Maintenance of Efficacy and Safety of Rabeprazole in Children with Endoscopically Proven GERD

ORIGINAL ARTICLE:GASTROENTEROLOGY

Maintenance of Efficacy and Safety of Rabeprazole in Children With Endoscopically Proven GERD

Ibrahim 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. 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 study protocol was approved by the independent ethics 1 (better), 0 (no change), and 1 (worse). The Global Treatment committee or institutional review board and the study was con- Satisfaction scores (9) and CGI-I score (10) were assessed on a ducted in accordance with the ethical principles originating in the 4-point scale ranging from 0 (poor) to 3 (excellent). Declaration of Helsinki and in accordance with the International Safety assessments included the monitoring of AEs, clinical Conference on Harmonisation Good Clinical Practice guidelines, laboratory testing, vital signs, and physical examination. AEs were applicable regulatory requirements, and in compliance with the classified into standardized medical terminology from the verbatim protocol. Parents or legally accepted representatives of children description (investigator term) according to the Medical Dictionary provided written informed consent before participation in the study. for Regulatory Activities Coding Dictionary, version 12.0. In Assent was also obtained from children 7 years old who were addition, an independent Data Safety Monitoring Committee capable of understanding the study. reviewed AEs on an ongoing basis.

Statistical Analysis Treatment Medication The 95% confidence interval was provided for healing rates The selected doses were considered to be therapeutically at the end of the 24-week maintenance phase. Secondary efficacy effective and safe, and the highest dose used did not exceed the endpoints were summarized by dose. The Overall GERD Symptom maximum labeled adult dose (20-mg dose). Dose selection was based Relief score and changes in the Hetzel-Dent Classification scale on earlier studies that demonstrated that the known target range for were analyzed with the Cochran-Mantel-Haenszel test stratified by plasma level of exposure (area under the curve [AUC]) of rabeprazole age group. Safety data were summarized. for therapeutic acid suppression in adults and adolescents treated with 1 Efficacy analyses were conducted in the intent-to-treat (ITT) 10- and 20-mg rabeprazole was 400 to 800 ng h L , and pharma- population, which included all of the randomized children who had cokinetic modeling derived from preliminary pharmacokinetic at least 1 postbaseline efficacy assessment in the maintenance studies in 1- to 11-year-old children with GERD, which showed that phase. The safety assessments were conducted in the safety popu- once-daily administration of 0.5- and 1-mg/kg rabeprazole produced lation, which included all of the randomized children who received plasma AUC1 values that were comparable to those observed in at least 1 dose of maintenance phase study drug. Computations for adults receiving 10- and 20-mg rabeprazole, respectively (5). A small all of the results were performed using SAS version 9.2 (SAS amount of soft food or infant formula was used as a dosing vehicle to Institute, Cary, NC) administer rabeprazole granules. Everyone, including the investigator, the contract research organization, and in-house study personnel were blinded to the study. RESULTS For adherence to study drug, the investigator or designated study personnel maintained a log of all of the study drugs dispensed Study Participation and returned during the study. Study drug supplies for each child The present study was conducted in 9 countries (United were inventoried and accounted for throughout the study to verify States, Belgium, Denmark, France, Italy, Poland, Israel, South the child’s compliance with the dosage regimen. Study drug was Africa, and India) from January 2009 to January 2011 (including administered by the parent/caregiver and recorded on the appro- the 12-week treatment and the 24-week maintenance phase). Of the priate form. Compliance was defined as administration of >70% of 87 children who achieved healing in the 12-week treatment phase, scheduled pill count. 64 elected to enroll in the maintenance phase and 52 (81%)

