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    Clinical Trial Results:
    A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate the Efficacy and Safety of Once Daily Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to Esomeprazole 40 mg for the Treatment of Subjects With Symptomatic Gastro-Esophageal Reflux Disease Who have a Partial Response Following Treatment with a High Dose of Proton Pump Inhibitor

    Summary
    EudraCT number
    		 2015-001154-14
    Trial protocol
    		 GB   EE   BE   CZ  
    Global end of trial date
    12 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2019
    First version publication date
    11 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Vonoprazan-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02743949
    WHO universal trial number (UTN)
    		 U1111-1172-2373
    Sponsors
    Sponsor organisation name
    Takeda Development Center Europe Ltd
    Sponsor organisation address
    61 Aldwych, WC2B 4AE, London, United Kingdom,
    Public contact
    Medical Director, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.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
    12 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine the effect of vonoprazan compared to esomeprazole for preventing heartburn symptoms over a 4-week treatment period in participants who have a partial response to treatment with esomeprazole.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jul 2016
    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
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 177
    Country: Number of subjects enrolled
    Czech Republic: 40
    Country: Number of subjects enrolled
    Estonia: 11
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    256
    EEA total number of subjects
    256
    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)
    193
    From 65 to 84 years
    63
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 33 investigative sites in Belgium, Bulgaria, Czech Republic, Estonia, Poland and United Kingdom from 14 July 2014 to 12 October 2018.

    Pre-assignment
    Screening details
    		 Participants with a symptomatic gastro-esophageal reflux disease who have a partial response following treatment with a high dose of proton pump inhibitor were enrolled in a 1:1:1 ratio to receive esomeprazole 40 mg, vonoprazan 20 mg, or vonoprazan 40 mg.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Esomeprazole 40 mg
    Arm description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over-encapsulated tablets, orally, once daily for 4 weeks during the active treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Esomeprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Esomeprazole over-encapsulated tablets

    Arm title
    		 Vonoprazan 20 mg
    Arm description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vonoprazan
    Investigational medicinal product code
    Other name
    TAK-438
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vonoprazan over-encapsulated capsules

    Arm title
    		 Vonoprazan 40 mg
    Arm description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vonoprazan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vonoprazan over-encapsulated capsules

    Number of subjects in period 1
    		Esomeprazole 40 mg Vonoprazan 20 mg Vonoprazan 40 mg
    Started
    86
    85
    85
    Completed
    82
    84
    82
    Not completed
    4
    1
    3
         Voluntary Withdrawal
    2
    1
    -
         Adverse event, non-fatal
    -
    -
    2
         Significant Protocol Deviation
    2
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Esomeprazole 40 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over-encapsulated tablets, orally, once daily for 4 weeks during the active treatment period.

    Reporting group title
    Vonoprazan 20 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period.

    Reporting group title
    Vonoprazan 40 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period.

    Reporting group values
    		 Esomeprazole 40 mg Vonoprazan 20 mg Vonoprazan 40 mg Total
    Number of subjects
    		 86 85 85 256
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 63 63 67 193
        From 65-84 years
    		 23 22 18 63
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.9 ( 13.94 ) 52.0 ( 14.67 ) 51.8 ( 14.09 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 48 53 51 152
        Male
    		 38 32 34 104
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 1
        Black or African American
    		 0 1 0 1
        White
    		 86 84 83 253
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Smoking Status
    Units: Subjects
        Participant has never smoked
    		 50 53 53 156
        Participant is a current smoker
    		 21 23 22 66
        Participant is an ex-smoker
    		 15 9 10 34
    Alcohol Classification
    Units: Subjects
        Participant has never drunk
    		 57 49 54 160
        Participant is a current drinker
    		 27 33 30 90
        Participant is an ex-drinker
    		 2 3 1 6
    Alcohol Use
    Units: Subjects
        Less than 21 units of alcohol per week
    		 27 33 30 90
        Missing
    		 59 52 55 166
    Caffeine Consumption
    Units: Subjects
        Consumed caffeine
    		 60 67 68 195
        Did not consume caffeine
    		 26 18 17 61
    Is Erosive Esophagitis Present?
    Units: Subjects
        Present
    		 30 28 17 75
        Not present
    		 56 57 68 181
    If Yes, Grade of Erosive Esophagitis
    Units: Subjects
        Grade 0
    		 0 1 1 2
        Grade A
    		 30 27 16 73
        Not graded
    		 56 57 68 181
    Did the Endoscopist Visualize Findings Suggestive of Eosinophilic Esophagitis?
    Units: Subjects
        Not Visualised
    		 86 85 85 256
    H Pylori Status
    Units: Subjects
        Positive
    		 8 13 8 29
        Negative
    		 78 72 76 226
        Not determined
    		 0 0 1 1
    Region of Enrollment
    Units: Subjects
        Belgium
    		 0 1 0 1
        Bulgaria
    		 61 55 61 177
        Czech Republic
    		 14 16 10 40
        Estonia
    		 2 5 4 11
        Poland
    		 8 7 7 22
        United Kingdom
    		 1 1 3 5
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    		 169.9 ( 9.17 ) 168.5 ( 9.07 ) 168.1 ( 7.81 ) -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 78.78 ( 17.003 ) 77.46 ( 16.353 ) 75.81 ( 16.126 ) -
    Body Mass Index (BMI)
    Body Mass Index=weight (kg)/[height (m)^2]
    Units: kg per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    		 27.13 ( 4.611 ) 27.21 ( 4.854 ) 26.76 ( 5.076 ) -
    Hospital Anxiety and Depression Scale (HADS) Anxiety Total
    HADS-A and HADS-D are 7-item subscales that measure the presence and severity of anxiety and depression symptoms, respectively, on a scale of 0 to 3. Total scores ≤ 7: no clinically relevant symptoms; 8 - 10: mild symptoms; 11 - 14: moderate symptoms; and ≥15 (maximum 21): more severe symptoms.
    Units: score on scale
        arithmetic mean (standard deviation)
    		 6.5 ( 3.81 ) 6.2 ( 3.38 ) 7.0 ( 3.78 ) -
    Depression Total
    Units: score on scale
        arithmetic mean (standard deviation)
    		 5.9 ( 3.62 ) 6.0 ( 3.50 ) 6.2 ( 3.99 ) -

