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    Clinical Trial Results:
    A Pharmacokinetic, Pharmacodynamic and Short-term Safety Study of Single and Multiple Day Doses of Rabeprazole Sodium in Neonates and Pre-term Infants with a Corrected Age of Less than 44 Weeks with a Presumptive Diagnosis of 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
    2009-015885-75
    Trial protocol
    GB   DE  
    Global end of trial date
    14 Jan 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Jul 2016
    First version publication date
    01 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
    RABGRD1005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00855361
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Johnson and Johnson Pharmaceutical Research and Development, L.L.C.
    Sponsor organisation address
    1125 Trenton-Harbourton Rd, Titusville, New Jersey, United States, 08560
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, 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
    14 Jan 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the pharmacokinetics (PK) using population PK methods, pharmacodynamics (PD) (intraesophageal and intragastric pH, assessment of the overall treatment effect [OTE] [overall GERD symptom relief]) and the short-term safety of rabeprazole after single and multiple dose administration for up to 28 days at one low dose level (Part 1) and two presumed effective dose levels (Part 2) in neonates and pre-term infants, with a corrected age of less than 44 weeks at the time of the first dose, who have been diagnosed with GERD.
    Protection of trial subjects
    The investigator is responsible for ensuring that the clinical study is performed in accordance with the protocol, current ICH guidelines on Good Clinical Practice (GCP) and all applicable regulatory and legal requirements. The safety evaluations were based on the following Reports of Adverse effects (AEs) and serious adverse effects (SAEs) : Clinical laboratory tests (hematology, serum chemistry, and urinalysis), Vital sign measurements (blood pressure [systolic and diastolic], pulse rate, and respiratory rate, and body temperature)
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    69
    EEA total number of subjects
    41
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    15
    Infants and toddlers (28 days-23 months)
    54
    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
    Total 69 subjects were enrolled in study from 22 sites in 4 countries.

    Pre-assignment
    Screening details
    A total of 69 neonates and pre-term infants having a presumptive diagnosis of GERD; including 19 subjects in Part 1 (rabeprazole 1 mg) and 50 subjects in Part 2 (25 subjects each in rabeprazole 2-mg and 3-mg treatment groups) were enrolled.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1: Rabeprazole 1 milligram (mg)
    Arm description
    Subject received 1 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 1). The study drug was administered through a nasogastric or orogastric tube.
    Arm type
    Experimental

    Investigational medicinal product name
    Rabeprazole Sodium
    Investigational medicinal product code
    R128546
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 1.0 milligram [mg] rabeprazole sodium every 24 hours for a minimum of 5 days and a maximum of 28 days.

    Arm title
    Part 2: Rabeprazole 2 mg
    Arm description
    Subject received 2 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug was administered through a nasogastric or orogastric tube.
    Arm type
    Experimental

    Investigational medicinal product name
    Rabeprazole sodium
    Investigational medicinal product code
    R128546
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 2.0 milligram [mg] rabeprazole sodium every 24 hours for a minimum of 5 days and a maximum of 28 days.

    Arm title
    Part 2: Rabeprazole 3 mg
    Arm description
    one single daily dose of rabeprazole sodium 3 mg as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug will be administered through a nasogastric or orogastric tube.
    Arm type
    Experimental

    Investigational medicinal product name
    Rabeprazole sodium
    Investigational medicinal product code
    R128546
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 3.0 milligram [mg] rabeprazole sodium every 24 hours for a minimum of 5 days and a maximum of 28 days.

    Number of subjects in period 1
    Part 1: Rabeprazole 1 milligram (mg) Part 2: Rabeprazole 2 mg Part 2: Rabeprazole 3 mg
    Started
    19
    25
    25
    Completed
    1
    0
    0
    Not completed
    18
    25
    25
         Other
    2
    1
    2
         Physician decision
    14
    23
    21
         Lack of efficacy
    1
    -
    1
         Consent withdrawn by subject
    -
    1
    -
         Adverse Event
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Rabeprazole 1 milligram (mg)
    Reporting group description
    Subject received 1 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 1). The study drug was administered through a nasogastric or orogastric tube.

    Reporting group title
    Part 2: Rabeprazole 2 mg
    Reporting group description
    Subject received 2 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug was administered through a nasogastric or orogastric tube.

    Reporting group title
    Part 2: Rabeprazole 3 mg
    Reporting group description
    one single daily dose of rabeprazole sodium 3 mg as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug will be administered through a nasogastric or orogastric tube.

