Rabeprazole sodium is a substituted benzimidazole molecule that inhibits H+/K+ ATPase, the proton pump responsible for the terminal step in gastric acid secretion (1) and is presently marketed globally as enteric coated 10- and 20-mg rabeprazole sodium tablets for acute as well as maintenance treatment of adults with erosive and nonerosive gastroesophageal reflux disease (GERD), healing of duodenal ulcers, and eradication of Helicobacter pylori and Zollinger-Ellison syndrome (2,3). Rabeprazole is approved in the United States for the short-term treatment of acid-related disorders, including GERD, in adolescents. It has been shown to be effective in double-blind, placebo-controlled trials in adults with acid-related GERD, H pylori infection, and peptic ulcer disease (2). It also has been shown to be effective in adolescents (12–16 years of age) with GERD. The efficacy characteristics and adverse event (AE) profile in adolescents were found to be similar to those reported for adults. There are no data, however, from prospectively designed trials in children with GERD <12 years.
The present study explored the number and percentage of children (1–11 years) who had achieved endoscopic/histologic healing during a preceding 12-week treatment phase and maintained healing during this 24-week maintenance phase. The safety and efficacy results of the 12-week treatment study are under publication (4).
Children 1 to 11 years of age who achieved healing (grade 0 on the Hetzel-Dent Classification and/or grade 0 on the Histological 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, which was either rabeprazole sodium 0.5 or 1.0 mg/kg. The dose was further determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing ≥15 kg (high-weight cohort) received 10 or 20 mg.
Before entering the 12-week treatment phase of the study, all of the children were screened for diagnosis of GERD through medical history, evaluation of symptoms, and confirmation by endoscopy/histology (biopsy). A physical examination was conducted, medical records were reviewed, and relevant medical history/current medical conditions were recorded on the appropriate study record form. Children of both sexes, ages 1 to 11 years, were required to have endoscopically proven GERD (defined as grade ≥1 on the Hetzel-Dent Classification scale and grade >0 on the Histological Features of Reflux Esophagitis scale) and a history of at least 1 GERD symptom (heartburn, dysphagia, belching/burping, regurgitation, vomiting, hoarseness, coughing, choking, fullness during eating, anorexia, nausea, abdominal pain) occurring at least 1 to 2 times daily within 3 months before screening. On average, children had 4 to 5 GERD symptoms at entry. The most prevalent symptom was belching (69%) followed by abdominal pain (68%), coughing (62%), fullness while eating (56%), regurgitation (55%), nausea (42%), heartburn (41%), hoarseness (31%), vomiting (29%), anorexia (27%), dysphagia (23%), and choking (16%). The study excluded children with a history of endoscopic findings of eosinophilic esophagitis, persistent milk protein allergy, allergic gastroenteropathy, tracheoesophageal fistula status postrepair, mental retardation, cerebral palsy, and infection with H pylori. The use of sucralfate, domperidone, or any medication that affects gastrointestinal (GI) motility (caffeine, baclofen, erythromycin, and metoclopramide) as well as digoxin, digitalis preparations, ketoconazole, and theophylline were prohibited from 3 days before randomization in the 12-week treatment phase and throughout the 24-week maintenance phase. To enter the 24-week maintenance phase of the study, children were required to have achieved healing (grade 0 on the Hetzel-Dent Classification and/or grade 0 on the Histological Features of Reflux Esophagitis scale) by the end of the preceding 12-week treatment phase.
The efficacy parameters evaluated at the end of the 12-week treatment phase (baseline for the maintenance phase) and at the end of the 24-week maintenance phase (week 36) included esophagogastroduodenoscopy (EGD) with histology, Total GERD Symptom and Severity score, GERD Symptom Relief score, Global Treatment Satisfaction score, and parent/caregiver-rated Clinical Global Impressions Improvement (CGI-I) score.
The study protocol was approved by the independent ethics committee or institutional review board and the study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki and in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the protocol. Parents or legally accepted representatives of children provided written informed consent before participation in the study. Assent was also obtained from children ≥7 years old who were capable of understanding the study.
