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    Clinical Trial Results:
    A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Withdrawal Study to Evaluate the Safety and Efficacy of Delayed-Release Rabeprazole in 1- to 11-Month-Old Pediatric Subjects with Symptomatic/Erosive Gastroesophageal Reflux Disease (GERD)

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2008-004847-12
    Trial protocol
    		 HU   BE   NL   IT   BG   DK  
    Global end of trial date
    16 Nov 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Jul 2016
    First version publication date
    02 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    RABGRD3004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00992589
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Antwerpseweg 15-17, B-2340 Beerse, Belgium,
    Public contact
    Clinical Registry Group, Janssen Research & Development, +353 21 4673500, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, +353 21 4673500, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000055-PIP01-07
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Nov 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and overall safety of rabeprazole sodium at doses of 5.0 milligram (mg) and 10.0 mg relative to placebo in infant subjects with GERD who are 1 to 11 months of age at screening. The primary efficacy endpoint will be measured by the changes from baseline to the end of the study in the Infant Gastroesophageal Reflux Questionnaire-Revised (I-GERQ-R) total score and the Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) total score between the active treatment and placebo groups.
    Protection of trial subjects
    Safety assessments were consisting of monitoring and recording all Adverse event (AE) and Serious Adverse events (SAEs), measurement of vital signs, Physical examination and Clinical laboratory assessments (hematology, blood chemistries, and urine values) were assessed throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Hungary: 51
    Country: Number of subjects enrolled
    Israel: 36
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    United States: 133
    Country: Number of subjects enrolled
    South Africa: 12
    Worldwide total number of subjects
    344
    EEA total number of subjects
    156
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    344
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is a phase 3 study conducted between 4 November 2009 to 16 November 2011.

    Pre-assignment
    Screening details
    		 Four hundred twenty-seven subjects were screened for this study and 83 of these subjects were screening failures. These screening failures included 79 subjects who did not meet entry criteria and 4 subjects who failed for other reasons.

    Period 1
    Period 1 title
    Open Label
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-Label Rabeprazole Sodium 10 Milligram (mg)
    Arm description
    		 Rabeprazole Sodium capsules once daily in the morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rabeprazole Sodium 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Rabeprazole Sodium 10 mg capsule once daily in the morning.

    Number of subjects in period 1
    		Open-Label Rabeprazole Sodium 10 Milligram (mg)
    Started
    344
    Completed
    267
    Not completed
    77
         Physician decision
    4
         Lost to follow-up
    1
         Protocol violation
    3
         Other
    6
         Adverse event
    4
         Noncompliance with study drug
    2
         Withdrawal of consent
    20
         Did not meet cgi criteria
    37
    Period 2
    Period 2 title
    Double Blind
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Placebo
    Arm description
    		 Matching placebo capsules once daily in the morning.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules once daily in the morning.

    Arm title
    		 Double-Blind Rabeprazole Sodium 5 Mg
    Arm description
    		 Rabeprazole Sodium 5 mg capsule once daily in the morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rabeprazole Sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Rabeprazole Sodium 5 mg capsule once daily in the morning.

    Arm title
    		 Double-Blind Rabeprazole Sodium 10 Mg
    Arm description
    		 Rabeprazole Sodium capsules once daily in the morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rabeprazole Sodium 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Rabeprazole Sodium 10 mg capsule once daily in the morning.

    Number of subjects in period 2
    		Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg
    Started
    89
    90
    88
    Completed
    76
    77
    78
    Not completed
    13
    13
    10
         Consent withdrawn by subject
    6
    5
    2
         Other
    1
    4
    3
         Adverse event
    6
    2
    3
         Noncompliance with study drug
    -
    2
    -
         Lost to follow-up
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-Label Rabeprazole Sodium 10 Milligram (mg)
    Reporting group description
    		 Rabeprazole Sodium capsules once daily in the morning.

    Reporting group values
    		 Open-Label Rabeprazole Sodium 10 Milligram (mg) Total
    Number of subjects
    		 344 344
    Title for AgeCategorical
    Units: subjects
        >= 1 to < 4 Months
    		 175 175
        >= 4 to < 8 Months
    		 124 124
        >= 8 to < 12 Months
    		 45 45
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.6 ± 2.55 -
    Title for Gender
    Units: subjects
        Female
    		 139 139
        Male
    		 205 205

    End points

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    End points reporting groups
    Reporting group title
    Open-Label Rabeprazole Sodium 10 Milligram (mg)
    Reporting group description
    		 Rabeprazole Sodium capsules once daily in the morning.
    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Matching placebo capsules once daily in the morning.

