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    Clinical Trial Results:
    A randomised, placebo controlled trial of extra-oesophageal reflux treatment in the management of upper respiratory symptoms. [TOPPITS: Trial of Proton Pump Inhibitors in Throat Symptoms]

    Summary
    EudraCT number
    		 2013-004249-17
    Trial protocol
    		 GB  
    Global end of trial date
    23 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NCTU:6831
    Additional study identifiers
    ISRCTN number
    		 ISRCTN38578686
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Joint Research Office, Level 1, Regent Point, Regent Farm Road, Gosforth, Newcastle upon Tyne, United Kingdom,
    Public contact
    Janet Wilson, Newcastle University, 0191 2231086, janet.wilson@ncl.ac.uk
    Scientific contact
    Janet Wilson, Newcastle University, 0191 2231086, janet.wilson@ncl.ac.uk
    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
    23 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the symptomatic response in patients with persistent throat symptoms at the end of four months' (16 weeks') therapy of treatment with lansoprazole versus placebo.
    Protection of trial subjects
    None
    Background therapy
    		 None
    Evidence for comparator
    		 Placebo control was chosen for this trial, as Extra Oesophageal Reflux (EOR) symptoms have long been recognised as having a strong placebo response. There is a growing trend to treat throat symptom patients empirically with proton pump inhibitors (PPIs), but most controlled studies fail to demonstrate a significant benefit of PPI over placebo. Hence, a placebo-controlled trial was chosen, to establish any benefit.
    Actual start date of recruitment
    03 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 346
    Worldwide total number of subjects
    346
    EEA total number of subjects
    346
    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)
    267
    From 65 to 84 years
    79
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The recruitment period ran from 27 May 2014 until 28 February 2017, at eight NHS hospital sites in the United Kingdom. Sites were in Newcastle upon Tyne, Sunderland, Nottingham, Brighton, Manchester, Birmingham and Stockport in England, and Glasgow in Scotland.

    Pre-assignment
    Screening details
    		 Potential participants will be referred direct from primary care, or by scrutiny of hospital/GP/primary care referral letters. All eligible (RSI ≥10), potential participants will be informed about TOPPITS, receive an invitation letter and PIS in the post, and be booked onto a TOPPITS screening clinic.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Placebo-matched capsules were made, to establish the blind from trial start. Sealed codebreak envelopes were stored in the Pharmacy/ISF, and opened only in an emergency, with CI authorisation. If the code was broken, participant number, staff name, why and when were recorded. At 12 months, participants were asked if they thought they were on lansoprazole or placebo, and why. The blind was maintained until all trial data were collected and the database locked, when participants were unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment
    Arm description
    		 Lansoprazole 30 mg bd
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lansoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg bd

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo twice-daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet, bd

    Number of subjects in period 1
    		Treatment Placebo
    Started
    172
    174
    Completed
    172
    174
    Period 2
    Period 2 title
    16 weeks' participation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Placebo-matched capsules were made, to establish the blind from trial start. Sealed code-break envelopes were stored in the Pharmacy/ISF, and opened only in an emergency, with CI authorisation. If the code was broken, participant number, staff name, why and when were recorded. At 12 months, participants were asked if they thought they were on lansoprazole or placebo, and why. The blind was maintained until all trial data were collected and the database locked, when participants were unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment
    Arm description
    		 Lansoprazole 30 mg bd
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lansoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30mg bd

    Arm title
    		 Placebo
    Arm description
    		 Matched placebo bd
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet, bd

    Number of subjects in period 2
    		Treatment Placebo
    Started
    172
    174
    Completed
    135
    148
    Not completed
    37
    26
         Lost to follow-up
    37
    26
    Period 3
    Period 3 title
    12 months' participation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Placebo-matched capsules were made, to establish the blind from trial start. Sealed code-break envelopes were stored in the Pharmacy/ISF, and opened only in an emergency, with CI authorisation. If the code was broken, participant number, staff name, why and when were recorded. At 12 months, participants were asked if they thought they were on lansoprazole or placebo, and why. The blind was maintained until all trial data were collected and the database locked, when participants were unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment
    Arm description
    		 Lansoprazole 30 mg bd
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lansoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg bd