The selected doses were considered to be therapeutically effective and safe, and the highest dose used did not exceed the maximum labeled adult dose (20-mg dose). Dose selection was based on earlier studies that demonstrated that the known target range for plasma level of exposure (area under the curve [AUC]) of rabeprazole for therapeutic acid suppression in adults and adolescents treated with 10- and 20-mg rabeprazole was 400 to 800 ng · h · L−1, and pharmacokinetic modeling derived from preliminary pharmacokinetic studies in 1- to 11-year-old children with GERD, which showed that once-daily administration of 0.5- and 1-mg/kg rabeprazole produced plasma AUC∞ values that were comparable to those observed in adults receiving 10- and 20-mg rabeprazole, respectively (5). A small amount of soft food or infant formula was used as a dosing vehicle to administer rabeprazole granules. Everyone, including the investigator, the contract research organization, and in-house study personnel were blinded to the study.
For adherence to study drug, the investigator or designated study personnel maintained a log of all of the study drugs dispensed and returned during the study. Study drug supplies for each child were inventoried and accounted for throughout the study to verify the child's compliance with the dosage regimen. Study drug was administered by the parent/caregiver and recorded on the appropriate form. Compliance was defined as administration of >70% of scheduled pill count.
Efficacy and Safety Assessments
The primary efficacy endpoint assessed the number and percentage of children who had achieved endoscopic/histologic healing by the end of the 12-week treatment period and maintained healing during this 24-week maintenance phase. Healing was defined as grade 0 on the Hetzel-Dent Classification scale (6), and/or grade 0 on the Histological Features of Reflux Esophagitis scale (7). Secondary efficacy endpoints included change from the end of the treatment phase (week 12) to the end of maintenance phase (week 36) in Total GERD Symptom and Severity, GERD Symptom Relief, Global Treatment Satisfaction, and CGI-I scores.
The Total GERD Symptom and Severity score assessed the severity and frequency of 12 predefined GERD symptoms, including heartburn, dysphagia, belching/burping, regurgitation, vomiting, hoarseness, coughing, choking, fullness during eating, anorexia, nausea, and abdominal pain. For each symptom, the frequency (0 = never; 1 = 1–2 times; 2 = 3–4 times; 3 = 5–6 times; 4 = 7 or more times) and severity (1 = mild; 2 = moderate; 3 = severe) were determined. For each individual symptom, the score is defined as the sum of the frequency and severity of that symptom (maximum attainable individual score = 7). The total score is defined as the sum of the scores of all of the symptoms (maximum attainable total score = 84) (8). Higher observed scores indicate more serious conditions (8).
The child's Overall GERD Symptom Relief was graded as 1 (better), 0 (no change), and −1 (worse). The Global Treatment Satisfaction scores (9) and CGI-I score (10) were assessed on a 4-point scale ranging from 0 (poor) to 3 (excellent).
Safety assessments included the monitoring of AEs, clinical laboratory testing, vital signs, and physical examination. AEs were classified into standardized medical terminology from the verbatim description (investigator term) according to the Medical Dictionary for Regulatory Activities Coding Dictionary, version 12.0. In addition, an independent Data Safety Monitoring Committee reviewed AEs on an ongoing basis.
The 95% confidence interval was provided for healing rates at the end of the 24-week maintenance phase. Secondary efficacy endpoints were summarized by dose. The Overall GERD Symptom Relief score and changes in the Hetzel-Dent Classification scale were analyzed with the Cochran-Mantel-Haenszel test stratified by age group. Safety data were summarized.
Efficacy analyses were conducted in the intent-to-treat (ITT) population, which included all of the randomized children who had at least 1 postbaseline efficacy assessment in the maintenance phase. The safety assessments were conducted in the safety population, which included all of the randomized children who received at least 1 dose of maintenance phase study drug. Computations for all of the results were performed using SAS version 9.2 (SAS Institute, Cary, NC)
The present study was conducted in 9 countries (United States, Belgium, Denmark, France, Italy, Poland, Israel, South Africa, and India) from January 2009 to January 2011 (including the 12-week treatment and the 24-week maintenance phase). Of the 87 children who achieved healing in the 12-week treatment phase, 64 elected to enroll in the maintenance phase and 52 (81%) completed assessments for the primary endpoint (EGD with histology) and were included in the ITT analysis (Fig. 1). Overall, 29% children received proton pump inhibitor (PPI) treatment, 22% received antacids, 15% used H2-blockers, and 2% were taking prokinetics before entering the study. None of the children underwent dietary therapy.
