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Efficacy and Safety of Pantoprazole Delayed-release Granules for Oral Suspension in a Placebo-controlled Treatment-withdrawal Study in Infants 1–11 Months Old With Symptomatic GERD

Winter, Harland*; Kum-Nji, Philip; Mahomedy, Suleman H; Kierkus, Jaroslaw§; Hinz, Michelle; Li, Huihua; Maguire, Mary K; Comer, Gail M

Journal of Pediatric Gastroenterology & Nutrition: June 2010 - Volume 50 - Issue 6 - p 609–618
doi: 10.1097/MPG.0b013e3181c2bf41
Original Articles: Gastroenterology

Objective: The objective of this study was to assess the efficacy of pantoprazole in infants with gastroesophageal reflux disease (GERD).

Materials and Methods: Infants ages 1 through 11 months with GERD symptoms after 2 weeks of conservative treatment received open-label (OL) pantoprazole 1.2 mg · kg−1 · day−1 for 4 weeks followed by a 4-week randomized, double-blind (DB), placebo-controlled, withdrawal phase. The primary endpoint was withdrawal due to lack of efficacy in the DB phase. Mean weekly GERD symptom scores (WGSSs) were calculated from daily assessments of 5 GERD symptoms. Safety was assessed.

Results: One hundred twenty-eight patients entered OL treatment, and 106 made up the DB modified intent-to-treat population. Mean age was 5.1 months (82% full-term, 64% male). One third of patients had a GERD diagnostic test before OL study entry. WGSSs at week 4 were similar between groups. WGSSs decreased significantly from baseline during OL therapy (P < 0.001), when all patients received pantoprazole. The decrease in WGSSs was maintained during the DB phase in both treatment groups. There was no difference in withdrawal rates due to lack of efficacy (pantoprazole 6/52; placebo 6/54) or time to withdrawal during the DB phase. The greatest between-group difference in WGSS was slightly worse with placebo at week 5 (P = 0.09), mainly due to episodes of arching back (P = 0.028). No between-group differences in adverse event frequency were noted. Serious adverse events in 8 patients were considered unrelated to treatment.

Conclusions: Pantoprazole significantly improved GERD symptom scores and was well tolerated. However, during the DB treatment phase, there were no significant differences noted between pantoprazole and placebo in withdrawal rates due to lack of efficacy.

*Massachusetts General Hospital for Children, Boston, MA, USA

Virginia Commonwealth University Children's Pavilion, Richmond, VA, USA

Hiway Medical Center/Westville Medical Center, Westville Durban, South Africa

§Department of Gastroenterology, Hepatology and Immunology, the Children's Memorial Health Institute, Warsaw, Poland

Pfizer Inc, Collegeville, PA, US.

Received 18 December, 2008

Accepted 25 July, 2009

Address correspondence and reprint requests to Gail M. Comer, Pfizer Inc, 500 Arcola Rd, Collegeville, PA 19426-3930 (e-mail:

Funding for this study was provided by Wyeth Pharmaceuticals, Collegeville, PA, which was acquired by Pfizer Inc in October 2009. Professional medical writing support was provided by Naomi Pliskow, MD, who was funded by Wyeth Pharmaceuticals.

H.W., P.K.-N., S.H.M., and J.K. were study investigators and they or their institutions received compensation for their participation. M.H., H.L., M.K.M., and G.M.C. were employees of Wyeth Research at the time of the study.

Gastroesophageal reflux (GER) occurs commonly in infants and is considered to be a normal physiologic process. Studies of normal infants have demonstrated episodes of reflux as frequent as 73 times per day (1), and GER-associated vomiting has been reported to occur in as many as 67% of infants during the fourth month of life (2). For more than 98% of infants, GER resolves by 12 to 15 months of age. Among infants who have significant regurgitation lasting longer than 90 days, some may experience symptoms of gastroesophageal reflux disease (GERD) a decade later (3). Whereas GER is common in infants, GERD, defined as reflux that is associated with pathologic signs and symptoms, is uncommon. GERD may be a significant source of morbidity in infants, manifesting as anorexia, dysphagia, arching of the back during feedings, irritability, hematemesis, anemia, and failure to thrive (4). GERD may also predispose some infants to chronic respiratory disease including cough, asthma, and recurrent pneumonia.