    End points

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    End points reporting groups
    Reporting group title
    Esomeprazole 40 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over-encapsulated tablets, orally, once daily for 4 weeks during the active treatment period.

    Reporting group title
    Vonoprazan 20 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period.

    Reporting group title
    Vonoprazan 40 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period.

    Primary: Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment

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    End point title
    		 Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment
    End point description
    Participants used the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD) every morning upon waking and every evening before going to sleep to document the presence of daytime and nighttime heartburn and regurgitation. The percentage of heartburn-free (HBF) 24-hour periods was calculated for each participant using the following formula: (total 24-hour periods that are heartburn free / total 24-hour periods for which both a daytime and nighttime result is marked) x 100%. The full analysis set (FAS) included all participants randomized to double-blind study medication.
    End point type
    Primary
    End point timeframe
    4 Weeks
    End point values
    		 Esomeprazole 40 mg Vonoprazan 20 mg Vonoprazan 40 mg
    Number of subjects analysed
    85
    85
    85
    Units: percentage of HBF 24-hour periods
        arithmetic mean (standard deviation)
    36.54 ( 35.570 )
    36.69 ( 33.420 )
    38.43 ( 34.793 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Esomeprazole 40 mg v Vonoprazan 20 mg
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.748 [1]
    Method
    		 Wilcoxon rank-sum test
    Parameter type
    		 Wilcoxon-Mann-Whitney odds estimator
    Point estimate
    1.0584
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.5778
    Notes
    [1] - P-values were obtained using a Pearson chi-square test for each Vonoprazan treatment compared with Esomeprazole.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Esomeprazole 40 mg v Vonoprazan 40 mg
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5985 [2]
    Method
    		 Wilcoxon rank-sum test
    Parameter type
    		 Wilcoxon-Mann-Whitney odds estimator
    Point estimate
    1.0975
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.7368
         upper limit
    		 1.6349
    Notes
    [2] - P-values were obtained using a Pearson chi-square test for each Vonoprazan treatment compared with Esomeprazole.

    Secondary: Percentage of Participants with ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period

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    End point title
    		 Percentage of Participants with ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period
    End point description
    ≥1 sustained resolution of heartburn is defined as ≥7 consecutive days without both daytime and nighttime heartburn anytime during the 4-week treatment period. Daytime and nighttime heartburn were documented by all participants using the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD). The full analysis set (FAS) included all participants randomized to a double-blind study medication.
    End point type
    Secondary
    End point timeframe
    4 Weeks
    End point values
    		 Esomeprazole 40 mg Vonoprazan 20 mg Vonoprazan 40 mg
    Number of subjects analysed
    86
    85
    85
    Units: percentage of participants
        number (not applicable)
    32.6
    30.6
    31.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Esomeprazole 40 mg v Vonoprazan 20 mg
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.782 [3]
    Method
    		 Pearson chi-square
    Parameter type
    		 Miettinen-Nurminen
    Point estimate
    0.91
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.91
    Notes
    [3] - P-values were obtained using a Pearson chi-square test for each Vonoprazan treatment compared with Esomeprazole.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Esomeprazole 40 mg v Vonoprazan 40 mg
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.912 [4]
    Method
    		 Pearson chi-square
    Parameter type
    		 Miettinen-Nurminen
    Point estimate
    0.96
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 2.01
    Notes
    [4] - P-values were obtained using a Pearson chi-square test for each Vonoprazan treatment compared with Esomeprazole.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5 weeks
    Adverse event reporting additional description
    Adverse event (AE) is any unfavorable, unintended sign, symptom or disease temporally associated with use of drug, considered related/not related to drug. Treatment-emergent AEs (TEAEs) are reported and defined as any AE that occurred after first dose of study drug during double-blind period and up to 1 week after study completion or withdrawal.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Esomeprazole 40 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over-encapsulated tablets, orally, once daily for 4 weeks during the active treatment period.

    Reporting group title
    Vonoprazan 20 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period.

    Reporting group title
    Vonoprazan 40 mg
    Reporting group description
    		 Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period.

    Serious adverse events
    		 Esomeprazole 40 mg Vonoprazan 20 mg Vonoprazan 40 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
    0 / 85 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
    0 / 85 (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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Esomeprazole 40 mg Vonoprazan 20 mg Vonoprazan 40 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
    6 / 85 (7.06%)
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 85 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    1
    0
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 85 (0.00%)
    3 / 85 (3.53%)
         occurrences all number
    0
    0
    3
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 85 (0.00%)
    2 / 85 (2.35%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    43 more participants enrolled due to lower screen failure rate in the 5 new sites and the long run in period limited predictability of enrolment in advance. Measures had been implemented maintaining scientific integrity and participant safety.
    For support, Contact us.
    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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