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completed assessments for the primary endpoint (EGD with Hetzel-Dent and histology scores were available for histology) and were included in the ITT analysis (Fig. 1). Overall, 61 children at baseline and 52 at the end of the maintenance phase. 29% children received proton pump inhibitor (PPI) treatment, 22% Overall, 93% of children had grade 0 and 7% had grade 1 on the received antacids, 15% used H2-blockers, and 2% were taking Hetzel-Dent Classification scale at entry into the maintenance prokinetics before entering the study. None of the children under- study. Of the 52 children who had baseline and end-of-study went dietary therapy. Hetzel-Dent scores, 83% maintained grade 0, 2% had an improve- The mean age of children was 6 years and the majority (80%) ment by 1, and 15% had a decline by 1. Of these 15% (8 patients) were white (Table 1). The median duration of exposure to rabe- who did not show mucosal healing, 3 were noncompliant with prazole was 168 days (range 38–189 days) and was similar across therapy during the maintenance phase; they took only 33%, 50%, the 4 dose groups. and 61% of the scheduled pill count. For the remaining 3 cases, no obvious reason was identified. All of the children in the low-weight cohort maintained grade 0, whereas in the high-weight cohort, only Primary Efﬁcacy (Endoscopic/Histologic 78% (10 mg) and 75% (20 mg) remained at grade 0 (Table 2). Healing) In comparison, 50% of children had grade 0, 19% grade 1, 14% grade 2, 15% grade 3, and 2% grade 4 on the Histological Sixty-four children who achieved healing (grade 0 on the Features of Reflux Esophagitis scale at entry into the maintenance Hetzel-Dent Classification and/or grade 0 on the Histological study. Of the 52 children who had baseline and end-of-study Features of Reflux Esophagitis scale) during the preceding 12-week histology scores, 27% showed an improvement of 1 grade, treatment study entered this 24-week maintenance study. Of the 48% no change, and 25% a decline of 1 grade at the end of 64 children, 52 completed both EGD and histology assessments. the maintenance study (P ¼ 0.925) (Table 2). The overall healing rate at the end of the maintenance study was 90% (47 of 52). There was no significant difference in the rate of Secondary Efﬁcacy healing between the 2 target dose groups, but all of the children (100%) in the low-weight cohort showed healing compared with The Total GERD Symptom and Severity score continued to only 89% (10 mg) and 85% (20 mg) children in the high-weight improve slightly during the maintenance phase with a significant cohort (Table 2). decrease in the overall score from 7.6 points (baseline) to 5.4 points

21-day screening period N = 237 Withdrawn n = 19

Randomization N = 127 - Adverse event n = 3 - Lost to follow-up n = 4 - Protocol violation n = 1 - Withdrew consent n = 8 12-week treatment phase* n = 108 - Other n = 2 Withdrawn n = 23 - Physicians’ decision n = 1

- Low improvement in symptom scores n = 23 24-week maintenance phase n = 64

Low-weight cohort High-weight cohort 6–14.9 kg body weight (n = 17) ≥ 15 kg body weight (n = 47)

Low dose High dose Low dose High dose 5 mg (0.5 mg/kg target 10 mg (1.0 mg/kg 10 mg (0.5 mg/kg target 20 mg (1.0 mg/kg target dose) n = 9 target dose) n = 8 dose) n = 24 dose) n = 23

Withdrawn n = 1 Withdrawn n = 2 Withdrawn n = 6 Withdrawn n = 5

- Other n = 1 - Withdrew - Noncompliance with - Adverse event n = 1 consent n = 2 study drug n = 1 - Noncompliance with - Withdrew consent n = 1 study drug n = 1 - Other n = 4 - Withdrew consent n = 1 - Other n = 2

Completed Completed Completed Completed n = 8 n = 6 n = 18 n = 18

FIGURE 1. Patient disposition.

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TABLE 1. Demographics and baseline characteristics (children entering 24-week maintenance phase)

Rabeprazole treatment

Low-weight cohort High-weight cohort

5mg10mg10mg20mg Total Parameter (n ¼ 9) (n ¼ 8) (n ¼ 24) (n ¼ 23) (N ¼ 64)