The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for Evaluation of Gastroesophageal Reflux in Infants and Children include treatment recommendations for both nonpharmacologic therapy, such as thickened infant formula and attention to positioning, and pharmacologic treatment (4). These guidelines do not recommend chronic use of antacids in infants because of concerns about the safety of aluminum and lack of data regarding magnesium- and calcium-containing antacids; however, they recommend a trial of histamine-2 receptor antagonists (H2RAs) or proton-pump inhibitors (PPIs). Limited data from small clinical trials of PPIs in full-term and preterm infants have demonstrated efficacy and safety in the treatment of GERD (5–7). No data from large randomized clinical trials of the use of PPIs in infants have been published.

Pantoprazole (Protonix; Wyeth Pharmaceuticals, Collegeville, PA) is a PPI that has been shown to be safe and effective in the treatment of GERD in adults and children in randomized controlled clinical trials (8–12). Pantoprazole delayed-release granules for oral suspension were developed as an age-appropriate formulation for use in infants and young children unable to swallow tablets. To further characterize the efficacy and safety of pantoprazole in infants, Wyeth Pharmaceuticals studied the effects of pantoprazole on GERD symptoms in infants ages 1 through 11 months with proven or suspected GERD.

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This was a multicenter, randomized, treatment-withdrawal study in which an initial open-label (OL) phase was followed by a double-blind (DB), placebo-controlled withdrawal phase. Each study center received approval from its institutional review board or independent ethics committee, and all parents of the patients provided written informed consent. Studies were conducted in accordance with the guidelines for good clinical practice and the ethical principles of the Declaration of Helsinki.

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Patients were post-term infants older than 28 days but younger than 12 months of age, or preterm infants with a corrected age of 44 weeks or older but younger than 12 months at the time of informed consent; weight was required to be 2.5 kg to ≤15 kg.

Patients were required to have a modified total GERD Symptom Questionnaire in Infants (GSQ-I) (Fig. 1) (13) mean symptom frequency >16 at screening and baseline and a clinical diagnosis of suspected, symptomatic, or endoscopically proven GERD (erosive or histologic esophagitis).

Exclusion criteria included a known history or presence of upper gastrointestinal (GI) anatomic or motility disorders or clinically significant medical conditions as indicated by physical examination, electrocardiogram (ECG), or laboratory test; use of PPIs or H2RAs within 14 days of completion of the GSQ-I baseline questionnaire; or use of any nonstudy medication for treatment of a GI condition within 3 days before completion of the GSQ-I baseline questionnaire. In addition, patients could not have any disorder requiring daily use of warfarin or other anticoagulants, carbamazepine, phenytoin, or anticholinergics.

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Study Design and Treatment

During the 2- to 4-week screening period, all patients received standardized conservative treatment for GERD, including smaller, more frequent feedings with hypoallergenic formula thickened with rice cereal for nonbreast-fed infants, and general instruction about GERD including positioning and environmental exposure. Calcium-containing rescue antacids were also provided. Patients remaining symptomatic after 2 weeks received OL pantoprazole granules for suspension approximately 1.2 mg · kg−1 · day−1 (5 mg/day for infants 2.5 kg to <7 kg, or 10 mg/day for infants ≥7 kg to ≤15 kg) for 4 weeks. The granules were provided in a single-dose packet including an inert powder blend. At the time of administration, the packet contents were emptied into a small cup. Five milliliters of water were added and stirred, forming a thick, grape-flavored suspension. The suspension was drawn up into an oral syringe and administered to the infant. The cup was then rinsed with water to dissolve any remaining granules, and the water drawn into the syringe for administration.

Patients who were ≥80% compliant during the OL phase entered the DB treatment-withdrawal phase, at which time they were randomly assigned in a 1:1 fashion, stratified by weight, to receive pantoprazole or placebo for an additional 4 weeks. Specified study calcium-containing rescue antacid (MYLANTA Supreme or local country equivalent) not to exceed 35 mg Ca2+ · kg−1 · day−1 or 87.5 mg CaHCO3 · kg−1 · day−1 was allowed as needed after ≥5 minutes of severe GERD symptoms, as determined by the caregiver. Other conservative measures were continued throughout the study.

