ORIGINAL ARTICLE:GASTROENTEROLOGY Maintenance of Efficacy and Safety of Rabeprazole in Children With Endoscopically Proven GERD ÃIbrahim Haddad, yJaroslaw Kierkus, zEduardo Tron, §April Ulmer, jjPeter Hu, jjSteven Silber, jjSheldon Sloan, and jjGerhard J. Leitz ABSTRACT Objective: The aim of the present study was to evaluate 24-week main- abeprazole sodium is a substituted benzimidazole molecule þ þ tenance of efficacy and safety of rabeprazole in children with endoscopically R that inhibits H /K ATPase, the proton pump responsible for proven gastroesophageal reflux disease (GERD). the terminal step in gastric acid secretion (1) and is presently Methods: Children ages 1 to 11 years who achieved endoscopic/histologic marketed globally as enteric coated 10- and 20-mg rabeprazole healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or sodium tablets for acute as well as maintenance treatment of adults grade 0 of the Histological Features of Reflux Esophagitis scale) in a with erosive and nonerosive gastroesophageal reflux disease 12-week treatment phase were continued on the same dose for an (GERD), healing of duodenal ulcers, and eradication of Helico- additional 24 weeks during the maintenance phase. The dose was bacter pylori and Zollinger-Ellison syndrome (2,3). Rabeprazole determined by weight: children weighing 6 to 14.9 kg (low-weight is approved in the United States for the short-term treatment of acid- cohort) received 5 or 10 mg and children weighing 15 kg (high-weight related disorders, including GERD, in adolescents. It has been cohort) received 10 or 20 mg. shown to be effective in double-blind, placebo-controlled trials Results: Healing was maintained in 90% of children (100% [low-weight in adults with acid-related GERD, H pylori infection, and peptic cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight ulcer disease (2). It also has been shown to be effective in cohort]). The Total GERD Symptom and Severity score continued to adolescents (12–16 years of age) with GERD. The efficacy charac- improve slightly in all of the children across all dose groups (P ¼ 0.026) teristics and adverse event (AE) profile in adolescents were found during the maintenance phase, except the 10-mg dose group (low-weight to be similar to those reported for adults. There are no data, cohort), which experienced a slight worsening of 3.6 points. Overall, 71% however, from prospectively designed trials in children with GERD children felt better on the GERD Symptom Relief score (P < 0.001); 95% of <12 years. investigators and 92% of parent/caregivers rated ‘‘Good to Excellent’’ on The present study explored the number and percentage of the Global Treatment Satisfaction scale and Clinical Global Impressions children (1–11 years) who had achieved endoscopic/histologic Improvement scale, respectively. Overall incidence of treatment-emergent healing during a preceding 12-week treatment phase and main- adverse events was 63%; upper respiratory tract infections (13%) and tained healing during this 24-week maintenance phase. The safety vomiting (11%) were the most commonly reported (>10%). and efficacy results of the 12-week treatment study are under Conclusions: Rabeprazole was effective in maintaining endoscopic/ publication (4). histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups. METHODS Key Words: endoscopic, gastroesophageal reflux disease, pediatric, Study Design rabeprazole Children 1 to 11 years of age who achieved healing (grade 0 on the Hetzel-Dent Classification and/or grade 0 on the Histological (JPGN 2014;58: 510–517) Features of Reflux Esophagitis scale) by the end of a 12-week, double-blind, treatment phase were offered to continue double- blind treatment at the same dose regimen for an additional 24 weeks, Received January 15, 2013; accepted October 22, 2013. Ã which was either rabeprazole sodium 0.5 or 1.0 mg/kg. The dose From Pediatric & Adolescent Gastroenterology & Nutrition, Youngstown, was further determined by weight: children weighing 6 to 14.9 kg OH, yChildren’s Memorial Health Institute, Warsaw, Poland, zGeisinger Medical Center Clinic, Wilkes-Barre, PA, §Gastrointestinal Associates, (low-weight cohort) received 5 or 10 mg and children weighing Jackson, MS, and jjJanssen Research & Development, LLC, Raritan, NJ. 15 kg (high-weight cohort) received 10 or 20 mg. Address correspondence and reprint requests to Ibrahim Haddad, MD, Before entering the 12-week treatment phase of the study, all Pediatric & Adolescent Gastroenterology & Nutrition, 8560 South of the children were screened for diagnosis of GERD through Avenue, #3, Youngstown, OH 44514 (e-mail: [email protected]). medical history, evaluation of