Age group, n (%) 1–5, y 9 (100) 8 (100) 9 (38) 6 (26) 32 (50) 6–11, y 0 0 15 (63) 17 (74) 32 (50) Age, y Mean (SD) 2.4 (1.24) 1.5 (0.53) 7.7 (2.74) 7.2 (2.66) 6.0 (3.38) Sex, n (%) Boys 4 (44) 4 (50) 16 (67) 13 (57) 37 (58) Race, n (%) White 6 (67) 6 (75) 22 (92) 17 (74) 51 (80) Black or African American 0 1 (13) 1 (4) 4 (17) 6 (9) Asian 2 (22) 1 (13) 0 0 3 (5) Other 1 (11) 0 1 (4) 2 (9) 4 (6) Weight, kg Mean (SD) 12.4 (1.9) 11.5 (2.3) 32.7 (15.2) 28.5 (11.8) 26.8 (15.5) BMI, kg/m2 Mean (SD) 14.0 (2.11) 14.8 (1.65) 19.0(4.86) 18.3 (3.43) 17.5 (4.17)

BMI ¼ body mass index; n ¼ size of subsample; N ¼ total sample size; SD ¼ standard deviation. Other races included mixed race, Mexican, North African, white, and so on.

(end of maintenance phase) (P ¼ 0.026; paired t test). All of the mild, 15 (23%) moderate, and 3 (5%) severe. Severe TEAEs treatment groups experienced an improvement (2.6–3.8 points), included lymphadenitis, bronchopneumonia, and partial seizures except for the 10-mg dose group (low-weight cohort), which with secondary generalization. showed a worsening of 3.6 points (Table 3). Five children experienced serious TEAEs during the main- Consistent with the findings in the Total GERD Symptom tenance phase. These included 1 mild head injury (5 mg), 1 moderate and Severity scores, there was a significant (P < 0.001; paired t test) conversion disorder (neurologic/psychiatric disorder) (20-mg difference in the mean Overall GERD Symptom Relief score for all dose), 1 severe bronchopneumonia (10-mg, low-weight cohort), of the children at the end of the maintenance phase. At the end of the 1 severe lymphadenitis (10-mg, low-weight cohort), and 1 partial maintenance phase, the GERD Symptom Relief score indicated that seizure with secondary generalization (10-mg, high-weight cohort). 64% of children felt better, 33% felt no change, and 3% felt worse. All of the 5 serious TEAEs were considered not related to the study Few patients from the 10-mg dose group (low-weight cohort) felt drug. One child in the 20-mg dose group discontinued the main- better (Table 3). The Global Treatment Satisfaction assessments tenance phase because of a nonserious TEAE of dyspepsia. There showed 32 of 61 children (52%) with ‘‘Excellent,’’ 26 (43%) were no deaths. There were no trends or clinically relevant changes ‘‘Good,’’ and 3 (5%) ‘‘Fair’’ scores at the end of the maintenance in mean clinical laboratory or vital sign data during the maintenance phase. phase. Overall, 56 (92%) of 61 children had their parent/caregiver- rated CGI-I scores as ‘‘Good’’ to ‘‘Excellent,’’ 4 (6%) had ‘‘Fair,’’ and 1 (2%) had ‘‘Poor’’ at the end of the maintenance phase. Similar DISCUSSION to the Total GERD Symptom and Severity and the GERD Symptom A total of 64 children (32 each in 1–5 years old age group Relief scores, the 10-mg dose group (low-weight cohort) had a and 6–11 years old age group) received double-blind, daily target slightly lower impression of improvement compared with other doses of 0.5 or 1.0 mg/kg for 24 weeks. The dose was further dose groups (Table 3). determined by weight: children weighing 6 to 14.9 kg received 5 or 10 mg/day and children weighing 15 kg received 10 or 20 mg/day. The doses were the same as given in the 12-week treatment phase. Safety All of the children in this study underwent 3 EGDs with histology: at baseline, end of the treatment phase (week 12), and end of the Overall, 40 of 64 (63%) children experienced 1 treatment- maintenance phase (week 36). The safety and efficacy results of the emergent adverse event (TEAE), with upper respiratory tract 12-week treatment phase are presented elsewhere (4). infection (13%), vomiting (11%), abdominal pain (8%), and diar- The extent of macroscopic/histologic healing achieved rhea (6%) being the most commonly reported (5% children). The during the 12-week treatment phase was maintained in 47 (90%) frequency of TEAEs was higher in the high-weight cohort (Table 4). of the 52 children who were dosed and had at least 1 postbaseline Of the 40 children who reported a TEAE, only 2 (5%) children in the endoscopy/histology assessment (ITT population). The frequency low-weight cohort experienced a TEAE considered to be related to and severity of GERD symptoms continued to slightly improve study medication (vomiting in one child and acidosis with increased during the maintenance phase compared with those in the treatment b-2 microglobulin in another child). A total of 22 (34%) children phase. The Total GERD Symptom and Severity score showed a experienced TEAEs that were considered by the investigator to be mean overall improvement of 10.0 points during the treatment

