Y.V. is a speaker for Johnson & Johnson, AstraZeneca LP, Wyeth, Nestle, Numico, United Pharmaceuticals, Biocodex, and others. B.T. and M.I. are employees of AstraZeneca LP. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0b013e318176b2cb

tolerated. The frequency and severity of GERD-related symptoms were significantly reduced during the active treatment period. Key Words: esomeprazole, gastroesophageal reflux disease, proton pump inhibitor, safety

(JPGN 2015: S16–S23)

T

he prevalence of gastroesophageal reflux disease (GERD) in the pediatric population is becoming increasingly recognized and documented (1,2). Although symptoms of GERD in older children resemble those seen in adults (eg, heartburn, regurgitation, dysphagia), intermittent vomiting may be the only symptom of GERD in younger children (2). Results of a survey completed by 566 parents of healthy children ages 3 to 9 years revealed that the classic symptoms of GERD reported in adults (ie, heartburn, epigastric pain, and regurgitation) were not rare, reported by 1.8%, 7.2%, and 2.3% of children, respectively, in the previous week (3). Study findings suggest that pediatric GERD is a chronic disease (4–6). Recently, the importance of studying histological improvement has been highlighted by the findings of a study in which infants ages 2.8 to 6.0 months who had biopsy-confirmed esophagitis thought to be GERD-related and did not receive pharmacological therapy continued to have abnormal biopsy results after 12 months despite symptom improvement (4). Moreover, pediatric GERD can persist through adolescence and adulthood in a large proportion of patients who continue to have GERD symptoms and use antisecretory agents (5). In addition, adults with GERD were more likely than those without GERD to recall having symptoms of GERD during childhood (6). Children who have GERD are more likely than those who do not to experience sinusitis, laryngitis, asthma, pneumonia, and bronchitis (7). At present, proton pump inhibitors (PPIs) are the treatment of choice for GERD in adult patients (8) and are increasingly recommended as first-line therapy in pediatric patients ages 1 to 17 years (2). Treatment with esomeprazole has been shown to be effective for healing erosive esophagitis and resolving symptoms of GERD in adults (9–12). Recently, esomeprazole was reported to be well tolerated for the treatment for GERD in adolescents (13) and was approved in the United States for this use in 12- to 17-year-old adolescents. The pharmacokinetic profile of esomeprazole in children ages 1 to 11 years has been reported (14); however, no studies to date have been conducted to assess the safety and tolerability of esomeprazole in children in this age group. The primary aim of the present study was to evaluate the safety and tolerability of oncedaily esomeprazole for the treatment of endoscopically proven GERD in a pediatric population ages 1 to 11 years inclusive. A secondary aim was to evaluate clinical outcome by measuring symptom severity throughout the active treatment period.

S16 JPGN  July 2015 Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

JPGN



July 2015

PATIENTS AND METHODS Study Design and Patients Institutional review boards from all of the participating sites approved the protocol for this international, multicenter, randomized, parallel-group, double-blind, 8-week study (AstraZeneca LP study code, D9614C00097; www.clinicaltrials.gov identifier NCT00228 527). Before any study-specific procedure was performed, each patient’s parent or guardian provided written, informed consent, and patient assent was obtained when age appropriate (typically from patients ages  6 years). The study procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki and its amendments and with the International Conference on Harmonization Good Clinical Practice guidelines. Within 21 days of the screening visit, patients with endoscopically proven GERD were stratified to receive treatment in a double-blind fashion based on their weight at screening. Patients weighing 8 to

Safety and Tolerability of Esomeprazole in Children With Gastroesophageal Reflux Disease.

To evaluate safety, tolerability, and symptom improvement with once-daily esomeprazole in children with endoscopically proven gastroesophageal reflux ...
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