    Arm title
    		 Placebo
    Arm description
    		 Matched placebo 30 mg bd
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet, bd

    Number of subjects in period 3
    		Treatment Placebo
    Started
    135
    148
    Completed
    109
    117
    Not completed
    26
    31
         Lost to follow-up
    26
    31

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Lansoprazole 30 mg bd

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo twice-daily

    Reporting group values
    		 Treatment Placebo Total
    Number of subjects
    		 172 174 346
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    The subject population was adults of age 18 and over.
    Units: years
        arithmetic mean (full range (min-max))
    		 53.5 (21 to 84) 50.8 (20 to 80) -
    Gender categorical
    Subjects were both male and female.
    Units: Subjects
        Female
    		 101 95 196
        Male
    		 71 79 150
    Site
    Trial site at which the participant was recruited.
    Units: Subjects
        Birmingham
    		 5 5 10
        Brighton
    		 5 4 9
        Glasgow
    		 18 21 39
        Manchester
    		 15 12 27
        Newcastle
    		 66 67 133
        Nottingham
    		 34 36 70
        Stockport
    		 5 6 11
        Sunderland
    		 24 23 47
    Weight
    Weight of participant.
    Units: kg
        arithmetic mean (standard deviation)
    		 79.4 ( 18.2 ) 79.3 ( 16.8 ) -
    Height
    Height of participant.
    Units: metres
        arithmetic mean (standard deviation)
    		 1.68 ( 0.12 ) 1.68 ( 0.10 ) -
    Body Mass Index (BMI)
    Body Mass Index of participants.
    Units: BMI
        arithmetic mean (standard deviation)
    		 28.2 ( 5.9 ) 28.1 ( 5.3 ) -
    Smoking pack years
    Smoking habits of participants.
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 0 (0 to 0) 0 (0 to 5) -
    Alcohol consumption
    Alcohol consumption of participants.
    Units: Units per week
        median (inter-quartile range (Q1-Q3))
    		 4 (0 to 10) 3 (0 to 10) -
    Baseline severity (RSI-HB)
    Baseline severity of throat symptoms (RSI score less heartburn score) for participants.
    Units: RSI units
        arithmetic mean (standard deviation)
    		 20.0 ( 6.8 ) 20.1 ( 6.5 ) -
    Subject analysis sets

    Subject analysis set title
    All trial participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This covers all trial participants, whether compliant or not.

    Subject analysis set title
    Pragmatic ITT group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    A distribution approach was used to determine a clinically relevant compliance window, to maximise inclusion of participants and exclude only significant outliers. Thus the compliant ITT group was defined, including all ineligible and protocol violator participants, in their randomised treatment groups, attending the 16-week follow-up visit at any time, and completing outcome measures at any time point. Secondary analysis, of the primary outcome measure, was of this group.

    Subject analysis set title
    Compliant Intention to Treat (ITT) group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A distribution approach was used to determine a clinically relevant compliance window, to maximise inclusion of participants and exclude only significant outliers. Thus the compliant ITT group was defined, including all ineligible and protocol violator participants, in their randomised treatment groups, attending the 16-week follow-up visit between 14 and 20 weeks, and completing outcome measures within 14 to 20 weeks of randomisation. Primary comparative analyses were of this group.