    Reporting group title
    Double-Blind Rabeprazole Sodium 5 Mg
    Reporting group description
    		 Rabeprazole Sodium 5 mg capsule once daily in the morning.

    Reporting group title
    Double-Blind Rabeprazole Sodium 10 Mg
    Reporting group description
    		 Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent to Treat population consisted of all subjects who completed the Open-label period, were randomly assigned to treatment in the Double-blind (DB) period, had taken at least 1 dose of DB study drug, and with evaluable data at each measurement time point.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium Total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Placebo - Baseline
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Matching placebo capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium 5 mg - Baseline
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium 10 mg - Baseline
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Placebo - Week 8
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Matching placebo capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium 5 mg - Week 8
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium 10 mg - Week 8
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium Total - Baseline
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Subject analysis set title
    Double-Blind Rabeprazole Sodium Total - Week 8
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Rabeprazole Sodium capsules once daily in the morning.

    Primary: Change From Baseline in I-GERQ-R Total Score (Double-blind Phase/ Baseline Observation Carried Forward)

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    End point title
    		 Change From Baseline in I-GERQ-R Total Score (Double-blind Phase/ Baseline Observation Carried Forward)
    End point description
    The Infant Gastroesophageal Reflux Questionnaire-Revised (I-GERQ-R) is a 12-item questionnaire that is completed by the primary caregiver at every office or telephonic visit. It has a weekly recall and the items cover the frequency, amount and discomfort attributed to spit-up, refusal or stopping feeding, crying and fussing, hiccups, arching back and stopping breathing or changing color. The total score is calculated as the sum of all 12 scores for the individual questions, and ranges from 0 to 42. A higher value indicates a worse outcome. Here, "Number of Subjects Analysed" is number of subject analysed for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    89 [1]
    89 [2]
    87 [3]
    176 [4]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -3.6 ± 6.41
    -3.8 ± 7.5
    -4.1 ± 7
    -3.9 ± 7.24
    Notes
    [1] - ITT Population
    [2] - ITT Population
    [3] - ITT Population
    [4] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Least-Squares Mean Difference
    Point estimate
    0.042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.615
         upper limit
    		 1.7
    Notes
    [5] - ANCOVA with Treatment as fixed effect, Region and Age as stratification factors and Change from Open-label (OL) Baseline to OL Endpoint as covariate to test the hypothesis of no difference in change in I-GERQ-R Total Score.

    Primary: Change From Baseline in in Weekly Average I-GERQ-DD Total Score (Double-blind Phase/ Baseline Observation Carried Forward)

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    End point title
    		 Change From Baseline in in Weekly Average I-GERQ-DD Total Score (Double-blind Phase/ Baseline Observation Carried Forward)
    End point description
    The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the participant has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. Each of the 9 items will be assigned a numeric score. The total score will be calculated as the sum of all 9 items, and ranges from 0 to 37. A higher value indicates a worse outcome. Here, "Number of subject analysed" were the subjects with evaluable data at each measurement time point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    88 [6]
    88 [7]
    87 [8]
    176 [9]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -1.9 ± 4.55
    -1.6 ± 4.85
    -2.1 ± 4.9
    -1.9 ± 4.86
    Notes
    [6] - ITT Population
    [7] - ITT Population
    [8] - ITT Population
    [9] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.968 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Least-Squares Mean Difference [4]
    Point estimate
    0.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.167
         upper limit
    		 1.214
    Notes
    [10] - Analysis of Covariance with Treatment as fixed effect, Region and Age as stratification factors and Change from Open-label (OL) Baseline to OL Endpoint as covariate to test the hypothesis of no difference in change in Weekly Average I-GERQ-DD Total S

    Secondary: Change From Baseline in Average Daily Frequency of Regurgitation (Double-blind Phase/ Baseline Observation Carried Forward)

