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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Two-Phase, Multicenter Study to Evaluate the Efficacy and Safety of Vonoprazan 20 mg Compared to Lansoprazole 30 mg for Healing in Patients with Erosive Esophagitis and to Evaluate the Efficacy and Safety of Vonoprazan (10 mg and 20 mg) Compared to Lansoprazole 15 mg for the Maintenance of Healing in Patients with Healed Erosive Esophagitis

    Summary
    EudraCT number
    		 2019-002579-33
    Trial protocol
    		 GB   CZ   HU   PL   BG  
    Global end of trial date
    24 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jul 2022
    First version publication date
    22 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EE-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04124926
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Phathom Pharmaceuticals, Inc.
    Sponsor organisation address
    2150 East Lake Cook Road, Suite 800, Buffalo Grove, Illinois, United States, 60089
    Public contact
    Phathom Medical Information, Phathom Pharmaceuticals, Inc., 1 888-775-PHAT (7428), medicalinformation@phathompharma.com
    Scientific contact
    Phathom Medical Information, Phathom Pharmaceuticals, Inc., 1 888-775-PHAT (7428), medicalinformation@phathompharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of vonoprazan compared to lansoprazole in participants with erosive esophagitis.
    Protection of trial subjects
    This study was conducted in compliance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E6 (Revision 2) Section 3, Institutional Review Board/Independent Ethics Committee guidelines, Good Clinical Practice regulations and guidelines, and all applicable local regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 The regulatory approved doses of lansoprazole 30 mg and 15 mg have been selected for the Healing and Maintenance Phase, respectively, as these are approved therapeutic doses in the United States and Europe.
    Actual start date of recruitment
    28 Oct 2019
    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
    Poland: 213
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Bulgaria: 47
    Country: Number of subjects enrolled
    Czechia: 70
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    United States: 644
    Worldwide total number of subjects
    1027
    EEA total number of subjects
    352
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    827
    From 65 to 84 years
    200
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was performed at 111 sites in 6 countries (Bulgaria, Czechia, Hungary, Poland, the United Kingdom and the United States) between 28 October 2019 and 24 August 2021. Of the 4,167 participants screened for the study, 1,027 participants with erosive esophagitis (EE) were randomized in the Healing Phase.

    Pre-assignment
    Screening details
    		 Participants were randomized to receive vonoprazan 20 mg once per day (QD) or lansoprazole 30 mg QD using a 1:1 ratio in the Healing Phase. Participants with endoscopic healing of EE at 2 or 8 weeks were re-randomized to receive vonoprazan 10 mg QD, vonoprazan 20 mg QD, or lansoprazole 15 mg QD using a 1:1:1 ratio in the Maintenance Phase.

    Period 1
    Period 1 title
    Healing Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    A double-blind design was employed so that both the investigators and the participants were unaware of the treatment assignment during the entire study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Healing Phase: Vonoprazan 20 mg
    Arm description
    		 Participants received oral vonoprazan 20 mg QD for a maximum of 8 weeks in the Healing Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vonoprazan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vonoprazan was administered orally as over-encapsulated tablets.

    Arm title
    		 Healing Phase: Lansoprazole 30 mg
    Arm description
    		 Participants received oral lansoprazole 30 mg QD for a maximum of 8 weeks in the Healing Phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lansoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lansoprazole was administered orally as over-encapsulated capsules.

    Number of subjects in period 1
    		Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Started
    514
    513
    Treated with study drug
    514
    510
    Completed
    483
    481
    Not completed
    31
    32
         Adverse event, non-fatal
    3
    7
         Protocol violation
    -
    1
         Randomized but not treated
    -
    3
         Miscellaneous
    8
    7
         Withdrawal of consent
    5
    3
         Lost to follow-up
    5
    4
         Voluntary withdrawal
    10
    7
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    A double-blind design was employed so that both the investigators and the participants were unaware of the treatment assignment during the entire study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance Phase: Vonoprazan 10 mg
    Arm description
    		 Participants received oral vonoprazan 10 mg QD for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vonoprazan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vonoprazan was administered orally as over-encapsulated tablets.

    Arm title
    		 Maintenance Phase: Vonoprazan 20 mg
    Arm description
    		 Participants received oral vonoprazan 20 mg QD for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vonoprazan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vonoprazan was administered orally as over-encapsulated tablets.