    Subject analysis sets values
    		 All trial participants Pragmatic ITT group Compliant Intention to Treat (ITT) group
    Number of subjects
    346
    267
    220
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    The subject population was adults of age 18 and over.
    Units: years
        arithmetic mean (full range (min-max))
    52.2 (20 to 84)
    53.5 (21 to 84)
    54.5 (21 to 84)
    Gender categorical
    Subjects were both male and female.
    Units: Subjects
        Female
    196
    153
    126
        Male
    150
    114
    94
    Site
    Trial site at which the participant was recruited.
    Units: Subjects
        Birmingham
    10
    9
    9
        Brighton
    9
    7
    5
        Glasgow
    39
    25
    19
        Manchester
    27
    23
    15
        Newcastle
    133
    97
    69
        Nottingham
    70
    64
    63
        Stockport
    11
    11
    9
        Sunderland
    47
    31
    31
    Weight
    Weight of participant.
    Units: kg
        arithmetic mean (standard deviation)
    79.4 ( 17.5 )
    78.7 ( 17.3 )
    79.5 ( 17.8 )
    Height
    Height of participant.
    Units: metres
        arithmetic mean (standard deviation)
    1.68 ( 0.11 )
    1.67 ( 0.10 )
    1.67 ( 0.12 )
    Body Mass Index (BMI)
    Body Mass Index of participants.
    Units: BMI
        arithmetic mean (standard deviation)
    28.1 ( 5.6 )
    28.1 ( 5.8 )
    28.5 ( 6.1 )
    Smoking pack years
    Smoking habits of participants.
    Units: number
        median (inter-quartile range (Q1-Q3))
    0 (0 to 3)
    0 (0 to 2.5)
    0 (0 to 1)
    Alcohol consumption
    Alcohol consumption of participants.
    Units: Units per week
        median (inter-quartile range (Q1-Q3))
    4 (0 to 10)
    3 (0 to 10)
    4 (0 to 10)
    Baseline severity (RSI-HB)
    Baseline severity of throat symptoms (RSI score less heartburn score) for participants.
    Units: RSI units
        arithmetic mean (standard deviation)
    20.1 ( 6.6 )
    20.0 ( 6.7 )
    20.0 ( 7.0 )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Lansoprazole 30 mg bd

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo twice-daily
    Reporting group title
    Treatment
    Reporting group description
    		 Lansoprazole 30 mg bd

    Reporting group title
    Placebo
    Reporting group description
    		 Matched placebo bd
    Reporting group title
    Treatment
    Reporting group description
    		 Lansoprazole 30 mg bd

    Reporting group title
    Placebo
    Reporting group description
    		 Matched placebo 30 mg bd

    Subject analysis set title
    All trial participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This covers all trial participants, whether compliant or not.

    Subject analysis set title
    Pragmatic ITT group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    A distribution approach was used to determine a clinically relevant compliance window, to maximise inclusion of participants and exclude only significant outliers. Thus the compliant ITT group was defined, including all ineligible and protocol violator participants, in their randomised treatment groups, attending the 16-week follow-up visit at any time, and completing outcome measures at any time point. Secondary analysis, of the primary outcome measure, was of this group.

    Subject analysis set title
    Compliant Intention to Treat (ITT) group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A distribution approach was used to determine a clinically relevant compliance window, to maximise inclusion of participants and exclude only significant outliers. Thus the compliant ITT group was defined, including all ineligible and protocol violator participants, in their randomised treatment groups, attending the 16-week follow-up visit between 14 and 20 weeks, and completing outcome measures within 14 to 20 weeks of randomisation. Primary comparative analyses were of this group.