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    End point title
    		 Change From Baseline in Average Daily Frequency of Regurgitation (Double-blind Phase/ Baseline Observation Carried Forward)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    89 [11]
    90 [12]
    88 [13]
    178 [14]
    Units: Frequency of Regurgitation
        arithmetic mean (standard deviation)
    -0.8 ± 1.58
    -0.8 ± 1.55
    -1.6 ± 3.63
    -1.2 ± 2.79
    Notes
    [11] - ITT Population
    [12] - ITT Population
    [13] - ITT Population
    [14] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of Covariance with Treatment as fixed effect, Region and Age as stratification factors and Change from Open-label (OL) Baseline to OL Endpoint as covariate to test the hypothesis of no difference in change in daily average frequency of regurgitation from Double-blind (DB) Baseline to DB Endpoint between rabeprazole sodium total and placebo.
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.168
    Method
    		 ANCOVA
    Parameter type
    		 Least-Squares Mean Difference
    Point estimate
    -0.449
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.087
         upper limit
    		 0.19

    Secondary: Change From Baseline in Weight-for-Age Z-Score (Double-blind Phase/ Baseline Observation Carried Forward)

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    End point title
    		 Change From Baseline in Weight-for-Age Z-Score (Double-blind Phase/ Baseline Observation Carried Forward)
    End point description
    Body weight was measured with the participant unclothed and before a feeding during each office visit. In the analysis of weight data, weight will be transformed to the weight-for-age Z-score using World Health Organization Child Growth Standards, taking into account the infant’s age and gender (Borghi E, 2006). Here, "Number of Subjects Analysed" is number of subject analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    89 [15]
    90 [16]
    88 [17]
    178 [18]
    Units: Z-score
        arithmetic mean (standard deviation)
    0.11 ± 0.329
    0.16 ± 0.322
    0.11 ± 0.264
    0.14 ± 0.295
    Notes
    [15] - ITT Population
    [16] - ITT Population
    [17] - ITT Population
    [18] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Least-Squares Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.047
         upper limit
    		 0.108
    Notes
    [19] - ANCOVA with Treatment as fixed effect, Region and Age as stratification factors and Double-blind (DB) Baseline as covariate to test the hypothesis of no difference in change in Weight-for-Age Z-Score.

    Secondary: The Daily Average Number of Episodes Related to Each Volume of Regurgitation During the Double-blind Treatment Period

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    End point title
    		 The Daily Average Number of Episodes Related to Each Volume of Regurgitation During the Double-blind Treatment Period
    End point description
    The Daily Average Number of Episodes Related to Each Volume of Regurgitation During the Double-blind Treatment Period. Here, Number of subject analysed is the subjects is the subjects with evaluable data at each measurement time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo - Baseline Double-Blind Rabeprazole Sodium 5 mg - Baseline Double-Blind Rabeprazole Sodium 10 mg - Baseline Double-Blind Placebo - Week 8 Double-Blind Rabeprazole Sodium 5 mg - Week 8 Double-Blind Rabeprazole Sodium 10 mg - Week 8 Double-Blind Rabeprazole Sodium Total - Baseline Double-Blind Rabeprazole Sodium Total - Week 8
    Number of subjects analysed
    89 [20]
    90 [21]
    88 [22]
    89 [23]
    90 [24]
    88 [25]
    178 [26]
    178 [27]
    Units: number of episodes
    number (not applicable)
        Less than 1 tablespoon
    1.7
    1.7
    2.7
    1.6
    1.6
    2.1
    2.1
    1.8
        1 to 2 tablespoons
    1.1
    1.2
    1.7
    1.1
    1
    1.4
    1.5
    1.2
        More than 2 tablespoons to 2 fluid oz
    0.4
    0.3
    0.4
    0.5
    0.3
    0.4
    0.4
    0.4
        More than 2 fluid oz to 4 fluid oz
    0.1
    0
    0
    0.1
    0.1
    0.1
    0
    0.1
        More than 4 fluid oz
    0
    0
    0.1
    0
    0
    0
    0.1
    0
    Notes
    [20] - ITT Population
    [21] - ITT Population
    [22] - ITT Population
    [23] - ITT Population
    [24] - ITT Population
    [25] - ITT Population
    [26] - ITT Population
    [27] - ITT Population
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Average I-GERQ-DD Regurgitation Subscale Score (Double-blind Phase/ Last Observation Carried Forward)

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    End point title
    		 Change From Baseline in Weekly Average I-GERQ-DD Regurgitation Subscale Score (Double-blind Phase/ Last Observation Carried Forward)
    End point description
    The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the participant has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. The Regurgitation subscale will be calculated as the sum of the 3 questions regarding regurgitation (Questions 1, 2, 3) and will range from 0 to 13. For each subscale score, a higher value indicates a worse outcome. Here, number of subject analysed is the number of subject with evaluable data at each measurement time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    88 [28]
    88 [29]
    85 [30]
    173 [31]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.8 ± 2.57
    -0.8 ± 2.56
    -1 ± 2.38
    -0.9 ± 2.47
    Notes
    [28] - ITT Population
    [29] - ITT Population
    [30] - ITT Population
    [31] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.984 [32]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least square mean
    Point estimate
    0.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.619
         upper limit
    		 0.632
    Notes
    [32] - ANCOVA with Treatment as fixed effect, Region and Age as stratification factors and Double-blind (DB) Baseline as covariate to test the hypothesis of no difference in change Weekly Average I-GERQ-DD.