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TABLE 2. Endoscopic/histologic healing rates during the double-blind maintenance phase and change from baseline to week 36 in the Hetzel- Dent Endoscopic Classiﬁcation scale scores and Histological Features of Reﬂux Esophagitis scale scores during the double-blind maintenance phase (ITT population)

Rabeprazole treatment

Low-weight cohort High-weight cohort

5mg 10mg 10mg 20mg Total

Endoscopic/histologic healing Wk 36, n (%) 8 (100) 6 (100) 16 (89) 17 (85) 47 (90) Hetzel-Dent Endoscopic Classiﬁcation scale scores Baseline, n 8 7 24 22 61 Mean (SD) 0.0 (0.0) 0.0 (0.0) 0.0 (0.20) 0.1 (0.35) 0.1 (0.25) Wk 36, n 8 6 18 20 52 Change from baseline to wk 36 Mean (SD) 0.0 (0.0) 0.0 (0.0) 0.3 (0.57) 0.2 (0.62) 0.2 (0.51) Category, n (%) 4 0000 0 3 0000 0 2 0000 0 1 0 0 0 1 (5) 1(2) 0 8 (100) 6 (100) 14 (78) 15 (75) 43 (83) 1 0 0 3 (17) 3 (15) 6 (11) 2 0 0 1 (6) 1 (5) 2 (4) 3 0000 0 4 0000 0 Histologic features of Reﬂux Esophagitis Scale Scores Baseline, n 8 7 24 22 61 Mean (SD) 1.0 (1.2) 0.9 (1.07) 1.1 (1.18) 0.9 (1.25) 1.0 (1.17) Wk 36, n 8 6 18 20 52 Change from baseline to wk 36 Mean (SD) 0.0 (1.85) 0.2 (1.94) 0.1 (1.35) 0.1 (1.36) 0.0 (1.46) Change from baseline, n (%) 5 0000 0 4 0000 0 3 1 (13) 1 (17) 1 (6) 1 (5) 4 (8) 2 0 0 1 (6) 2 (10) 3 (6) 1 2 (25) 1 (17) 2 (11) 2 (10) 7 (13) 0 3 (38) 3 (50) 9 (50) 10 (50) 25 (48) 1 0 0 3 (17) 3 (15) 6 (12) 2 1 (13) 0 1 (6) 1 (5) 3 (6) 3 1 (13) 1 (17) 1 (6) 1 (5) 4 (8) 4 0000 0 5 0000 0

ITT ¼ intent-to-treat; SD ¼ standard deviation.

phase and 2.2 points during the maintenance phase. Continued The majority (64%) of children reported an overall GERD clinical symptom improvement was expected because not all Symptom Relief score of ‘‘feel better’’ at the end of the mainten- of the children had complete macroscopic/histologic remission ance phase. Similar maintenance of healing rates and reflux symp- at the beginning of the maintenance phase. The definition of tom improvement have been reported in a prospectively controlled healing (grade 0 on the Hetzel-Dent Classification scale and/or study (7) and 2 open-label (OL) studies (11,12). grade 0 on the Histological Features of Reflux Esophagitis In a randomized controlled prospective study of omeprazole scale) allowed patients entering the maintenance phase with a with a similar design as that of the present study, of the 46 children Hetzel-Dent score or Histological Features of Reflux Esophagitis (ages 2.5–14 years) with erosive esophagitis (Hetzel-Dent grade score of >0. At entrance to the maintenance phase, 7% of 2) who achieved macroscopic healing of erosive esophagitis children still had grade 1 on the Hetzel-Dent scale and 49% (Hetzel-Dent grade 0 or 1) during the 3-month treatment phase, had a score of >0 on the Histological Features of Reflux only 1 (2.2%) child had erosive esophagitis relapse and 12 (26.1%) Esophagitis scale. Eight (15%) patients had a decline by had mild symptoms 3 months postmaintenance therapy (6 months) 1 on the Hetzel-Dent scale during the maintenance phase; (13). In another single-arm, OL, prospective study of maintenance 3 of these patients took only 33%, 50%, and 61% of the scheduled therapy with omeprazole in 46 children (ages 1–16 years) with pill count, respectively. For the remaining 5 cases, no obvious erosive esophagitis (Hetzel-Dent grade 2) who achieved endo- reason was identified. scopic healing of erosive esophagitis (Hetzel-Dent grade 0 or 1)