    Primary: RSI score at 16 weeks

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    End point title
    		 RSI score at 16 weeks
    End point description
    Symptomatic response measured using the Reflux Symptom Index (RSI) in patients with persistent throat symptoms at the end of 16 weeks’ therapy with lansoprazole versus placebo. The RSI score is calculated from a nine-item, self-administered questionnaire scored on a Likert scale with each item score ranging from 0-5 giving a total score range of 0-45. A higher score indicates more severe symptoms.
    End point type
    Primary
    End point timeframe
    16 weeks post-randomisation.
    End point values
    		 Treatment Placebo Pragmatic ITT group Pragmatic ITT group Compliant Intention to Treat (ITT) group Compliant Intention to Treat (ITT) group
    Number of subjects analysed
    127
    140
    127
    140
    102
    118
    Units: no units
        arithmetic mean (confidence interval 95%)
    17.1 (15.5 to 18.8)
    16.0 (14.4 to 17.6)
    17.1 (15.5 to 18.8)
    16.0 (14.4 to 17.6)
    17.4 (15.5 to 19.4)
    15.6 (13.8 to 17.3)
    Statistical analysis title
    		 Two sample t test compliant ITT group
    Statistical analysis description
    Univariate analysis of unadjusted primary outcome measure for compliant analysis group.
    Comparison groups
    Compliant Intention to Treat (ITT) group v Compliant Intention to Treat (ITT) group
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.162 [2]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 4.487
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Notes
    [1] - The primary hypothesis to be tested is H0: The mean RSI scores at primary end-point (16-week visit) are equal for both arms (lansoprazole v placebo). A two-sided significance level of p<0.05 is used throughout.
    [2] - Test statistic: t=1.402, two-sided P-value= 0.162, concluding that there is no statistically significant difference in the RSI score at 16 weeks between lansoprazole and placebo.
    Statistical analysis title
    		 Multilevel mixed effect linear regression
    Statistical analysis description
    Adjusted for stratification factor recruiting centre (as a random effect) at randomisation and baseline severity in terms of RSI-HB as a continuous measure (as a fixed effect).
    Comparison groups
    Compliant Intention to Treat (ITT) group v Compliant Intention to Treat (ITT) group
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.196 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 3.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.091
    Notes
    [3] - The continuous covariate (RSI-HB) was explored to assess whether transformation of RSI-HB was a better fit to the relationship with outcome than an untransformed continuous measure based on a reduction in Akaike information criterion (AIC). There was no reduction in AIC so to build the most parsimonious, clinically interpretable model, RSI-HB was retained as an un-transformed continuous covariate, under the assumption of linearity with outcome
    [4] - There is no statistically significant difference between randomised arms, lansoprazole compared to placebo (p=0.196), when adjusted for site and baseline continuous RSI-HB.
    Statistical analysis title
    		 Two sample t test pragmatic ITT group
    Statistical analysis description
    Univariate analysis of unadjusted primary outcome measure for compliant analysis group.
    Comparison groups
    Pragmatic ITT group v Pragmatic ITT group
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 = 0.309 [6]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 3.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.17
    Notes
    [5] - The secondary hypothesis to be tested is H0: The mean RSI scores at primary end-point (16-week visit) are equal for both arms (lansoprazole v placebo). A two-sided significance level of p<0.05 is used throughout.
    [6] - Test statistic: t=1.020, two-sided P-value= 0.154, concluding that there is no statistically significant difference in the RSI score at 16 weeks between lansoprazole and placebo.
    Statistical analysis title
    		 Multilevel mixed effect linear regression
    Statistical analysis description
    Adjusted for stratification factor recruiting centre (as a random effect) at randomisation and baseline severity in terms of RSI-HB as a continuous measure (as a fixed effect).
    Comparison groups
    Pragmatic ITT group v Pragmatic ITT group
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    P-value
    		 = 0.264 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 3.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.99
    Notes
    [7] - The continuous covariate (RSI-HB) was explored to assess whether transformation of RSI-HB was a better fit to the relationship with outcome than an untransformed continuous measure based on a reduction in Akaike information criterion (AIC). There was no reduction in AIC so to build the most parsimonious, clinically interpretable model, RSI-HB was retained as an un-transformed continuous covariate, under the assumption of linearity with outcome
    [8] - There is no statistically significant difference between randomised arms, lansoprazole compared to placebo (p=0.264), when adjusted for site and baseline continuous RSI-HB.

    Secondary: RSI at 12 months

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    End point title
    		 RSI at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    This is RSI score at 12 months' participation - eight months after the end of the treatment period.
    End point values
    		 Treatment Placebo Compliant Intention to Treat (ITT) group
    Number of subjects analysed
    82
    99
    181
    Units: none
        arithmetic mean (confidence interval 95%)
    16.0 (13.6 to 18.4)
    13.6 (11.7 to 15.5)
    14.7 (13.2 to 16.2)
    Statistical analysis title
    		 Univariate analysis of unadjusted 2-sample t-test
    Statistical analysis description
    Univariate analysis of unadjusted primary outcome measure for compliant analysis group at 12 months.
    Comparison groups
    Treatment v Placebo v Compliant Intention to Treat (ITT) group
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.115 [9]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 5.414
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.52
    Notes
    [9] - Test statistic: t=1.583, two-sided P-value= 0.115, concluding that there is no statistically significant difference in the RSI score at 12 months between lansoprazole and placebo.
    Statistical analysis title
    		 Multivariable analysis of RSI at 12 months
    Statistical analysis description
    Compliant ITT group
    Comparison groups
    Treatment v Placebo v Compliant Intention to Treat (ITT) group
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.157 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 4.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.22
    Notes
    [10] - No statistically significant difference between lansoprazole and placebo, when adjusted for site and baseline continuous RSI-HB. Estimated difference that lansoprazole participants have RSI score at 12 months 1.7 points higher (worse) than placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All non-SAEs/SARs occurring during drug treatment were reported on the eCRF system within four weeks of the form being due.
    Adverse event reporting additional description
    All Adverse Events were recorded. PIs were responsible for managing all AEs/ARs according to local protocols.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Participants receiving active treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receiving placebo.