    Arm title
    		 Maintenance Phase: Lansoprazole 15 mg
    Arm description
    		 Participants received oral lansoprazole 15 mg QD for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lansoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lansoprazole was administered orally as over-encapsulated capsules.

    Number of subjects in period 2 [1]
    		Maintenance Phase: Vonoprazan 10 mg Maintenance Phase: Vonoprazan 20 mg Maintenance Phase: Lansoprazole 15 mg
    Started
    298
    298
    297
    Treated with study drug
    296
    296
    297
    Completed
    274
    269
    269
    Not completed
    24
    29
    28
         Adverse event, non-fatal
    3
    5
    4
         Protocol violation
    3
    -
    -
         Randomized but not treated
    2
    2
    -
         Miscellaneous
    1
    2
    4
         Pregnancy
    -
    1
    -
         Withdrawal of consent
    5
    5
    5
         Lost to follow-up
    7
    8
    9
         Voluntary withdrawal
    3
    6
    5
         Lack of efficacy
    -
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only participants with endoscopic healing of EE at 2 or 8 weeks were re-randomized to receive vonoprazan 10 mg QD, vonoprazan 20 mg QD, or lansoprazole 15 mg QD in the Maintenance Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Healing Phase: Vonoprazan 20 mg
    Reporting group description
    		 Participants received oral vonoprazan 20 mg QD for a maximum of 8 weeks in the Healing Phase.

    Reporting group title
    Healing Phase: Lansoprazole 30 mg
    Reporting group description
    		 Participants received oral lansoprazole 30 mg QD for a maximum of 8 weeks in the Healing Phase.

    Reporting group values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg Total
    Number of subjects
    		 514 513 1027
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 421 406 827
        >=65 years
    		 93 107 200
    Gender categorical
    Units: Subjects
        Female
    		 256 289 545
        Male
    		 258 224 482
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 62 59 121
        Not Hispanic or Latino
    		 450 451 901
        Unknown or Not Reported
    		 2 3 5
    Race
    Units: Subjects
        White
    		 474 458 932
        Black or African-American
    		 23 41 64
        Asian
    		 7 6 13
        American Indian or Alaska Native
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
        Other
    		 5 5 10
        Unknown
    		 1 1 2
        Not Reported
    		 1 0 1
    Adjudicated Los Angeles (LA) Classification of Esophagitis Grading Scale
    LA Classification of Esophagitis Grading Scale: Grade A: One or more mucosal breaks with a length of no longer than 5 mm that did not extend between the tops of 2 mucosal folds. Grade B: One or more mucosal breaks with a length of longer than 5 mm that did not extend between the tops of 2 mucosal folds. Grade C: One or more mucosal breaks that are continuous between the tops of 2 or more mucosal folds, which involves less than 75% of the circumference. Grade D: One or more mucosal breaks, which involves at least 75% of the circumference.
    Units: Subjects
        Grade A or B
    		 337 336 673
        Grade C or D
    		 177 174 351
        Unknown or Not Reported
    		 0 3 3

    End points

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    End points reporting groups
    Reporting group title
    Healing Phase: Vonoprazan 20 mg
    Reporting group description
    		 Participants received oral vonoprazan 20 mg QD for a maximum of 8 weeks in the Healing Phase.

    Reporting group title
    Healing Phase: Lansoprazole 30 mg
    Reporting group description
    		 Participants received oral lansoprazole 30 mg QD for a maximum of 8 weeks in the Healing Phase.
    Reporting group title
    Maintenance Phase: Vonoprazan 10 mg
    Reporting group description
    		 Participants received oral vonoprazan 10 mg QD for 24 weeks.

    Reporting group title
    Maintenance Phase: Vonoprazan 20 mg
    Reporting group description
    		 Participants received oral vonoprazan 20 mg QD for 24 weeks.

    Reporting group title
    Maintenance Phase: Lansoprazole 15 mg
    Reporting group description
    		 Participants received oral lansoprazole 15 mg QD for 24 weeks.