Medications to treat non-GI conditions were allowed as needed at stable doses with the exception of glucocorticoids (except topical or inhaled), prostaglandins, or anticoagulants. Any medication used to treat a GI condition or any supplement or herbal medication that could interfere with the metabolism of pantoprazole was not allowed.

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Office visits occurred every other week until 2 weeks after the end of study treatment, with telephone contact in intervening weeks. Parents completed an electronic diary on a daily basis with questions assessing the frequency of 5 key GERD symptoms during the previous 24-hour period; questions for the caregiver assessment of GERD symptoms in infants (Table 1) were developed from the modified version of the GSQ-I (Fig. 1), which has been validated to discriminate between healthy infants and those with GERD (13). A weekly GERD symptom score (WGSS) was defined as the sum of the 5 selected individual weekly GERD symptom mean frequencies for vomiting/regurgitation (1a), irritability/fussiness (2b), choking/gagging (3a), arching back (4a), and refusal to feed (higher score of 5a and 5b). Frequency and amount of antacid use were also recorded.

The primary efficacy endpoint was withdrawal rate due to lack of efficacy in the DB phase, defined as at least 1 of the following: significant worsening of GERD symptom frequency; a diagnostic test demonstrating worsening of esophagitis, if performed; maximal antacid use for ≥7 continuous days; severe GERD symptoms as based on physician's judgment. Secondary endpoints were lack of efficacy per withdrawal criteria, withdrawal for any reason, time to withdrawal due to lack of efficacy, time to withdrawal for any reason, WGSS and individual mean frequency for each GERD symptom, amount of antacid taken during each week, and number of patients taking antacids.

Safety was assessed via adverse events (AEs) reported by the parents throughout the study and 2 weeks following the last dose. Physical examinations including growth parameter evaluation were performed and vital signs were assessed at site visits throughout the study. Routine clinical laboratory tests were performed at screening and week 4 and the final visit, and 12-lead ECGs were performed at screening and the final visit.

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Statistical Analysis

The primary population of efficacy analyses was the modified intent-to-treat (mITT) population, defined as patients who had a GERD diagnosis, participated in the OL study for ≥21 days, were randomly assigned into the DB treatment phase and received at least 1 dose of DB treatment. Efficacy analyses were also performed on 2 predefined valid-for-efficacy (VFE) populations (Fig. 2). Safety analyses were performed on all patients who received at least 1 dose of investigational drug (safety population).

Baseline demographics and other characteristics were summarized, and test P values between treatment groups were calculated using the Fisher exact test or the chi-square test for categorical variables and an analysis of variance model with treatment group as a factor for continuous variables.

The withdrawal rate for each treatment group was defined as the ratio of the number of patients who were withdrawn from the study due to lack of efficacy during the DB phase over the total number of patients who entered the DB phase. The withdrawal rates between treatment groups were compared using the Fisher exact test. The rate of lack of efficacy per withdrawal criteria was the ratio of the number of patients who met the lack of efficacy withdrawal criteria during the DB phase over the number of patients who entered the DB phase, and the withdrawal rate for any reason was the ratio of the number of patients who withdrew from the study for any reason during the DB phase over the number of patients who entered the DB phase; these were analyzed using the same statistical methods as the primary endpoint. Time to withdrawal data were summarized by the Kaplan-Meier method and compared by the log-rank test between treatment groups.

Secondary efficacy parameters such as WGSS, individual mean frequency scores for GERD symptoms, and the amount of antacid used were analyzed using a paired t test for within-group comparison of change from baseline to the end of the OL phase, from baseline to the end of the DB phase, and from the end of the OL phase to the end of DB phase. The changes from baseline to the end of DB phase as well as the changes from week 4 to the end of DB phase were analyzed by an analysis of covariance that included treatment and age group (≤6 months, >6 months) as factors and antacid use and the value of the corresponding endpoint at the end of the OL phase as covariates.

A WGSS was calculated as the sum of the 5 individual weekly GERD mean frequencies of questions 1a, 2b, 3a, 4a, and the maximum score of 5a/5b. The individual weekly GERD mean frequency score was calculated as the sum of the daily symptom scores at a given week divided by the number of days with nonmissing scores in the week.