The mean age of children was 6 years and the majority (80%) were white (Table 1). The median duration of exposure to rabeprazole was 168 days (range 38–189 days) and was similar across the 4 dose groups.
Primary Efficacy (Endoscopic/Histologic Healing)
Sixty-four children who achieved healing (grade 0 on the Hetzel-Dent Classification and/or grade 0 on the Histological Features of Reflux Esophagitis scale) during the preceding 12-week treatment study entered this 24-week maintenance study. Of the 64 children, 52 completed both EGD and histology assessments. 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 healing between the 2 target dose groups, but all of the children (100%) in the low-weight cohort showed healing compared with only 89% (10 mg) and 85% (20 mg) children in the high-weight cohort (Table 2).
Hetzel-Dent and histology scores were available for 61 children at baseline and 52 at the end of the maintenance phase. Overall, 93% of children had grade 0 and 7% had grade 1 on the Hetzel-Dent Classification scale at entry into the maintenance study. Of the 52 children who had baseline and end-of-study Hetzel-Dent scores, 83% maintained grade 0, 2% had an improvement by ≥1, and 15% had a decline by ≥1. Of these 15% (8 patients) who did not show mucosal healing, 3 were noncompliant with therapy during the maintenance phase; they took only 33%, 50%, 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 78% (10 mg) and 75% (20 mg) remained at grade 0 (Table 2).
In comparison, 50% of children had grade 0, 19% grade 1, 14% grade 2, 15% grade 3, and 2% grade 4 on the Histological Features of Reflux Esophagitis scale at entry into the maintenance study. Of the 52 children who had baseline and end-of-study histology scores, 27% showed an improvement of ≥1 grade, 48% no change, and 25% a decline of ≥1 grade at the end of the maintenance study (P = 0.925) (Table 2).
The Total GERD Symptom and Severity score continued to improve slightly during the maintenance phase with a significant decrease in the overall score from 7.6 points (baseline) to 5.4 points (end of maintenance phase) (P = 0.026; paired t test). All of the treatment groups experienced an improvement (2.6–3.8 points), except for the 10-mg dose group (low-weight cohort), which showed a worsening of 3.6 points (Table 3).
Consistent with the findings in the Total GERD Symptom and Severity scores, there was a significant (P < 0.001; paired t test) difference in the mean Overall GERD Symptom Relief score for all of the children at the end of the maintenance phase. At the end of the maintenance phase, the GERD Symptom Relief score indicated that 64% of children felt better, 33% felt no change, and 3% felt worse. Few patients from the 10-mg dose group (low-weight cohort) felt better (Table 3). The Global Treatment Satisfaction assessments showed 32 of 61 children (52%) with “Excellent,” 26 (43%) “Good,” and 3 (5%) “Fair” scores at the end of the maintenance 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 to the Total GERD Symptom and Severity and the GERD Symptom Relief scores, the 10-mg dose group (low-weight cohort) had a slightly lower impression of improvement compared with other dose groups (Table 3).
Overall, 40 of 64 (63%) children experienced ≥1 treatment-emergent adverse event (TEAE), with upper respiratory tract infection (13%), vomiting (11%), abdominal pain (8%), and diarrhea (6%) being the most commonly reported (≥5% children). The frequency of TEAEs was higher in the high-weight cohort (Table 4). Of the 40 children who reported a TEAE, only 2 (5%) children in the low-weight cohort experienced a TEAE considered to be related to study medication (vomiting in one child and acidosis with increased β-2 microglobulin in another child). A total of 22 (34%) children experienced TEAEs that were considered by the investigator to be mild, 15 (23%) moderate, and 3 (5%) severe. Severe TEAEs included lymphadenitis, bronchopneumonia, and partial seizures with secondary generalization.