    Primary: Healing Phase: Percentage of Participants Who Had Complete Healing of EE by Week 8

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    End point title
    		 Healing Phase: Percentage of Participants Who Had Complete Healing of EE by Week 8
    End point description
    A participant was considered to have complete healing of EE if healing was demonstrated during endoscopy. The Modified Intent-to-Treat (MITT) Set (Healing Phase) included all participants randomized into the Healing Phase who had documented EE at baseline and received at least 1 dose of study drug during the Healing Phase. All analyses using the MITT Set grouped subjects according to the randomized treatment.
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Number of subjects analysed
    514
    510
    Units: percentage of participants
        number (not applicable)
    92.9
    84.6
    Statistical analysis title
    		 Vonoprazan 20 mg versus (vs) Lansoprazole 30 mg
    Statistical analysis description
    The 2-sided 95% confidence interval (CI) of the difference in EE healing rates between vonoprazan 20 mg and lansoprazole 30 mg was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Healing Phase: Vonoprazan 20 mg v Healing Phase: Lansoprazole 30 mg
    Number of subjects included in analysis
    1024
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.49
         upper limit
    		 12.23
    Notes
    [1] - The noninferiority of vonoprazan to lansoprazole was evaluated with a Farrington and Manning test with a noninferiority margin of 10 percentage points for the difference in EE rates between treatments (vonoprazan minus lansoprazole).
    [2] - 2-sided p-value.

    Primary: Maintenance Phase: Percentage of Participants Who Maintained Complete Healing of EE at Week 24

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    End point title
    		 Maintenance Phase: Percentage of Participants Who Maintained Complete Healing of EE at Week 24
    End point description
    A participant was considered to have complete healing of EE if healing was demonstrated during endoscopy. The MITT Set (Maintenance Phase) included all participants randomized into the Maintenance Phase who had healed EE at the end of the Healing Phase and received at least 1 dose of study drug during the Maintenance Phase. All analyses using the MITT Set grouped participants according to the randomized treatment.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Maintenance Phase: Vonoprazan 10 mg Maintenance Phase: Vonoprazan 20 mg Maintenance Phase: Lansoprazole 15 mg
    Number of subjects analysed
    293
    291
    294
    Units: percentage of participants
        number (not applicable)
    79.2
    80.7
    72.0
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 15 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in EE maintenance rates between each vonoprazan group and lansoprazole group was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Maintenance Phase: Vonoprazan 20 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    8.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 15.53
    Notes
    [3] - The noninferiority of each dose group of vonoprazan to lansoprazole was evaluated with a Farrington and Manning test with a noninferiority margin of 10 percentage points for the difference in maintenance of healing rates between treatments (vonoprazan minus lansoprazole).
    [4] - 2-sided p-value.
    Statistical analysis title
    		 Vonoprazan 10 mg vs Lansoprazole 15 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in EE maintenance rates between each vonoprazan group and lansoprazole group was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Maintenance Phase: Vonoprazan 10 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 14.09
    Notes
    [5] - The noninferiority of each dose group of vonoprazan to lansoprazole was evaluated with a Farrington and Manning test with a noninferiority margin of 10 percentage points for the difference in maintenance of healing rates between treatments (vonoprazan minus lansoprazole).
    [6] - 2-sided p-value.
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 15 mg
    Comparison groups
    Maintenance Phase: Vonoprazan 20 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0136 [8]
    Method
    		 Farrington and Manning test
    Confidence interval
    Notes
    [7] - The superiority of the vonoprazan 20 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [8] - 2-sided p-value.
    Statistical analysis title
    		 Vonoprazan 10 mg vs Lansoprazole 15 mg
    Comparison groups
    Maintenance Phase: Vonoprazan 10 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0436 [10]
    Method
    		 Farrington and Manning test
    Confidence interval
    Notes
    [9] - The superiority of the vonoprazan 10 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [10] - 2-sided p-value.

    Secondary: Healing Phase: Percentage of 24-hour Heartburn-free Days

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    End point title
    		 Healing Phase: Percentage of 24-hour Heartburn-free Days
    End point description
    A 24-hour heartburn-free day was defined as a day having no heartburn among all diary entries for that day. The percentage of 24-hour heartburn-free days was calculated using all days with at least 1 evening or morning diary entry during the treatment period of this phase. The MITT Set (Healing Phase) including only participants with at least one heartburn diary entry.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 8
    End point values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Number of subjects analysed
    509
    507
    Units: percentage of days
        arithmetic mean (standard deviation)
    66.8 ( 34.60 )
    64.1 ( 35.46 )
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 30 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in mean percentage of 24-hour heartburn-free days between vonoprazan 20 mg and lansoprazole 30 mg was calculated from Welch's t-test.
    Comparison groups
    Healing Phase: Lansoprazole 30 mg v Healing Phase: Vonoprazan 20 mg
    Number of subjects included in analysis
    1016
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 difference in mean percentage
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 7.03
    Notes
    [11] - If the lower bound of the CI was greater than -15%, noninferiority would be concluded.