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TABLE 3. Change from baseline to end of maintenance phase in total GERD Symptom and Severity Score, GERD Symptom Relief, and CGI-I Scores (ITT population)

Rabeprazole treatment

Low-weight cohort High-weight cohort

5mg(n¼ 8) 10 mg (n ¼ 7) 10 mg (n ¼ 24) 20 mg (n ¼ 22) Total (N ¼ 61)

GERD Symptom and Severity Score Baseline, mean (SD) 5.0 (4.63) 4.0 (4.12) 7.1 (6.20) 10.1 (8.48) 7.6 (7.00) Wk 36, mean (SD) 1.3 (1.04) 7.6 (9.68) 4.5 (4.35) 7.1 (7.56) 5.4 (6.40) Change from baseline to wk 36 Mean, (SD) 3.8 (4.03) 3.6 (7.68) 2.6 (5.09) 3.0 (9.74) 2.2 (7.45) GERD Symptom Relief Scores at wk 36, n (%) Better 7 (88) 3 (43) 14 (58) 15 (68) 39 (64) No change 1 (13) 3 (43) 10 (42) 6 (27) 20 (33) Worse 0 1 (14) 0 1 (5) 2 (3) CGI-I scores at wk 36, n (%) Poor (very dissatisfied) 0 0 1 (4) 0 1 (2) Fair (dissatisfied) 1 (13) 2 (29) 0 1 (5) 4 (6) Good (satisfied) 4 (50) 3 (43) 11 (46) 8 (36) 26 (42) Excellent (very satisfied) 3 (38) 2 (29) 12 (50) 13 (59) 30 (50)

CGI-I ¼ Clinical Global Impressions Improvement; GERD ¼ gastrointestinal reﬂux disease; ITT ¼ intent-to-treat; n ¼ size of subsample; N ¼ total sample size; SD ¼ standard deviation.

following the 3-month treatment phase, 35 (76.1%) children main- The incidence (63% in maintenance phase vs 76% in treat- tained healing of erosive esophagitis. The slightly lower rate of ment phase) and severity (mild 34% vs 42%; moderate 23% vs 28%; maintenance of healing may be attributed to the specific patient severe 5% vs 6%) of TEAEs were generally lower during the population studied because the majority of children had moderate- 24-week maintenance phase. Headache was reported in 2% of to-severe erosive esophagitis (Hetzel-Dent grade 3 or 4) at baseline children during the maintenance phase compared with 9% inci- of the treatment phase. Twenty-two of the 46 children had GERD- dence reported in the 12-week treatment phase. The low frequency predisposing disorders at baseline, including 15 children with of headache may be because of tachyphylaxis related to long-term cerebral palsy or other neurologic conditions and 7 with repaired treatment. There was no apparent dose-response relation with esophageal atresia (12). It should, however, be noted that, an earlier respect to TEAEs, and no trends or clinically relevant changes study with omeprazole had patients with underlying diseases that in mean clinical laboratory or vital sign data observed in either predispose to GERD such as tracheoesophageal fistula status post- treatment phase or maintenance phase. repair, mental retardation, and cerebral palsy, which was not seen in It has been observed in adults that long-term exposure to our study. PPIs may be associated with an increased risk for osteoporosis- A single-arm, OL, prospective study (11) of PPI maintenance associated bone fracture, as a result of partial malabsorption of therapy in healed erosive esophagitis was conducted in 52 institu- dietary calcium, secondary to gastric acid suppression. Although tionalized, intellectually disabled children ages 4 to 19 years with this concern is not clear in children, it is of particular relevance endoscopically proven erosive esophagitis. At the end of 3-month considering the importance of maintaining healthy calcium homeo- treatment phase, 47 (90%) of 52 patients did not have symptom stasis and bone mineral density during childhood. Other metabolic relapse. disturbances that may be associated with prolonged duration of acid