Five children experienced serious TEAEs during the maintenance phase. These included 1 mild head injury (5 mg), 1 moderate conversion disorder (neurologic/psychiatric disorder) (20-mg dose), 1 severe bronchopneumonia (10-mg, low-weight cohort), 1 severe lymphadenitis (10-mg, low-weight cohort), and 1 partial seizure with secondary generalization (10-mg, high-weight cohort). All of the 5 serious TEAEs were considered not related to the study drug. One child in the 20-mg dose group discontinued the maintenance phase because of a nonserious TEAE of dyspepsia. There were no deaths. There were no trends or clinically relevant changes in mean clinical laboratory or vital sign data during the maintenance phase.
A total of 64 children (32 each in 1–5 years old age group and 6–11 years old age group) received double-blind, daily target doses of 0.5 or 1.0 mg/kg for 24 weeks. The dose was further 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. 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 maintenance phase (week 36). The safety and efficacy results of the 12-week treatment phase are presented elsewhere (4).
The extent of macroscopic/histologic healing achieved during the 12-week treatment phase was maintained in 47 (90%) of the 52 children who were dosed and had at least 1 postbaseline endoscopy/histology assessment (ITT population). The frequency and severity of GERD symptoms continued to slightly improve during the maintenance phase compared with those in the treatment phase. The Total GERD Symptom and Severity score showed a mean overall improvement of 10.0 points during the treatment phase and 2.2 points during the maintenance phase. Continued clinical symptom improvement was expected because not all of the children had complete macroscopic/histologic remission at the beginning of the maintenance phase. The definition of healing (grade 0 on the Hetzel-Dent Classification scale and/or grade 0 on the Histological Features of Reflux Esophagitis scale) allowed patients entering the maintenance phase with a Hetzel-Dent score or Histological Features of Reflux Esophagitis score of >0. At entrance to the maintenance phase, 7% of children still had grade 1 on the Hetzel-Dent scale and 49% had a score of >0 on the Histological Features of Reflux Esophagitis scale. Eight (15%) patients had a decline by ≥1 on the Hetzel-Dent scale during the maintenance phase; 3 of these patients took only 33%, 50%, and 61% of the scheduled pill count, respectively. For the remaining 5 cases, no obvious reason was identified.
The majority (64%) of children reported an overall GERD Symptom Relief score of “feel better” at the end of the maintenance phase. Similar maintenance of healing rates and reflux symptom improvement have been reported in a prospectively controlled study (7) and 2 open-label (OL) studies (11,12).
In a randomized controlled prospective study of omeprazole with a similar design as that of the present study, of the 46 children (ages 2.5–14 years) with erosive esophagitis (Hetzel-Dent grade ≥2) who achieved macroscopic healing of erosive esophagitis (Hetzel-Dent grade 0 or 1) during the 3-month treatment phase, only 1 (2.2%) child had erosive esophagitis relapse and 12 (26.1%) had mild symptoms 3 months postmaintenance therapy (6 months) (13). In another single-arm, OL, prospective study of maintenance therapy with omeprazole in 46 children (ages 1–16 years) with erosive esophagitis (Hetzel-Dent grade ≥2) who achieved endoscopic healing of erosive esophagitis (Hetzel-Dent grade 0 or 1) following the 3-month treatment phase, 35 (76.1%) children maintained healing of erosive esophagitis. The slightly lower rate of maintenance of healing may be attributed to the specific patient population studied because the majority of children had moderate-to-severe erosive esophagitis (Hetzel-Dent grade 3 or 4) at baseline of the treatment phase. Twenty-two of the 46 children had GERD-predisposing disorders at baseline, including 15 children with cerebral palsy or other neurologic conditions and 7 with repaired esophageal atresia (12). It should, however, be noted that, an earlier study with omeprazole had patients with underlying diseases that predispose to GERD such as tracheoesophageal fistula status postrepair, mental retardation, and cerebral palsy, which was not seen in our study.
A single-arm, OL, prospective study (11) of PPI maintenance therapy in healed erosive esophagitis was conducted in 52 institutionalized, intellectually disabled children ages 4 to 19 years with endoscopically proven erosive esophagitis. At the end of 3-month treatment phase, 47 (90%) of 52 patients did not have symptom relapse.