    Secondary: Change From Baseline in Weekly Average I-GERQ-DD Eating Behavior Subscale Score (Double-blind Phase/ Last Observation Carried Forward)

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    End point title
    		 Change From Baseline in Weekly Average I-GERQ-DD Eating Behavior Subscale Score (Double-blind Phase/ Last Observation Carried Forward)
    End point description
    The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the subject has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. The Eating Behavior subscale score will be calculated as the sum of the 3 questions regarding eating behavior (Questions 4, 5, 6) and will range from 0 to 12. For each subscale score, a higher value indicates a worse outcome. Here, "Number of Subjects Analysed" is number of subject analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    88 [33]
    88 [34]
    85 [35]
    173 [36]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.1 ± 2.54
    -0.1 ± 2.19
    -0.4 ± 2.15
    -0.3 ± 2.17
    Notes
    [33] - ITT Population
    [34] - ITT Population
    [35] - ITT Population
    [36] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.498
    Method
    		 ANCOVA
    Parameter type
    		 Least-Squares Mean Difference
    Point estimate
    -0.192
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.751
         upper limit
    		 0.366

    Secondary: Change From Baseline in Weekly Average I-GERQ-DD Discomfort Subscale Score (Double-blind Phase/ Last Observation Carried Forward)

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    End point title
    		 Change From Baseline in Weekly Average I-GERQ-DD Discomfort Subscale Score (Double-blind Phase/ Last Observation Carried Forward)
    End point description
    The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the subject has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. The Discomfort subscale score will be calculated as the sum of the 3 questions regarding discomfort (Questions, 7, 8, 9) and will range from 0 to 12. For each subscale score, a higher value indicates a worse outcome. Here, "Number of Subjects Analysed" is number of subject analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Double-Blind Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium Total
    Number of subjects analysed
    88 [37]
    88 [38]
    85 [39]
    173 [40]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0 ± 2.24
    -0.1 ± 1.88
    -0.4 ± 1.94
    -0.2 ± 1.9
    Notes
    [37] - ITT population
    [38] - ITT Population
    [39] - ITT Population
    [40] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Double-Blind Placebo v Double-Blind Rabeprazole Sodium Total
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.479
    Method
    		 ANCOVA
    Parameter type
    		 Least-Squares Mean Difference
    Point estimate
    -0.182
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 0.325

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to End of study (Week 8)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Matching placebo capsules once daily in the morning.

    Reporting group title
    Double-Blind Rabeprazole Sodium 5 Mg
    Reporting group description
    		 Rabeprazole Sodium capsules once daily in the morning.

    Reporting group title
    Open-Label Rabeprazole Sodium 10 Mg
    Reporting group description
    		 Rabeprazole Sodium capsules once daily in the morning.

    Reporting group title
    Double-Blind Rabeprazole Sodium 10 Mg
    Reporting group description
    		 Rabeprazole Sodium capsules once daily in the morning.

