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graded by the parent/caregiver as 1 (better), 0 (no change), and

1 (worse). Treatment satisfaction and impression of improve-
ment at the end of treatment were assessed using the investigator-
rated, 4-point Global Treatment Satisfaction (21) and the parent/
caregiver-rated 4-point Clinical Global Impressions-Improvement
(CGI-I) scores (both 0 poor, 1 fair, 2 good, 3 excellent)
(22). Safety assessments included the monitoring of adverse events,
clinical laboratory testing, vital signs, and physical examination.
Statistical Analysis
To determine the macroscopic and histologic healing of the
4 dose groups, the percentage of patients who were healed was
calculated for each group. A logistic regression was performed
using the 0 to 1 healing indicator (healing indicator was set to 1 if
the child had grade 0 on either of the 2 scales by week 12 [healed],
and was set to 0 if neither scale had a value of grade 0 by week
12 [not healed]) at week 12 as the dependent variable, treatment
group and age group as categorical factors, and body weight as a
covariate. The estimate of the healing rate and the 95% confidence
interval was derived for each treatment dose group. No formal
hypothesis was tested for the 12-week, DB treatment phase.
Secondary efficacy endpoints were analyzed with the
Cochran-Mantel-Haenszel test stratified by age group (15 years
and 611 years). The change in the weekly average Total GERD
Symptom score, change in the weekly average GERD Symptom
Severity score, the frequency and amount of antacid use, and the
change in the percentage of days with any GERD symptom were
summarized by dose and age group.
Efficacy analyses were conducted in the intention-to-treat
population, which included all of the randomized patients who had
at least 1 postbaseline efficacy assessment. The safety assessments
were conducted in the safety population, which included all of the
randomized patients who received at least 1 dose of study drug.
Computations for all of the results were performed using the
Statistical Analysis System version 9.2 (SAS Institute, Cary, NC).
Sample Size Determination
Following the Food and Drug Administrations guidance
regarding this type of study (Food and Drug Administrations
written request and recommendations from the pediatric committee
of the European Medical Evaluations Agency for the pediatric
investigational plan for the European Union), a sample size of
100 children was determined as appropriate to evaluate the efficacy
and safety of rabeprazole at target doses of 0.5 mg/kg (10 mg
maximum dose) and 1.0 mg/kg (20 mg maximum dose) in this
study. This was based on the assumption that if the healing rate was
85%, then the lower limit of the 95% confidence interval would be
74%, which was much higher than the most conservative scenario of
a spontaneous healing rate of 58% (23).
RESULTS
Study Participation
This study was conducted in 9 countries (United States,
Belgium, Denmark, France, Italy, Poland, Israel, South Africa,
and India) from January 30, 2009 to August 19, 2010. Of the
239 children screened, 127 children were randomized and 108
(85%) had at least 1 postbaseline assessment for primary endpoint
(intention-to-treat population). The majority of the children who
were screened but did not enroll into the study either did not meet
the inclusion criteria or refused to undergo endoscopic and/or
biopsy evaluations. Overall, 19 (15%) children withdrew before
study completion (Fig. 1). None of the 127 children enrolled into the
study had a history of acute life-threatening events resulting from
manifestations of GERD.
The mean age of children was 5.7 years, with 54%of children
ages 1 to 5 years and 46% of children ages 6 to 11 years. Most
children (78%) were white (Table 1). All of the children in the older
age group (611 years) were 15 kg (high-weight cohort), whereas
42% of the children ages 1 to 5 years weighed 15 kg.
Before study entry, 29% children were receiving PPI treat-
ment, 22% received antacids, 15% used H
2
-blockers, and 2% were
taking prokinetics. On average, children had 4 to 5 GERD symp-
toms at baseline. 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 median duration of study drug
exposure was 84 days (range 6119 days).
Primary Efcacy (Endoscopic/Histological
Healing)
Overall, 81% (87/108) children achieved endoscopic/histo-
logic healing during the 12-week DB treatment period. The healing
rates were higher in the low-weight cohort (82% [5-mg dose]; 94%
[10-mg dose]) compared with those of the high-weight cohort (76%
[10-mg dose]; 78% [20-mg dose]). Nine (10%) children achieved
healing as a result of improvement in histology score while not
reaching Hetzel-Dent grade 0 (2 children each in 5-mg and 10-mg
groups of low-weight cohort, 1 child of the 10-mg high-weight
cohort and 4 in the 20-mg group).
There was a significant (P<0.001; paired t test) decrease in
the mean (standard deviation) Hetzel-Dent score from 1.5 (0.71)
points (baseline) to 0.3 (0.63) points (week 12) for all of the
children. At baseline, 61% of 108 children had a Hetzel-Dent score
identified as grade 1, 30% had grade 2, 6% had grade 3, and 3% had
grade 4. At the end of 12 weeks, 72%of all of the children improved
to grade 0, 81% had a Hetzel-Dent score improvement of 1, 18%
had no change, and 1% experienced a Hetzel-Dent score increase
from grade 1 to grade 2. A similar proportion of children in each
dose group had a Hetzel-Dent score improvement of 1: 82%
(5 mg, low-weight cohort), 81% (10 mg, low-weight cohort), 87%
(10 mg, high-weight cohort), and 76% (20 mg, high-weight cohort)
(Table 2).
During the esophagogastroduodenoscopy, biopsies were
obtained from the duodenum, the stomach (antrum), mid-esopha-
gus, and 2.5 cm above the gastroesophageal junction. Overall, 38%
of 108 children had a histology score of grade 1 at baseline, 15%had
grade 2, 39% had grade 3, 4% had grade 4, and 5% had grade 5.
There was a significant (P<0.001; paired t test) decrease in the
mean (standard deviation) histology score from 2.2 (1.13) points
(baseline) to 1.4 (1.35) points (week 12) for all of the children. At
the end of the 12-week treatment period, 38% children improved to
grade 0, 57% had an improvement in the histology score 1, 28%
had no change, and 5% showed worsening (Table 2).
Secondary Efcacy
Total GERD Symptom and Severity Score
There was a significant (P<0.001; paired t test) decrease in
the mean Total GERD Symptoms and Severity score from 19.3
points (baseline) to 8.6 points (week 12) for all of the children. The
frequency and severity of GERD symptoms decreased rapidly in all
4 dose groups until week 4. Thereafter, the score remained
unchanged until week 12 (Fig. 2). The change from baseline at
Haddad et al JPGN

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