    Secondary: Healing Phase: Percentage of Participants With Baseline LA Classification Grades C or D Who Had Complete Healing of EE at Week 2

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    End point title
    		 Healing Phase: Percentage of Participants With Baseline LA Classification Grades C or D Who Had Complete Healing of EE at Week 2
    End point description
    A participant was considered to have complete healing of EE if healing was demonstrated during endoscopy. LA Classification of Esophagitis Grading Scale: Grade C: One or more mucosal breaks that are continuous between the tops of 2 or more mucosal folds, which involves less than 75% of the circumference. Grade D: One or more mucosal breaks, which involves at least 75% of the circumference. The MITT Set (Healing Phase) including only participants with baseline LA Classification Grades C or D.
    End point type
    Secondary
    End point timeframe
    Week 2
    End point values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Number of subjects analysed
    177
    174
    Units: percentage of participants
        number (not applicable)
    70.2
    52.6
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 30 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in EE healing rates between vonoprazan 20 mg and lansoprazole 30 mg was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Healing Phase: Vonoprazan 20 mg v Healing Phase: Lansoprazole 30 mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.0008 [13]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    17.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.44
         upper limit
    		 27.43
    Notes
    [12] - The superiority of the vonoprazan 20 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [13] - 2-sided p-value.

    Secondary: Healing Phase: Percentage of Participants With Onset of Sustained Resolution of Heartburn by Day 3

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    End point title
    		 Healing Phase: Percentage of Participants With Onset of Sustained Resolution of Heartburn by Day 3
    End point description
    Sustained resolution was defined as at least 7 consecutive days with no daytime or night time heartburn as assessed by the daily diary. A participant was considered to have sustained resolution of heartburn by Day 3 if the first day of the 7 consecutive days without symptoms was on Days 1, 2, or 3. The MITT Set (Healing Phase) included all participants randomized into the Healing Phase who had documented EE at baseline and received at least 1 dose of study drug during the Healing Phase. All analyses using the MITT Set grouped subjects according to the randomized treatment.
    End point type
    Secondary
    End point timeframe
    Day 1 to maximum of Day 10 (inclusive of 7 day heartburn assessment)
    End point values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Number of subjects analysed
    514
    510
    Units: percentage of participants
        number (not applicable)
    34.4
    32.2
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 30 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in sustained resolution rates between vonoprazan 20 mg and lansoprazole 30 mg was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Healing Phase: Vonoprazan 20 mg v Healing Phase: Lansoprazole 30 mg
    Number of subjects included in analysis
    1024
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.4392 [15]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 8.04
    Notes
    [14] - The superiority of the vonoprazan 20 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [15] - 2-sided p-value.

    Secondary: Healing Phase: Percentage of Participants With Baseline LA Classification Grades C or D Who Had Complete Healing of EE by Week 8

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    End point title
    		 Healing Phase: Percentage of Participants With Baseline LA Classification Grades C or D Who Had Complete Healing of EE by Week 8
    End point description
    A participant was considered to have complete healing of EE if healing was demonstrated during endoscopy. LA Classification of Esophagitis Grading Scale: Grade C: One or more mucosal breaks that are continuous between the tops of 2 or more mucosal folds, which involves less than 75% of the circumference. Grade D: One or more mucosal breaks, which involves at least 75% of the circumference. The MITT Set (Healing Phase) including only participants with baseline LA Classification Grades C or D.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Number of subjects analysed
    177
    174
    Units: percentage of participants
        number (not applicable)
    91.7
    72.0
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 30 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in EE healing rates between vonoprazan 20 mg and lansoprazole 30 mg was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Healing Phase: Vonoprazan 20 mg v Healing Phase: Lansoprazole 30 mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.0001 [17]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    19.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.84
         upper limit
    		 27.58
    Notes
    [16] - Observed p-value and not a formal test per the preplanned fixed-sequence testing procedure. The superiority of the vonoprazan 20 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [17] - 2-sided p-value.