    Serious adverse events
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Open-Label Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium 10 Mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 89 (2.25%)
    6 / 90 (6.67%)
    5 / 344 (1.45%)
    2 / 88 (2.27%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Beta 2 Microglobulin Increased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 344 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 90 (1.11%)
    0 / 344 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    0 / 344 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Stridor
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 90 (1.11%)
    0 / 344 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 90 (1.11%)
    0 / 344 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 344 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 90 (1.11%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 90 (1.11%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 90 (2.22%)
    0 / 344 (0.00%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic Acidosis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Double-Blind Placebo Double-Blind Rabeprazole Sodium 5 Mg Open-Label Rabeprazole Sodium 10 Mg Double-Blind Rabeprazole Sodium 10 Mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 89 (40.45%)
    26 / 90 (28.89%)
    79 / 344 (22.97%)
    39 / 88 (44.32%)
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 344 (0.00%)
    2 / 88 (2.27%)
         occurrences all number
    0
    0
    0
    2
    Blood Gastrin Increased
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 90 (2.22%)
    1 / 344 (0.29%)
    7 / 88 (7.95%)
         occurrences all number
    0
    2
    1
    7
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    5 / 344 (1.45%)
    2 / 88 (2.27%)
         occurrences all number
    1
    0
    5
    2
    Pyrexia
         subjects affected / exposed
    2 / 89 (2.25%)
    6 / 90 (6.67%)
    9 / 344 (2.62%)
    5 / 88 (5.68%)
         occurrences all number
    2
    9
    9
    5
    Ear and labyrinth disorders
    Tympanic Membrane Hyperaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    0 / 344 (0.00%)
    2 / 88 (2.27%)
         occurrences all number
    0
    0
    0
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 89 (3.37%)
    0 / 90 (0.00%)
    2 / 344 (0.58%)
    0 / 88 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 89 (4.49%)
    4 / 90 (4.44%)
    11 / 344 (3.20%)
    2 / 88 (2.27%)
         occurrences all number
    4
    5
    11
    2
    Constipation
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 90 (1.11%)
    11 / 344 (3.20%)
    2 / 88 (2.27%)
         occurrences all number
    2
    1
    11
    2
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    7 / 89 (7.87%)
    2 / 90 (2.22%)
    0 / 344 (0.00%)
    4 / 88 (4.55%)
         occurrences all number
    7
    2
    0
    4
    Teething
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 90 (2.22%)
    3 / 344 (0.87%)
    3 / 88 (3.41%)
         occurrences all number
    1
    2
    3
    3
    Vomiting
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 90 (4.44%)
    4 / 344 (1.16%)
    1 / 88 (1.14%)
         occurrences all number
    5
    4
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 90 (2.22%)
    5 / 344 (1.45%)
    1 / 88 (1.14%)
         occurrences all number
    3
    3
    5
    1
    Nasal Congestion
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 90 (0.00%)
    3 / 344 (0.87%)
    2 / 88 (2.27%)
         occurrences all number
    2
    0
    3
    2
    Skin and subcutaneous tissue disorders
    Dermatitis Diaper
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    2 / 88 (2.27%)
         occurrences all number
    1
    0
    1
    2
    Intertrigo
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 90 (2.22%)
    0 / 344 (0.00%)
    0 / 88 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Rash
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 90 (1.11%)
    8 / 344 (2.33%)
    1 / 88 (1.14%)
         occurrences all number
    2
    1
    8
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    4 / 88 (4.55%)
         occurrences all number
    1
    0
    1
    4
    Bronchiolitis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 90 (0.00%)
    2 / 344 (0.58%)
    1 / 88 (1.14%)
         occurrences all number
    2
    0
    2
    1
    Ear Infection
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 90 (1.11%)
    4 / 344 (1.16%)
    0 / 88 (0.00%)
         occurrences all number
    4
    1
    4
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 90 (2.22%)
    11 / 344 (3.20%)
    3 / 88 (3.41%)
         occurrences all number
    3
    2
    11
    4
    Otitis Media
         subjects affected / exposed
    2 / 89 (2.25%)
    4 / 90 (4.44%)
    6 / 344 (1.74%)
    3 / 88 (3.41%)
         occurrences all number
    2
    4
    6
    3
    Otitis Media Acute
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 90 (1.11%)
    1 / 344 (0.29%)
    1 / 88 (1.14%)
         occurrences all number
    2
    1
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 90 (0.00%)
    1 / 344 (0.29%)
    2 / 88 (2.27%)
         occurrences all number
    0
    0
    1
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 90 (1.11%)
    6 / 344 (1.74%)
    7 / 88 (7.95%)
         occurrences all number
    5
    1
    6
    7
    Rhinitis
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 90 (2.22%)
    1 / 344 (0.29%)
    1 / 88 (1.14%)
         occurrences all number
    1
    2
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2010
    This amendment included reduction of blood sampling volumes, provided additional exclusion criteria, provided clarification concerning the collection of PK samples, provided a larger window for blood draws, added an additional temperature sampling method, and provided additional clarification of symptom management of GERD, criteria for study completion, and data entry.
    13 May 2011
    This amendment included the addition of an interim analysis to rule out potential futility of continuing the trial in the absence of a positive response, provided clarification of an exclusion criterion (receipt of an investigational drug or use of an investigational device), and clarified PK sampling procedures.
    22 Aug 2011
    This amendment changed the method of imputation of missing data for statistical analyses and provided clarification of the definition of how baseline values for the primary endpoints were calculated.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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