When calculating WGSS and individual GERD symptom mean scores before and during treatment, some values were imputed. If item 1a in the electronic diary was answered “none,” the answers for items 1b and 1c were assigned a value of zero. If item 2a was answered “no,” then the answers for items 2b and 2c were assigned a value of zero. For the mITT analyses of symptom scores, if all values of frequency scores were missing for 7 days within a week, then the last weekly mean frequency score preceding the missing score was carried forward within each phase.

The number of patients with AEs and/or potentially clinically important laboratory test results and vital sign measurements were summarized and compared by treatment group as appropriate using the Fisher exact test. Mean changes from baseline in safety and growth parameters were summarized and presented by treatment group using analysis of covariance as appropriate. The number of patients who were withdrawn prematurely from the study for any reason was summarized by treatment group.

In a previous study for children 5 to 11 years treated with pantoprazole (Wyeth Research, data on file), only 1 of 53 (1.9%) dropped out due to lack of efficacy. In a study comparing famotidine to placebo in infants, the dropout rate in the placebo group was 3 of 11 (27%) (14). Assuming that the withdrawal rates in the pantoprazole 1.2 mg/kg and placebo groups in the present study are 3% and 27%, respectively, it was determined that 38 patients per group entering the DB treatment-withdrawal phase would be needed to detect the assumed difference, using a 2-sided Fisher exact test at the 0.05 level with at least 80% power. It was further determined that approximately 136 patients were to be screened to ensure that at least 38 patients per treatment group would enter the 4-week treatment-withdrawal phase of the study.

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A total of 154 patients with GERD symptoms were screened at 31 investigative sites. Of the 25 screen failures, 6 did not meet inclusion criteria, 3 had clinically significant abnormal laboratory test results, and the rest were due to poor compliance/noncompliance, parental request, or withdrawal of consent. Of the 6 who did not meet inclusion criteria, 5 had improved GSQ-I scores following the 2 weeks of conservative treatment and no longer met the criterion of a GSQ-I score >16, and 1 patient did not meet the age requirements.

A total of 129 patients received at least 1 dose of pantoprazole (safety population). Twenty-one (16.4%) patients were withdrawn from the study during the OL phase, the most common reason being parental noncompliance with electronic diary completion in 9 patients (7.0%) and AEs and parental request in an additional 4 (3.1%) patients each. A total of 106 patients received DB treatment and constituted the mITT population (Fig. 2).

Twenty (18.5%; pantoprazole n = 11, placebo n = 9) patients were discontinued during the DB phase. Lack of efficacy accounted for most study discontinuations; details are presented in the Efficacy section. Of discontinuations for reasons other than lack of efficacy, 4 (3.7%) were because of protocol violation, 2 (1.9%) were due to noncompliance with the study protocol, and parental request or failure to return accounted for 1 patient each (0.9%).

In the mITT population, the majority of patients were white males whose mean age was 5.1 months (Table 2). The mean corrected age of pantoprazole preterm infants (5.42 months, n = 9) was greater than that of placebo preterm infants (3.15 months, n = 10); however, the overall calculated mean population ages and all other demographic data were comparable between treatment groups. Approximately one third of the patients had undergone any previous diagnostic tests for GERD at baseline (15 [28.8%] and 20 [37.0%], pantoprazole and placebo, respectively); a diagnosis of GERD was suggested or confirmed in 10 (19.2%) and 13 (24.1%) of these patients, respectively. Mean baseline GSQ-I scores were also similar between treatment groups. The baseline GSQ-I score was highly correlated with the baseline WGSS (r = 0.747, P < 0.0001). Of the safety population, approximately 56 (43.4%) had used medication for GERD before study entry.

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Mean compliance with study medication in the DB phase was 97.7% and 97.6%, with pantoprazole and placebo, respectively. Mean compliance with electronic diary completion in the mITT population during the OL phase was 87.83% with a minimum of 60.71%. In the DB phase, overall mean compliance was 84.54% with a minimum of 32.14%. There were no significant between-group differences during either treatment phase.

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In the DB phase, 6 patients in each treatment group were withdrawn from the study due to lack of efficacy. There were no significant between-group differences in rates of withdrawal due to lack of efficacy, lack of efficacy per withdrawal criteria, or withdrawal for any reason (Table 3). There were also no between-group differences in these rates when they were calculated for either VFE population (data not shown). Additional analysis of time to withdrawal data demonstrated no statistically significant difference between treatment groups (Fig. 3).