    Secondary: Healing Phase: Percentage of Participants Who Had Complete Healing of EE at Week 2

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    End point title
    		 Healing Phase: Percentage of Participants Who Had Complete Healing of EE at Week 2
    End point description
    A participant was considered to have complete healing of EE if healing was demonstrated during endoscopy. The MITT Set (Healing Phase) included all participants randomized into the Healing Phase who had documented EE at baseline and received at least 1 dose of study drug during the Healing Phase. All analyses using the MITT Set grouped subjects according to the randomized treatment.
    End point type
    Secondary
    End point timeframe
    Week 2
    End point values
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg
    Number of subjects analysed
    514
    510
    Units: percentage of participants
        number (not applicable)
    74.3
    68.2
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 30 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in EE healing rates between vonoprazan 20 mg and lansoprazole 30 mg was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Healing Phase: Vonoprazan 20 mg v Healing Phase: Lansoprazole 30 mg
    Number of subjects included in analysis
    1024
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.0348 [19]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 11.6
    Notes
    [18] - Observed p-value and not a formal test per the preplanned fixed-sequence testing procedure. The superiority of the vonoprazan 20 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [19] - 2-sided p-value.

    Secondary: Maintenance Phase: Percentage of Participants With Baseline LA Classification Grades C or D Who Maintained Complete Healing of EE at Week 24

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    End point title
    		 Maintenance Phase: Percentage of Participants With Baseline LA Classification Grades C or D Who Maintained Complete Healing of EE at Week 24
    End point description
    A participant was considered to have complete healing of EE if healing was demonstrated during endoscopy. LA Classification of Esophagitis Grading Scale: Grade C: One or more mucosal breaks that are continuous between the tops of 2 or more mucosal folds, which involves less than 75% of the circumference. Grade D: One or more mucosal breaks, which involves at least 75% of the circumference. The MITT Set (Maintenance Phase) including only participants with baseline LA Classification Grades C or D with nonmissing data.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Maintenance Phase: Vonoprazan 10 mg Maintenance Phase: Vonoprazan 20 mg Maintenance Phase: Lansoprazole 15 mg
    Number of subjects analysed
    95
    92
    96
    Units: percentage of participants
        number (not applicable)
    74.7
    77.2
    61.5
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 15 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in maintenance rates between each vonoprazan group and lansoprazole 15 mg group was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Maintenance Phase: Vonoprazan 20 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.0196 [21]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    15.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 28.44
    Notes
    [20] - The superiority of the vonoprazan 20 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [21] - 2-sided p-value.
    Statistical analysis title
    		 Vonoprazan 10 mg vs Lansoprazole 15 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in maintenance rates between each vonoprazan group and lansoprazole 15 mg group was calculated via the Miettinen and Nurminen method.
    Comparison groups
    Maintenance Phase: Vonoprazan 10 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.049 [23]
    Method
    		 Farrington and Manning test
    Parameter type
    		 difference in percentage
    Point estimate
    13.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 26.14
    Notes
    [22] - The superiority of the vonoprazan 10 mg group to lansoprazole group p-value was evaluated with a Farrington and Manning test with the null hypothesis difference ≤0 versus the alternative hypothesis difference >0.
    [23] - 2-sided p-value.