TABLE 4. Treatment-emergent adverse events occurring in 5% of children in any treatment group during the study (safety analysis set)

Rabeprazole treatment

Low-weight cohort High-weight cohort

5mg(n¼ 9), 10 mg (n ¼ 8), 10 mg (n ¼ 24), 20 mg (n ¼ 23), Total (N ¼ 64), n (%) n (%) n (%) n (%) n (%)

No. children with at least 1 TEAE 4 (44) 4 (50) 15 (63) 17 (74) 40 (63) Abdominal pain 1 (11) 0 2 (8) 2 (9) 5 (8) Diarrhea 0 1 (13) 1 (4) 2 (9) 4 (6) Vomiting 1 (11) 0 3 (13) 3 (13) 7 (11) Pyrexia 0 1 (13) 0 2 (9) 3 (3) Upper respiratory tract infection 1 (11) 0 3 (13) 4 (17) 8 (13) Cough 1 (11) 0 1 (4) 0 2 (3)

TEAE ¼ treatment-emergent adverse event.

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suppressive therapy in adults include vitamin B12 and iron Diego; Argento, Salvatore; De Giacomo, Costantino; Mancini, deficiency, and rare occurrence of hypomagnesemia (14–17), Valentina; Romano, Claudio; Comito, Donatella; Ferrau`, Valeria; all of which are considered to be of increased clinical significance Staiano, Annamaria; Coccorullo, Paola; Miele, Erasmo; Ummarino, in children, especially those with severe reflux esophagitis who Dario. Poland: Cichy, Wojciech; Ignys, Iwona; Klincewicz, Beata; have GERD-predisposing disorders that may also impair their Lisowska, Aleksandra; Walkowiak, Jaroslaw; Hapyn, Ewa; health and growth. Separately, there have been reports linking Buzalska, Barbara; Gaszewska-Ladniak, Hanna; Pawlowska, long-term PPI therapy with an increased risk for certain infections Joanna; Iwanczak, Barbara; Iwanczak, Franciszek; Krzesiek, Elz- such as community-acquired pneumonia, Clostridium difficile bieta; Matusiewicz, Krzysztof; Mowszet, Krystyna; Pytrus, infection, and other enteric infections in adults (18–22). In Tomasz; Kaczmarski, Maciej; Kondej-Muszynska, Katarzyna; children, an increased risk of acute gastroenteritis and com- Matuszewska, Elzbieta; Sidor, Katarzyna; Uscinowicz, Miroslawa; munity-acquired pneumonia was reported after 4 months of Kierkus, Jaroslaw; Dadalski, Maciej; Oracz, Grzegorz; Korczowski, completion of a 2-month PPI regimen (23). In the present study, Bartosz; Bijos, Artur; Jakobiec, Radoslawa; Lewanowicz, Wieslaw; except for an increased incidence of upper respiratory tract Klimza, Malgorzata; Tomecka, Ewa; Obuchowicz, Anna Karolina; infections (13%), there was no evidence of any other AE as seen Kaczmaryk, Agnieszka; Kula-Gradzik, Joanna; Slimok, Marta; in earlier studies. Wasowska-Krolikowska, Krystyna; Gebora-Kowalaks, Beata; A significant limitation of this study is the lack of a placebo Modzelewska-Holynska, Malgorzata; Toporowska-Kowalska, arm; however, there are other studies (24) that indicate that Ewa; South Africa: Mitha, Ismail; Mitha, Haroon Mohammed; extended treatment may not be necessary to maintain healing. Natha, Farahnaz; Wadvalla, Shahid; Schuman, Hester C; Du Preez, Moreover, the design of this study does not allow us to answer Jacomina C F; Mulder, Isak; Steyn, Ca; Van Aswegen, Dina this question, although continued improvement of symptoms and Johanna; Vermeulen, Jan; Brown, Robin Alexander; De Villiers, the high percentage (90%) of children maintaining macroscopic/ Gerrit Stephanus; Wadvalla, Shahid; Mohammed, Haroon. United histologic healing may indicate a