Significant cumulative reductions from baseline in mean WGSSs occurred each week to week 4 in all of the patients and in both treatment groups to week 8 (P < 0.001 for both groups) (Fig. 4). In the pantoprazole group, the overall decrease in WGSS was primarily due to the decrease observed during the first 4 weeks of treatment; however, this decrease was maintained during the DB phase. In the placebo group, a nonsignificant increase in WGSS was observed between weeks 4 and 5, but significant catch-up improvement from week 4 occurred at weeks 7 and 8. No statistically significant between-group differences in change from baseline or from week 4 were observed during the DB phase. The greatest between-group difference in overall WGSS change from baseline occurred at week 5 (P = 0.092). Comparable results were observed in the analysis of WGSS based on the VFE population.

Individual symptom scores decreased in both groups in both OL and DB phases, with arching back and crying/irritability accounting for 55% of the overall change (Table 4). Figure 5 depicts graphically the relative contribution of each symptom to the observed decrease in the WGSS. The observed between-group difference in the overall WGSS change at week 5 was primarily due to a greater decrease in episodes of arching back with pantoprazole than with placebo (P = 0.028). With the exception of vomiting/regurgitation, the percentage of patients reporting each individual symptom decreased by >10% from baseline at week 4 and decreased further by approximately 10% for each symptom at week 8. The reductions in the percentage of patients reporting each symptom were similar between the 2 treatment groups.

A post hoc, stepwise multiple regression analysis with 13 medical history and clinical baseline variables in addition to the treatment group was performed to identify potential predictors of WGSS in the change from baseline to the final week. The 13 baseline variables were baseline GSQ-I score, birth term status (preterm vs full term), weight (<7 kg vs ≥7 kg), week 4 WGSS, race (white vs nonwhite), baseline age (≤6 months vs >6 months), sex (male vs female), feeding type (infant formula, breast milk, or both), food type (solid vs nonsolid), use of prior PPI or H2RA (yes, no), GERD objective test (yes, no), region (United States/Canada, Europe, South Africa), and site size (large vs small enrolling sites).

Baseline GSQ-I score, birth term status, baseline age, week 4 WGSS, and treatment group were selected as potential predictors. Older patients (older than 6 months; P < 0.005), those with higher GSQ-I scores at baseline (P < 0.0001), and full-term infants (gestational age 37 weeks or older; P < 0.005) had greater improvement in WGSS. To determine whether there were 2-way interactions among the selected variables, all 2-way interactions were tested in a multiple regression model. The final model including the selected variables and an interaction between age and baseline GSQ-I score was fitted. The greatest change from baseline in WGSS at the final week was observed in patients older than 6 months of age with high baseline GSQ-I scores (P < 0.0005).

The mean amount of antacid taken weekly decreased significantly from baseline (11.9 mL) to week 4 in the overall population (6.7 mL; P < 0.001, change from baseline), as well as from baseline to week 8 in both treatment groups (5.1 mL and 4.1 mL, pantoprazole and placebo, respectively; P < 0.005). The percentage of patients taking antacids at least once weekly also decreased from baseline (62.5%) to week 4 (47.9%) and to week 8 in each group (39.1% and 32.6%, pantoprazole and placebo, respectively). There was no significant between-group difference in any measure of antacid use during the DB phase.

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Adverse events leading to discontinuation during the OL phase were diarrhea in 1 patient, excessive crying in 1 patient, and worsening of “GERD symptoms” in 2 patients. During the DB phase, 1 patient was discontinued due to sleep problems. Eight patients had 1 or 2 serious AEs during the study, of which 5 occurred during treatment with pantoprazole (Table 5). All serious AEs were considered unrelated to treatment by the investigators.

Treatment-emergent AEs reported in ≥5% of patients during the OL phase were upper respiratory infection in 25 (19.5%), fever and diarrhea in 13 (10.2%) each; otitis media in 12 (9.4%); rhinitis in 11 (8.6%); contact dermatitis/cutaneous moniliasis (diaper rash) in 10 (7.8%); and vomiting, oral moniliasis, and cough increased in 7 (5.5%) each. Events were mild or moderate in severity as assessed by the investigator, with the exception of 2 severe AEs (gastroenteritis and failure to thrive).