    Secondary: Maintenance Phase: Percentage of 24-hour Heartburn-free Days

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    End point title
    		 Maintenance Phase: Percentage of 24-hour Heartburn-free Days
    End point description
    A 24-hour heartburn-free day was defined as a day having no heartburn among all diary entries for that day. The percentage of 24-hour heartburn-free days was calculated using all days with at least 1 evening or morning diary entry during the treatment period of this phase. The MITT Set (Maintenance Phase) including only participants with at least one heartburn diary entry.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 24
    End point values
    		 Maintenance Phase: Vonoprazan 10 mg Maintenance Phase: Vonoprazan 20 mg Maintenance Phase: Lansoprazole 15 mg
    Number of subjects analysed
    291
    290
    294
    Units: percentage of days
        arithmetic mean (standard deviation)
    80.9 ( 28.59 )
    80.6 ( 29.96 )
    78.6 ( 27.49 )
    Statistical analysis title
    		 Vonoprazan 20 mg vs Lansoprazole 15 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in mean percentage of 24-hour heartburn-free days between each vonoprazan group and the lansoprazole group was calculated from Welch's t-test.
    Comparison groups
    Maintenance Phase: Vonoprazan 20 mg v Maintenance Phase: Lansoprazole 15 mg
    Number of subjects included in analysis
    584
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [24]
    Method
    Parameter type
    		 difference in mean percentage
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.63
         upper limit
    		 6.72
    Notes
    [24] - If the lower bound of the CI was greater than -15%, noninferiority would be concluded.
    Statistical analysis title
    		 Vonoprazan 10 mg vs Lansoprazole 15 mg
    Statistical analysis description
    The 2-sided 95% CI of the difference in mean percentage of 24-hour heartburn-free days between each vonoprazan group and the lansoprazole group was calculated from Welch's t-test.
    Comparison groups
    Maintenance Phase: Lansoprazole 15 mg v Maintenance Phase: Vonoprazan 10 mg
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [25]
    Method
    Parameter type
    		 difference in mean percentage
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.27
         upper limit
    		 6.84
    Notes
    [25] - If the lower bound of the CI was greater than -15%, noninferiority would be concluded.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Healing Phase: Day 1 to Week 8; Maintenance Phase: Day 1 to Week 28
    Adverse event reporting additional description
    The Safety Set included all randomized participants who received at least 1 dose of study drug. All analyses using the Safety Set grouped subjects according to the treatment actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Healing Phase: Vonoprazan 20 mg
    Reporting group description
    		 Participants received oral vonoprazan 20 mg QD for a maximum of 8 weeks in the Healing Phase.

    Reporting group title
    Healing Phase: Lansoprazole 30 mg
    Reporting group description
    		 Participants received oral lansoprazole 30 mg QD for a maximum of 8 weeks in the Healing Phase.

    Reporting group title
    Maintenance Phase: Vonoprazan 10 mg
    Reporting group description
    		 Participants received oral vonoprazan 10 mg QD for 24 weeks.

    Reporting group title
    Maintenance Phase: Vonoprazan 20 mg
    Reporting group description
    		 Participants received oral vonoprazan 20 mg QD for 24 weeks.

    Reporting group title
    Maintenance Phase: Lansoprazole 15 mg
    Reporting group description
    		 Participants received oral lansoprazole 15 mg QD for 24 weeks.