benefit. States of America: Bishop, Phyllis; Adcock, Kim; Nowicki, Considering a similar efficacy and safety profile with respect Michael; Parker, Paul; Bornstein, Jeffrey; Figueroa-Colon, Rein- to dose strength and in consideration of the potential increased risks aldo; Mehta, Devendra; Crissinger, Karen; Kowalski, Donna; Madi- for bone fracture and metabolic disturbances such as vitamin B12 son, Betty; Francisco, Mary; Fischer, Francis H; Hunt, Kimberley deficiency and hypomagnesemia, the lowest effective dose is A; Johnson, Anna M; Ley, Joseph A; Miller, Nicole M; Morelock, recommended. There are, however, studies indicating that children Christopher M; Ragsdale, Rhonda; Ray, Lori L; Shone, Dallas N; who are prone to more severe esophagitis such as those with Tipton, Stephanie R; Valente, Maria; Williams, Tara N; Gremse, preexisting esophageal anatomic/motility abnormalities or neuro- David; Haddad, Ibrahim; Jibaly, Rima; Zureikat, George; Melamed, logic or respiratory disorders have the greatest need for long-term Isaac; Driscoll, Lynette; McDonald, Angela; O’Brien, Kevin therapy to maintain healing of reflux esophagitis and symptomatic Patrick; Rosenweig, Jeffrey Neal; Misra, Sudipta; Lukacik, Marek; control. Some of these patients may require a more rigorous Nguyen, Christine; Boushey, Sarah; Quiros, J. Antonio; Ruben, treatment regimen (eg, higher dose, twice daily, longer treatment Elizabeth A; Patterson, Edward; Pfefferkorn, Marian; Corkins, duration). Mark; Croffie, Joseph; Fitzgerald, Joseph; Gupta, Sandeep; Lim, Joel; Subbarao, Girish; Qureshi, Azim; Longenecker, Amy; McMo- nagle, Amyee; Stokes, Jennifer; Sturgis, Sarah; Vallati, Julie; Watts, CONCLUSIONS Heidi; Ramakrishna, Jyoti; Fong, Jay; Shah, Smita; Laney, Donald Rabeprazole granules were effective and safe in maintaining Wayne; McClellan, Randall Douglas; Sullivan, Janice; Condurache, endoscopic/histologic healing and for improvement of symptoms Carmen; Dillard, Robert; Jeffries, Angela M; Morton, Ronald; for 24 weeks in children, 1 to 11 years of age. The clinical effect and Stephen, Thomas; Stutts, John; Tolia, Vasundhara; Tomasovic, safety profile was largely similar across all dose groups. No new Jerry; Ibarguen-Secchia, Joseph; Tron, Eduardo; Focht III, Dean safety findings were observed. R; Maksimak, Martin; Peters, John Murphy; Tung, John; Lopez- Bernard, Edwin; Ulmer, April; Williams, Joe Lynn; Doody, James; Acknowledgments: Shruti Shah, PhD (SIRO Clinpharm Pvt Husk, Cynthia J; Markham, Karen; O’Brien, Kevin P; Rosensweig, Ltd) provided writing assistance and Bradford Challis, PhD Jeffrey Neal. (Janssen Research & Development, LLC) provided additional editorial and scientific support for this article. The authors thank Dr Andrew Mulberg for contributions to the study and for reviewing REFERENCES the article while employed at Janssen. The authors also thank the 1. Pace F, Pallotta S, Casalini S, et al. A review of rabeprazole in the study participants, without whom this study would not have been treatment of acid-related diseases. Ther Clin Risk Manag 2007;3:363– accomplished, as well as the following investigators for their 79. participation in this study: 2. ACIPHEX (rabeprazole sodium) [package insert]. 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