symptoms, and confirmation by www.clinicaltrials.gov registration number: NCT00787891. endoscopy/histology (biopsy). A physical examination was con- The present study is supported by funding from Janssen Research & ducted, medical records were reviewed, and relevant medical Development, LLC (previously known as Johnson & Johnson Pharma- history/current medical conditions were recorded on the appropriate ceutical Research & Development, LLC) and Eisai Medical Research study record form. Children of both sexes, ages 1 to 11 years, were Inc. The sponsors also provided a formal review of this article. G.L., P.H., S.S., and S.S. are employees of Janssen Research & Develop- required to have endoscopically proven GERD (defined as grade ment, LLC. The other authors report no conflicts of interest. 1 on the Hetzel-Dent Classification scale and grade >0 on the Copyright # 2014 by European Society for Pediatric Gastroenterology, Histological Features of Reflux Esophagitis scale) and a history of Hepatology, and Nutrition and North American Society for Pediatric at least 1 GERD symptom (heartburn, dysphagia, belching/burping, Gastroenterology, Hepatology, and Nutrition regurgitation, vomiting, hoarseness, coughing, choking, fullness DOI: 10.1097/MPG.0000000000000229 during eating, anorexia, nausea, abdominal pain) occurring at least 510 JPGN Volume 58, Number 4, April 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited. JPGN Volume 58, Number 4, April 2014 Efficacy and Safety of Rabeprazole in Pediatric Patients With GERD 1 to 2 times daily within 3 months before screening. On average, Efficacy and Safety Assessments children had 4 to 5 GERD symptoms at entry. The most prevalent symptom was belching (69%) followed by abdominal pain (68%), The primary efficacy endpoint assessed the number and coughing (62%), fullness while eating (56%), regurgitation percentage of children who had achieved endoscopic/histologic (55%), nausea (42%), heartburn (41%), hoarseness (31%), vomiting healing by the end of the 12-week treatment period and main- (29%), anorexia (27%), dysphagia (23%), and choking (16%). The tained healing during this 24-week maintenance phase. Healing study excluded children with a history of endoscopic findings of was defined as grade 0 on the Hetzel-Dent Classification scale (6), eosinophilic esophagitis, persistent milk protein allergy, allergic and/or grade 0 on the Histological Features of Reflux Esophagitis gastroenteropathy, tracheoesophageal fistula status postrepair, scale (7). Secondary efficacy endpoints included change from the mental retardation, cerebral palsy, and infection with H pylori. end of the treatment phase (week 12) to the end of maintenance The use of sucralfate, domperidone, or any medication that affects phase (week 36) in Total GERD Symptom and Severity, GERD gastrointestinal (GI) motility (caffeine, baclofen, erythromycin, and Symptom Relief, Global Treatment Satisfaction, and CGI-I metoclopramide) as well as digoxin, digitalis preparations, keto- scores. conazole, and theophylline were prohibited from 3 days before The Total GERD Symptom and Severity score assessed randomization in the 12-week treatment phase and throughout the severity and frequency of 12 predefined GERD symptoms, the 24-week maintenance phase. To enter the 24-week maintenance including heartburn, dysphagia, belching/burping, regurgitation, phase of the study, children were required to have achieved healing vomiting, hoarseness, coughing, choking, fullness during eating, (grade 0 on the Hetzel-Dent Classification and/or grade 0 on the anorexia, nausea, and abdominal pain. For each symptom, the Histological Features of Reflux Esophagitis scale) by the end of the frequency (0 ¼ never; 1 ¼ 1–2 times; 2 ¼ 3–4 times; 3 ¼ 5–6 times; preceding 12-week treatment phase. 4 ¼ 7 or more times) and severity (1 ¼ mild; 2 ¼ moderate; The efficacy parameters evaluated at the end of the 12-week 3 ¼ severe) were determined. For each individual symptom, the treatment phase (baseline for the maintenance phase) and at the end score is defined as the sum of the frequency and severity of that of the 24-week maintenance phase (week 36) included esophago- symptom (maximum attainable individual score ¼ 7). The total gastroduodenoscopy (EGD) with histology, Total GERD Symptom score is defined as the sum of the scores of all of the symptoms and Severity score, GERD Symptom Relief score, Global Treatment (maximum attainable total score ¼ 84) (8). Higher observed scores Satisfaction score, and parent/caregiver-rated Clinical Global indicate more serious conditions (8). Impressions Improvement (CGI-I) score. The child’s Overall GERD Symptom Relief was graded as The