During the DB phase, upper respiratory infection was the most commonly reported treatment emergent AE in each treatment group, occurring in 7 patients (13.0%) in each group (Table 6). All events were mild or moderate in severity; no between-group differences were noted in the incidence and severity of AEs during this phase.

Mean gastrin levels increased significantly from baseline during the OL phase. This increase was maintained through week 8 in the pantoprazole group but not in the placebo group. Other observed changes in mean laboratory values as well as ECGs were consistent with maturation and/or were not significantly different between treatment groups during the DB phase and were therefore considered unrelated to treatment.

Patients grew normally during the study as measured by significant increases in weight, height, and head circumference from baseline to week 8. Increases in z scores were observed for all 3 parameters among patients completing the DB phase. There were no between-group differences in mean growth parameters.

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In infants 1 through 11 months with GERD symptoms, 4 weeks of OL pantoprazole therapy was associated with significant improvement in GERD symptom scores that persisted into the DB placebo-controlled withdrawal phase. Withdrawal rates in the DB phase were comparable between placebo and pantoprazole. Pantoprazole was generally safe and well tolerated, with an AE profile comparable to placebo.

The major indicator of efficacy in this study was improvement in the WGSS from baseline to study endpoint. This score is derived from symptom frequency responses to the caregiver assessment of GERD symptom questionnaire (Table 1), which was developed from a modified version of the GSQ-I (Fig. 1), a validated questionnaire developed as an easy-to-use tool for evaluation of outcomes of short therapeutic trials (13). Symptoms on the original GSQ-I are rated weekly by parents for frequency (unlimited numerical scale) as well as severity (7-point scale) (Appendix). The symptom severity rating was excluded from both the modified GSQ-I and the caregiver assessment of GERD symptoms questionnaire because of the inherent subjectivity of a severity assessment; however, all of the individual symptoms on the original GSQ-I except hiccups are included in the WGSS. These symptoms have been demonstrated to be meaningful and useful in distinguishing infants with GERD from those without. Findings in the present study demonstrated a high correlation between WGSS and GSQ-I scores at baseline, supporting the conclusion that the WGSS has similar validity in distinguishing patients with GERD from healthy patients, and that the decrease in the WGSS associated with 8 weeks of pantoprazole therapy has clinical validity.

The finding of improvement in GERD symptoms associated with pantoprazole therapy is somewhat confounded by the normal maturation that would have occurred during the 2-month study period. As the gastroesophageal sphincter matures, solid food is introduced and greater time is spent upright, GER symptoms tend to improve. GERD symptoms are more common in younger infants, peaking at approximately 4 months of age and tending to resolve in the second half of the first year (2,15). The contribution of maturation to the WGSS improvement demonstrated in this study is supported by the fact that infants older than 6 months of age had the greatest improvement in WGSS from baseline, as well as by the greater improvement in full-term than preterm infants; preterm infants are developmentally “younger” by birth date than full-term infants. However, most of the observed improvement occurred during the first 4 weeks of therapy, which is likely too short a period to achieve symptomatic improvement of this magnitude due to maturation alone.

Withdrawal rates in the DB phase were comparable between placebo and pantoprazole. This was unexpected because many authors have reported an expected rebound increase in gastric acid upon discontinuation of PPIs (16). If rebound had occurred, a difference in withdrawals due to lack of efficacy between continued treatment with pantoprazole and placebo would have been expected, whereas only a nonsignificant (P = 0.092) increase in symptoms in the placebo group was demonstrated at week 5. The reason for the lack of rebound effect demonstrated in this study is unclear, but it may have been related to the short duration of OL treatment (4 weeks).

There are several possible reasons for the failure to demonstrate a difference in withdrawal rates or symptom improvement between patients treated with pantoprazole and placebo in the DB phase of the trial. One possibility is that significant esophageal healing (if esophagitis were present at the start of the study) occurred with 4 weeks of treatment, as has been demonstrated in adults, and that symptomatic relapse within 4 weeks was unlikely if healing had occurred (17–20). Additionally, conservative treatment and rescue antacid use were continued throughout the study. The effect of maturation may also have contributed by decreasing symptoms in both treatment groups and obscuring between-group differences. Thus, a DB, parallel-treatment design may be preferable in future studies of this infant population to control the confounding effect of maturation on treatment, as well as the possible carryover effect of treatment from the OL phase.