    Serious adverse events
    		 Treatment Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 174 (1.15%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid carcinoma
    Additional description: Left hemithyroidectomy for BA lesion, the cause of which was found to be papillary thyroid carcinoma.
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Asthma
    Additional description: Exacerbation of asthma.
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Unintentional digestion of bleach/cleaning fluid
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Collapse
    Additional description: Transient loss of consciousness, followed by collapse.
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Surgical and medical procedures
    Colonoscopy
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Elective surgery
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Insertion of septal button
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Headaches, stomach pains
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Sickness
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Voice fatigue
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Immune system disorders
    Allergy
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Respiratory, thoracic and mediastinal disorders
    Cold
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Cough
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Sore throat
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Nasal polyps
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Nasal sores
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Pulmonary oedema
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Psychiatric disorders
    Low mood
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Depression
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Injury, poisoning and procedural complications
    Electric shock
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Cardiac disorders
    Cardiac symptoms
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Nervous system disorders
    Headache
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Migraine
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Amnesia
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Numbness
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Pins and needles
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Eye disorders
    Peripheral vision disturbance
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Swollen eyes
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Eye ulcer
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Constipation
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Diarrhoea
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Flatulence
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Food poisoning
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Gastrointestinal symptoms
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Indigestion
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Nausea
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Pain, upper right quadrant
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Stomach ache
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Vomiting
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Colic
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Dry mouth
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Dyspepsia
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Mouth ulceration
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Swallowing difficult
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Hepatobiliary disorders
    Gallbladder disorder
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Back pain
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Polyarthritis
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Pain in joints
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Infections and infestations
    Chest infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Flu
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Viral throat infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Ear infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Gum infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Helicobacter infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Tonsillitis
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52
    Viral infection
         subjects affected / exposed
    39 / 172 (22.67%)
    35 / 174 (20.11%)
         occurrences all number
    60
    52

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2015
    IMP Label: • Wording changed for emergency contact details Protocol changes: • Eligibility criteria clarified • Addition of information on washout periods prior to study participation • Addition of ‘You are in a washout period’ card to provide to participants • Provision for participants to find out whether their treatment, post-trial • Administrative changes to protocol Addition of new site: University Hospitals Birmingham NHS Foundation Trust Addition of PIC into Manchester: Tameside Hospital NHS Foundation Trust Change of PI at the Sunderland site Additions to PIS and ICF for Birmingham site Study poster and GP/Clinician Summary Information Sheet
    07 Dec 2015
    New Statistician working on trial Protocol updates: • Clarified wording of consent-washout-randomisation process • Revised ‘Schedule of Events’ table • Amended details of use of DVD • Clarified blinding arrangements • Clarified timescales for laryngoscopy Added new site: Stockport NHS Foundation Trust Added PIC site into Stockport: University Hospital of South Manchester NHS Foundation Trust (now re-named Manchester University NHS Foundation Trust) Clarified use of ‘internal PICs’ in Scotland
    07 Dec 2015
    Change of PI at Sunderland site
    07 Dec 2015
    Updated Reference Safety Information (RSI) for the trial, in response to risk assessment. Correction of exclusion criteria, in response to minor safety issue. Correction of Statistician name updated as part of previous Amendment, but not included in protocol at that time.
    03 Mar 2017
    Change in Principal Investigator at the Sunderland site Addition of Senior Clinical Trial Statistician to the trial team, who replaces current Statistician as signatory on trial protocol Minor updates to trial protocol Update of relevant authorities of Funder-approved extension of trial, including exceeding planned sample size

    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.
    Despite extensive efforts, the PPI strand of the trial proved disappointing. Improvements could be made to investigate reasons for non-engagement, consulting patients who declined participation or with other symptoms, and involving site staff more.
    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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