    Reporting group values
    Part 1: Rabeprazole 1 milligram (mg) Part 2: Rabeprazole 2 mg Part 2: Rabeprazole 3 mg Total
    Number of subjects
    19 25 25 69
    Title for AgeCategorical
    Units: subjects
        Newborns (0-27 days)
    2 5 8 15
        infants and toddlers(28 - 135 days)
    17 20 17 54
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    52.5 ± 26.99 58.3 ± 33.52 46.4 ± 26.74 -
    Title for Gender
    Units: subjects
        Female
    7 13 13 33
        Male
    12 12 12 36

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Rabeprazole 1 milligram (mg)
    Reporting group description
    Subject received 1 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 1). The study drug was administered through a nasogastric or orogastric tube.

    Reporting group title
    Part 2: Rabeprazole 2 mg
    Reporting group description
    Subject received 2 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug was administered through a nasogastric or orogastric tube.

    Reporting group title
    Part 2: Rabeprazole 3 mg
    Reporting group description
    one single daily dose of rabeprazole sodium 3 mg as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug will be administered through a nasogastric or orogastric tube.

    Primary: Maximum Observed Plasma Concentration (Cmax) of Rabeprazole and Thioether Metabolite

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of Rabeprazole and Thioether Metabolite [1]
    End point description
    The Cmax is the maximum observed plasma concentration.
    End point type
    Primary
    End point timeframe
    Up to Day 5
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    Part 1: Rabeprazole 1 milligram (mg) Part 2: Rabeprazole 2 mg Part 2: Rabeprazole 3 mg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Nanogram per milliliter [ng/ml]
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [2] - Data not reoprted as only sparse PK sampling was done no quantitative analysis were performed.
    [3] - Data not reoprted as only sparse PK sampling was done no quantitative analysis were performed.
    [4] - Data not reoprted as only sparse PK sampling was done no quantitative analysis were performed.
    No statistical analyses for this end point

    Primary: Change From Baseline in Intraesophageal pH concentration and intragastric pH Concentration

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    End point title
    Change From Baseline in Intraesophageal pH concentration and intragastric pH Concentration [5]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, Day 5
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    Part 1: Rabeprazole 1 milligram (mg) Part 2: Rabeprazole 2 mg Part 2: Rabeprazole 3 mg
    Number of subjects analysed
    19
    25
    25
    Units: millimole. hour per liter (mmol.h/L)
    arithmetic mean (standard deviation)
        Baseline: Intragastric pH
    31.43 ± 22.8523
    35.539 ± 18.3496
    44.357 ± 22.9909
        Baseline: Intraesophageal pH
    4.179 ± 5.4933
    6.946 ± 9.6122
    18.232 ± 24.1211
        Change at Day 5: Intragastric pH
    -19.394 ± 30.3668
    -35.645 ± 19.5423
    -23.055 ± 20.5577
        Change at Day 5: Intraesophageal pH
    -1.555 ± 7.8498
    -5.541 ± 10.5261
    -17.512 ± 23.9473
    No statistical analyses for this end point

    Secondary: Number of Participants With Serious and Non-Serious Adverse Events

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    End point title
    Number of Participants With Serious and Non-Serious Adverse Events
    End point description
    Safety and tolerability was measured by number of reported adverse events (serious and non-serious) and repeated clinical evaluation of physical examinations, vital signs, 12-lead electrocardiogram (ECG), 24-hour continuous cardiac monitoring, and laboratory tests (hematology/blood chemistry/urinalysis).
    End point type
    Secondary
    End point timeframe
    Approximately 8 weeks
    End point values
    Number of subjects analysed
    Units: Number of participants
        Serious Adverse Events
        Non-serious Adverse Events
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with GERD Symptom Releif Relative to Baseline

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    End point title
    Percentage of Subjects with GERD Symptom Releif Relative to Baseline
    End point description
    Overall Treatment Effectiveness was reported by assessing the overall GERD symptom relief as compared to baseline. Here, number of sbuject analysed is the subject anaysed for this outcome measure and "n" is number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 5, 10 and 28
    End point values
    Part 1: Rabeprazole 1 milligram (mg) Part 2: Rabeprazole 2 mg Part 2: Rabeprazole 3 mg
    Number of subjects analysed
    18
    25
    25
    Units: percentage of subject
    number (not applicable)
        Day 5: Better (n=18, 25, 25)
    13
    20
    20
        Day 5: No change (n=18, 25, 25)
    4
    5
    4
        Day 5: Worse (n=18, 25, 25)
    1
    0
    1
        Day 10: Better (n=9, 7, 11)
    8
    7
    9
        Day 10: No Change (n=9, 7, 11)
    1
    7
    2
        Day 10: Worse (n=9, 7, 11)
    0
    0
    0
        Day 28: Better (n=1, 0, 0)
    1
    0
    0
        Day 28: No Change (1, 0, 0)
    0
    0
    0
        Day 28: Worse (n=1, 0, 0)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 28
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Part 1: Rabeprazole 1 mg
    Reporting group description
    Subject received 1 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 1). The study drug was administered through a nasogastric or orogastric tube.