    Serious adverse events
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg Maintenance Phase: Vonoprazan 10 mg Maintenance Phase: Vonoprazan 20 mg Maintenance Phase: Lansoprazole 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 514 (0.58%)
    3 / 510 (0.59%)
    10 / 296 (3.38%)
    14 / 296 (4.73%)
    7 / 297 (2.36%)
         number of deaths (all causes)
    0
    0
    0
    2
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer stage I
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 510 (0.20%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestine adenocarcinoma
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Gastric bypass
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 510 (0.20%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatolithiasis
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Stress urinary incontinence
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    2 / 296 (0.68%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 510 (0.20%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    2 / 296 (0.68%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    1 / 296 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    1 / 296 (0.34%)
    0 / 296 (0.00%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 514 (0.00%)
    0 / 510 (0.00%)
    0 / 296 (0.00%)
    0 / 296 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Healing Phase: Vonoprazan 20 mg Healing Phase: Lansoprazole 30 mg Maintenance Phase: Vonoprazan 10 mg Maintenance Phase: Vonoprazan 20 mg Maintenance Phase: Lansoprazole 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 514 (9.73%)
    46 / 510 (9.02%)
    72 / 296 (24.32%)
    81 / 296 (27.36%)
    74 / 297 (24.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 514 (0.58%)
    4 / 510 (0.78%)
    9 / 296 (3.04%)
    8 / 296 (2.70%)
    6 / 297 (2.02%)
         occurrences all number
    3
    4
    9
    9
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 514 (1.17%)
    6 / 510 (1.18%)
    3 / 296 (1.01%)
    2 / 296 (0.68%)
    8 / 297 (2.69%)
         occurrences all number
    6
    6
    3
    2
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 514 (2.14%)
    13 / 510 (2.55%)
    3 / 296 (1.01%)
    7 / 296 (2.36%)
    13 / 297 (4.38%)
         occurrences all number
    11
    13
    3
    7
    14
    Abdominal pain
         subjects affected / exposed
    8 / 514 (1.56%)
    2 / 510 (0.39%)
    4 / 296 (1.35%)
    10 / 296 (3.38%)
    3 / 297 (1.01%)
         occurrences all number
    9
    2
    4
    12
    3
    Chronic gastritis
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 510 (0.20%)
    9 / 296 (3.04%)
    4 / 296 (1.35%)
    5 / 297 (1.68%)
         occurrences all number
    2
    1
    9
    4
    5
    Dyspepsia
         subjects affected / exposed
    1 / 514 (0.19%)
    3 / 510 (0.59%)
    11 / 296 (3.72%)
    12 / 296 (4.05%)
    8 / 297 (2.69%)
         occurrences all number
    1
    3
    12
    12
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 514 (1.17%)
    2 / 510 (0.39%)
    7 / 296 (2.36%)
    11 / 296 (3.72%)
    6 / 297 (2.02%)
         occurrences all number
    6
    2
    7
    12
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 510 (0.00%)
    2 / 296 (0.68%)
    5 / 296 (1.69%)
    7 / 297 (2.36%)
         occurrences all number
    2
    0
    2
    5
    9
    Back pain
         subjects affected / exposed
    2 / 514 (0.39%)
    4 / 510 (0.78%)
    6 / 296 (2.03%)
    8 / 296 (2.70%)
    4 / 297 (1.35%)
         occurrences all number
    2
    4
    6
    8
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 514 (0.39%)
    2 / 510 (0.39%)
    2 / 296 (0.68%)
    1 / 296 (0.34%)
    7 / 297 (2.36%)
         occurrences all number
    2
    2
    2
    1
    8
    COVID-19
         subjects affected / exposed
    8 / 514 (1.56%)
    6 / 510 (1.18%)
    12 / 296 (4.05%)
    26 / 296 (8.78%)
    18 / 297 (6.06%)
         occurrences all number
    8
    6
    12
    26
    18
    Sinusitis
         subjects affected / exposed
    1 / 514 (0.19%)
    3 / 510 (0.59%)
    7 / 296 (2.36%)
    4 / 296 (1.35%)
    1 / 297 (0.34%)
         occurrences all number
    1
    3
    7
    4
    1
    Urinary tract infection
         subjects affected / exposed
    6 / 514 (1.17%)
    4 / 510 (0.78%)
    8 / 296 (2.70%)
    1 / 296 (0.34%)
    5 / 297 (1.68%)
         occurrences all number
    6
    4
    8
    1
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2019
    The purposes of Amendment 1 were to: • Remove double-dummy and placebo from study drugs and other applicable sections. • Change exclusion period for proton pump inhibitors and histamine-2 receptor antagonist from 14 days prior to screening to 14 days prior to screening 13carbon-urea breath test. • Update footnote on table of excluded medications and treatments regarding prohibition period of medications that could have interfered with 13carbon-urea breath test. • Remove ‘x’ from dispense study drug at Maintenance Week 4 (Maintenance Day 29) in the Schedule of Events. • Update a footnote in the Schedule of Events to clarify that subjects may need to return for study drug administration after Week 2 and Week 8.
    01 Oct 2019
    The purposes of Amendment 2 were to: • Remove wording that allowed a subject’s legally acceptable representative as a party capable of giving consent for the study. • Add wording allowing the extension of the endoscopy Screening Period to 10 days in rare instances with sponsor approval. • Exclude the use of Cytochrome P450 Family 3 Subfamily A Member 4 substrates with a narrow therapeutic index from 4 days prior to Day 1 through the end of the study. • Add overall study stopping criteria (Appendix 16.1.1; Protocol Section 6.3.1.15). • Clarify requirements for the informed consent process for pharmacogenetic sampling and analysis. • Add collection of smoking status and alcohol use in the Schedule of Events and to include them as variables for subgroup analyses. • Update the protocol with the most recent sample version of the Patient Assessment of Gastrointestinal Disorders-Symptom Severity Index.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Mar 2020
    New participant screening and enrollment was paused due to the COVID-19 pandemic. Participants already enrolled in the study were allowed to continue at the discretion of the Principal Investigators.
    11 May 2020

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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