The incidence (63% in maintenance phase vs 76% in treatment phase) and severity (mild 34% vs 42%; moderate 23% vs 28%; severe 5% vs 6%) of TEAEs were generally lower during the 24-week maintenance phase. Headache was reported in 2% of children during the maintenance phase compared with 9% incidence reported in the 12-week treatment phase. The low frequency of headache may be because of tachyphylaxis related to long-term treatment. There was no apparent dose-response relation with respect to TEAEs, and no trends or clinically relevant changes in mean clinical laboratory or vital sign data observed in either treatment phase or maintenance phase.
It has been observed in adults that long-term exposure to PPIs may be associated with an increased risk for osteoporosis-associated bone fracture, as a result of partial malabsorption of dietary calcium, secondary to gastric acid suppression. Although this concern is not clear in children, it is of particular relevance considering the importance of maintaining healthy calcium homeostasis and bone mineral density during childhood. Other metabolic disturbances that may be associated with prolonged duration of acid suppressive therapy in adults include vitamin B12 and iron deficiency, and rare occurrence of hypomagnesemia (14–17), all of which are considered to be of increased clinical significance in children, especially those with severe reflux esophagitis who have GERD-predisposing disorders that may also impair their health and growth. Separately, there have been reports linking long-term PPI therapy with an increased risk for certain infections such as community-acquired pneumonia, Clostridium difficile infection, and other enteric infections in adults (18–22). In children, an increased risk of acute gastroenteritis and community-acquired pneumonia was reported after 4 months of completion of a 2-month PPI regimen (23). In the present study, except for an increased incidence of upper respiratory tract infections (13%), there was no evidence of any other AE as seen in earlier studies.
A significant limitation of this study is the lack of a placebo arm; however, there are other studies (24) that indicate that extended treatment may not be necessary to maintain healing. Moreover, the design of this study does not allow us to answer this question, although continued improvement of symptoms and the high percentage (90%) of children maintaining macroscopic/histologic healing may indicate a benefit.
Considering a similar efficacy and safety profile with respect to dose strength and in consideration of the potential increased risks for bone fracture and metabolic disturbances such as vitamin B12 deficiency and hypomagnesemia, the lowest effective dose is recommended. There are, however, studies indicating that children who are prone to more severe esophagitis such as those with preexisting esophageal anatomic/motility abnormalities or neurologic or respiratory disorders have the greatest need for long-term therapy to maintain healing of reflux esophagitis and symptomatic control. Some of these patients may require a more rigorous treatment regimen (eg, higher dose, twice daily, longer treatment duration).
Rabeprazole granules were effective and safe in maintaining endoscopic/histologic healing and for improvement of symptoms for 24 weeks in children, 1 to 11 years of age. The clinical effect and safety profile was largely similar across all dose groups. No new safety findings were observed.
Shruti Shah, PhD (SIRO Clinpharm Pvt Ltd) provided writing assistance and Bradford Challis, PhD (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 the article while employed at Janssen. The authors also thank the study participants, without whom this study would not have been accomplished, as well as the following investigators for their participation in this study:
Belgium: Scaillon, Michele; Bontems, Patrick; Cadranel, Samy; Muyshont, Laurence; Sokal, Etienne; Paganelli, Massimiliano; Smets, Francoise; Stephenne, Xavier; VandenPlas, Yvan; Devreker, Thierry; Hauser, Bruno; Vertruyen, André; De Meulder, Frederic. Denmark: Husby, Steffen; Pedersen, Rikke Neess; Thorup, Jorgen; Fonnest, Gert. France: Dupont, Christophe; Kalach, Nicolas; Spyckerelle, Claire. India: Jain, Hemant; Dubey, Ashish; Mehta, Nirbhay; Patel, Gal Singh; Shende, Atul; Thora, Sharad; Krishna, Palakurthy Murali; Kaliyanan, Jyanthi. Israel: Levine, Arie; Zangen, Tzili; On, Avi; Said, Abozaid; Shamir, Raanan; Hartman, Corina; Rosenbach, Yoram; Shapiro-Preminger, Rivka; Zevit, Noam; Shaoul, Ron; Eshach-Adiv, Orly; Peleg, Sarit; Rosen, Irit; Turner, Dan; Rachman, Elena; Silbermintz, Ari. Italy: Falchetti, Diego; Argento, Salvatore; De Giacomo, Costantino; Mancini, Valentina; Romano, Claudio; Comito, Donatella; Ferraù, Valeria; Staiano, Annamaria; Coccorullo, Paola; Miele, Erasmo; Ummarino, Dario. Poland: Cichy, Wojciech; Ignys, Iwona; Klincewicz, Beata; Lisowska, Aleksandra; Walkowiak, Jaroslaw; Hapyn, Ewa; Buzalska, Barbara; Gaszewska-Ladniak, Hanna; Pawlowska, Joanna; Iwanczak, Barbara; Iwanczak, Franciszek; Krzesiek, Elzbieta; Matusiewicz, Krzysztof; Mowszet, Krystyna; Pytrus, Tomasz; Kaczmarski, Maciej; Kondej-Muszynska, Katarzyna; Matuszewska, Elzbieta; Sidor, Katarzyna; Uscinowicz, Miroslawa; Kierkus, Jaroslaw; Dadalski, Maciej; Oracz, Grzegorz; Korczowski, Bartosz; Bijos, Artur; Jakobiec, Radoslawa; Lewanowicz, Wieslaw; Klimza, Malgorzata; Tomecka, Ewa; Obuchowicz, Anna Karolina; Kaczmaryk, Agnieszka; Kula-Gradzik, Joanna; Slimok, Marta; Wasowska-Krolikowska, Krystyna; Gebora-Kowalaks, Beata; Modzelewska-Holynska, Malgorzata; Toporowska-Kowalska, Ewa; South Africa: Mitha, Ismail; Mitha, Haroon Mohammed; Natha, Farahnaz; Wadvalla, Shahid; Schuman, Hester C; Du Preez, Jacomina C F; Mulder, Isak; Steyn, Ca; Van Aswegen, Dina Johanna; Vermeulen, Jan; Brown, Robin Alexander; De Villiers, Gerrit Stephanus; Wadvalla, Shahid; Mohammed, Haroon. United States of America: Bishop, Phyllis; Adcock, Kim; Nowicki, Michael; Parker, Paul; Bornstein, Jeffrey; Figueroa-Colon, Reinaldo; Mehta, Devendra; Crissinger, Karen; Kowalski, Donna; Madison, Betty; Francisco, Mary; Fischer, Francis H; Hunt, Kimberley A; Johnson, Anna M; Ley, Joseph A; Miller, Nicole M; Morelock, Christopher M; Ragsdale, Rhonda; Ray, Lori L; Shone, Dallas N; Tipton, Stephanie R; Valente, Maria; Williams, Tara N; Gremse, David; Haddad, Ibrahim; Jibaly, Rima; Zureikat, George; Melamed, Isaac; Driscoll, Lynette; McDonald, Angela; O’Brien, Kevin Patrick; Rosenweig, Jeffrey Neal; Misra, Sudipta; Lukacik, Marek; Nguyen, Christine; Boushey, Sarah; Quiros, J. Antonio; Ruben, Elizabeth A; Patterson, Edward; Pfefferkorn, Marian; Corkins, Mark; Croffie, Joseph; Fitzgerald, Joseph; Gupta, Sandeep; Lim, Joel; Subbarao, Girish; Qureshi, Azim; Longenecker, Amy; McMonagle, Amyee; Stokes, Jennifer; Sturgis, Sarah; Vallati, Julie; Watts, Heidi; Ramakrishna, Jyoti; Fong, Jay; Shah, Smita; Laney, Donald Wayne; McClellan, Randall Douglas; Sullivan, Janice; Condurache, Carmen; Dillard, Robert; Jeffries, Angela M; Morton, Ronald; Stephen, Thomas; Stutts, John; Tolia, Vasundhara; Tomasovic, Jerry; Ibarguen-Secchia, Joseph; Tron, Eduardo; Focht III, Dean R; Maksimak, Martin; Peters, John Murphy; Tung, John; Lopez-Bernard, Edwin; Ulmer, April; Williams, Joe Lynn; Doody, James; Husk, Cynthia J; Markham, Karen; O’Brien, Kevin P; Rosensweig, Jeffrey Neal.
© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,