    Reporting group title
    Part 2: Rabeprazole 3 mg
    Reporting group description
    Subject received 3 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug was administered through a nasogastric or orogastric tube.

    Reporting group title
    Part 2: Rabeprazole 2 mg
    Reporting group description
    Subject received 2 mg of rabeprazole sodium as a microgranule formulation for up to 28 consecutive days (Part 2). The study drug was administered through a nasogastric or orogastric tube.

    Serious adverse events
    Part 1: Rabeprazole 1 mg Part 2: Rabeprazole 3 mg Part 2: Rabeprazole 2 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 19 (10.53%)
    4 / 25 (16.00%)
    1 / 25 (4.00%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral Atrophy
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy of Prematurity
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Necrotising Colitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal Necrosis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Part 1: Rabeprazole 1 mg Part 2: Rabeprazole 3 mg Part 2: Rabeprazole 2 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 19 (31.58%)
    16 / 25 (64.00%)
    12 / 25 (48.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema Peripheral
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Feeding Tube Complication
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Haematocrit Decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Oxygen Saturation Decreased
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    Head Circumference Abnormal
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Red Blood Cell Count Decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    3
    1
    Congenital, familial and genetic disorders
    Atrial Septal Defect
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal Congestion
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Apnoea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    6 / 25 (24.00%)
    5 / 25 (20.00%)
         occurrences all number
    2
    6
    5
    Anaemia Neonatal
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Conjunctival Disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    1
    2
    Retinopathy of Prematurity
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Eye Discharge
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    2
    Gastrointestinal disorders
    Aphthous Stomatitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Impaired Gastric Emptying
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Infantile Colic
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Inguinal Hernia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Umbilical Hernia
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis Diaper
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Skin Lesion
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Feeding Disorder Neonatal
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes Virus Infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2010
    The amendment was implemented after completion of Part 1 of the study, but before study drug administration began in Part 2 of the study. The important changes in the amendment included the following: participants need to be admitted to NICU or step-down unit prior to alimentation by a feeding tube (6 F NG or OG); Clarification on minimum number of subjects needed in Part 2 of study and undergoing pHmetry; Clarification on changes made to reflect the selection of 2 dose levels and formulation for Part 2. Dosing instructions for Part 2 were updated; Clarification on certain assessments done in subjects undergoing or not undergoing pHmetry in the Part 2 of study; Additional exclusion criteria for continuous feeding, and mothers taking PPIs and breast feeding; In Part 1 of the study, for serum laboratory assessment, the safety laboratory parameters were changed to: Hemoglobin, hematocrit, sodium, potassium, chloride, calcium, bicarbonate, AST, ALT, total bilirubin, direct bilirubin, albumin, BUN, glucose, creatinine, and total protein; Clarification on certain medications allowed or disallowed during the study; Capillary sampling for PK was allowed; but venous collection was preferable; Blood volume for PK evaluation was reduced to 0.4 mL per sample; Indication that the PK samples collected between 2- to 3-hours postdose and 3- to 4-hours postdose should be separated by at least 1 hour.
    18 May 2011
    The amendment was implemented in Part 2 of the study before study drug administration which began for 21 participants. The important changes in amendment included the following: Instead of 6 F NG or OG feeding tube only, a ≥6 F NG or OG feeding tube may be used; 6.5 F silicone NG or OG tubes should be avoided. Due to dosing issues with vehicle tablet (described below), vehicle granules supplied in sachets instead of vehicle tablets were used for dosing in Part 2 -directions for dose preparation were updated The reason for this amendment was the occurrence of clogging of NG or OG tube in 5 participants (participants 1175001, 1085003, 1105002, 1085004 and 1455001) who had been randomized to the 3 mg dose group of rabeprazole. In one participants (participants 1105002), the occurrence of tube clogging was reported as a study-drug related TEAE. This dose (3 mg) of study drug required 2 vehicle tablets to be added to water in order to form suspension with the rabeprazole granules. Participants randomized to the 2 mg dose only required one vehicle tablet to form the suspension and did not experience NG or OG tube clogging. After reports of difficulty with infusion of the study drug during the first administration in some participants receiving the 3 mg dose, several mitigation strategies were employed including avoidance of 6.5 F silicone NG or OG tubes (more adherence of suspension in silicone tubes vs. tubes made of other materials); vigorous shaking of the suspension in syringe just prior to infusion via NG or OG tube; Use of an interval water flush midway through the infusion of the suspension; and changing to an 8 F feeding tube in infants with a 6 F tube in place. With these mitigation strategies, full timely doses of study drug were able to be administered to participants. Protocol Amendment INT-2 substituted the vehicle granules as suspending agent instead of the vehicle tablet.
    13 Sep 2011
    The amendment was implemented in Part 2 of the study before study drug administration began for 18 participants. This included a further clarification on the feeding regimens for participants undergoing pHmetry and not undergoing pHmetry.

    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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