The necessity and validity of treating infants with GER symptoms is dependent on the ability to distinguish pathologic GER from nonpathologic GER. “Happy spitters,” infants who regurgitate or vomit without distress or additional consequence, do not necessarily need pharmacologic treatment (2,4). In infants with additional symptoms, diagnostic tests may be inconclusive. Results of endoscopy, histology, and pH-metry may demonstrate conflicting results and/or may correlate poorly with clinical symptom questionnaires (21,22). It is standard in clinical practice to use empirical PPI therapy for a clinical diagnosis of GERD based solely on history and physical examination. Thus, the present study, in which only approximately one third of the patients had any diagnostic studies, approximates “real-world” clinical practice. In fact, a 2007 survey of 1245 pediatricians found that 82% instituted acid suppression as empirical therapy before ordering a diagnostic test (23).

In the same survey of pediatricians regarding the diagnosis and treatment of GERD, the length of the empirical trial instituted by the clinicians varied, ranging from 2 to >12 weeks, with most clinicians treating for 8 or >12 weeks (23). Interestingly, the guidelines recommend a 2-week trial of acid suppression and/or conservative measures in infants with GER symptoms and irritability. The recommended duration of an empirical trial of therapy for other specific clinical scenarios varies. The present study suggests that a 4-week trial of PPI therapy along with conservative measures is appropriate for managing GERD symptoms in infants with a GERD diagnosis based on history or confirmed by diagnostic studies.

Extensive evidence in adults confirms the superiority of PPIs in healing esophagitis as well as their safety with long-term use (24–28). However, data for infants from PPI clinical trials are limited (5–7,29). One study on infants and children ages 0.8 to 17 years with severe esophagitis who had failed to respond to treatment with an H2RA demonstrated improvement following treatment with omeprazole, suggesting that the superiority of PPIs over H2RAs also extends to this population (30). Concerns about safety of PPIs in infants and children have also been expressed (4); however, a study of the safety of a PPI used for 3 to 11 years in 166 infants (8% of the study population at first prescription) and children reported only 6 AEs considered to be related to treatment, all of which occurred in adolescents (31). The present study adds to the evidence that acid suppression with a PPI is safe for short-term use in infants and is an effective therapy in infants with GERD symptoms.

In this study, to attempt to eliminate infants with formula or dietary protein intolerance, all of the patients received initial conservative treatment with hypoallergenic formula thickened with rice cereal, smaller and more frequent feeds, positioning recommendations, and other standard measures. Only 5 of 154 (3.2%) screened patients withdrew before the OL phase because of significant improvement in their symptoms associated with conservative treatment alone, with failure to meet GSQ-I criteria for OL study entry. This response to conservative treatment is considerably less than that reported in a study of 394 infants with GERD treated with conservative measures, in which 24% responded within 2 weeks and needed no additional intervention (32). The lower rate of adequate response to conservative treatment in the present study may be due to selection of subjects for this trial, prior failure of conservative therapy, or relapse or inadequate response to prior acid suppression therapy.

The strengths of this study include its international multicenter, randomized, placebo-controlled design. It also reflects real-world clinical practice because it included symptomatic patients who failed 2 weeks of conservative therapy with thickened hypoallergenic formula and had few diagnostic tests. The OL treatment period is comparable to a clinical trial of PPIs.

Limitations of the present study include a carryover effect from 4 weeks of OL treatment and the impact of maturation on GERD symptoms. Furthermore, a withdrawal study design measures a subjective decision that may result from a focus on this potential outcome by investigators and parents, which may bias them toward reacting to small changes or differences in symptoms that may be interpreted as lack of efficacy.

In conclusion, this study demonstrated that short-term OL treatment with pantoprazole in infants with GERD symptoms was effective in reducing these symptoms. However, the study failed to demonstrate a significant difference from placebo in withdrawal due to lack of efficacy or in symptom control during the DB treatment phase. Pantoprazole was generally safe and well tolerated.

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gastroesophageal reflux disease; infants; pantoprazole

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