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    Clinical Trial Results:
    The Role of GABAb receptor mechanisms in cough: Double-blind randomised controlled trial of Lesogaberan in Chronic cough patients with positive and negative symptom association probabilities

    Summary
    EudraCT number
    2014-005074-11
    Trial protocol
    GB  
    Global end of trial date
    30 Aug 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jun 2020
    First version publication date
    03 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14/GAR/002
    Additional study identifiers
    ISRCTN number
    ISRCTN77000698
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    REC reference: 14/NW/1497
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Oxford Road, Manchester, United Kingdom, M13 9WL
    Public contact
    Jaclyn Smith, University of Manchester, +44 01612915863, jacky.smith@manchester.ac.uk
    Scientific contact
    Jaclyn Smith, University of Manchester, +44 01612915863, jacky.smith@manchester.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
    30 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of 2 weeks of Lesogaberan treatment compared with 2 weeks of placebo treatment on 24 hour cough frequency. Lay description: To test what effect a drug called Lesogaberan has on how much a person coughs in a 24 hour period compared to if that person was taking a dummy drug with no active ingredients (called placebo).
    Protection of trial subjects
    Patients may experience side effects after taking Lesogaberan or placebo during the study. Lesogaberan has been previously been given to 489 healthy volunteers and 930 patients. The drug was generally well tolerated. The most common side effect of taking Lesogaberan (seen in 1 in 4 people)is tingling or numbness of the fingers, which only mild and temporary. The other side effects were headache (1 in 10), feeling hot, diarrhoea, flatulence and dizziness. During the study patients will be asked to perform a number of tests which may have side effects. Oesophageal studies (high resolution manometry and 24 hour pH impedance). This is a combination of 2 procedures where the patient has a small tube passed through their nose into their stomach, one of the tubes will be left in place for 24 hours. This procedure is not painful, there maybe some slight discomfort when the tube is passed through the nose, thus a numbing agent will be applied to the nasal area to reduce this. there may be some mild gagging or coughing too. Most patients tolerated this procedure well. A cough challenge involves inhaling capsaicin, which is a component of chilli peppers. Capsaicin can cause tightening of the airways, although this is rare. Breathing tests are performed during and after the test to monitor any chest tightening, which is easily treated by inhaling salbutamol (a medication to open up the airways. Blood tests sometimes cause bruising at the site of the needle puncture. Some people feel faint whilst blood is being withdrawn. Rarely a small blood clot or infection can occur. The electrodes and sticky pads placed on the skin during ECG tests and 24 hour cough monitoring can occasionally lead to skin irritation. Although lung function tests are not painful, they can be tiring to perform. Patients may experience shortness of breath, coughing or chest tightness. Some people can feel lightheaded or faint. A doctor will be present in the department at all times.
    Background therapy
    All study participants will continue with their usual clinical treatment and followup via the cough clinic.
    Evidence for comparator
    The treatment sequence for each subject number will be randomised. Each subject will receive, in a random order, and in a double-blind fashion, (1) Lesogaberan or (2) Placebo BD in the first dosing period of 14 days. They will then receive the alternate drug/ placebo following a minimum 1 week washout period.
    Actual start date of recruitment
    23 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    12
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients with chronic cough were recruited from the cough specialist clinic at Manchester University NHS Foundation Trust (Wythenshawe Hospital), Manchester, UK. All interested participants were required to read the information sheet carefully and be given at least 24 hours to consider the information before agreeing to take part.

    Pre-assignment
    Screening details
    27 patients screened; 4 failed screen (uncontrolled hypertension, declined contraceptive measures, current smoker, hypothyroidism), 1 lost to follow up. Inclusion criteria; signed, written, informed consent, age >18yr, compliance with contraceptive measures, BMI 19-35kg/m2 inc, normal spirometry, chronic cough >8weeks, normal CXR.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Randomisation sequences were generated by an external contractor independent to the study site. Blinded study medication and unblinding scratch cards were supplied to the hospital pharmacy department.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Lesogaberan
    Arm description
    120mg Lesogaberan MR BD for 2 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Lesogaberan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    120mg Lesogaberan (modified release) was taken twice a day at approximately 12 hour intervals. The first dose plus the morning doses on the last two treatment days were taken during study visits whilst in the department to allow measurement of secondary endpoints (blood pK and capsaicin cough response) at peak plasma levels (2 hours post dose).

    Arm title
    Placebo
    Arm description
    2 weeks treatment with matched placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Matched placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo administered twice a day at approximately 12 hour intervals for 2 weeks. The first dose and morning doses on final two treatment days were taken in the department to allow secondary endpoint measurements to be taken at peak plasma levels at 2 hours (capsaicin coughs and pK bloods)

    Number of subjects in period 1
    Lesogaberan Placebo
    Started
    22
    22
    Completed
    21
    20
    Not completed
    1
    2
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    All patients enrolled in the trial

    Reporting group values
    Overall Trial Total
    Number of subjects
    22 22
    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
    Units: years
        arithmetic mean (standard deviation)
    63 ± 7 -
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    6 6
    Smoking Status
    Units: Subjects
        Never Smoked
    16 16
        Ex Smoker
    6 6
    Symptom Association Probability (SAP)
    SAP describes the association between coughing and preceding reflux events. Patients are described being either SAP positive or SAP negative.
    Units: Subjects
        SAP Positive
    11 11
        SAP Negative
    8 8
        Not recorded
    3 3
    Classification of reflux events
    Units: Subjects
        Normal
    17 17
        Abnormal
    3 3
        Not recorded
    2 2
    Peristalsis Strength
    Units: Subjects
        Weak
    8 8
        Normal
    12 12
        Not recorded
    2 2
    Smoking History
    Units: Pack Years
        median (inter-quartile range (Q1-Q3))
    0 (0 to 2.4) -
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    25.8 ± 4.0 -
    Cough Duration
    Units: Years
        median (inter-quartile range (Q1-Q3))
    10.5 (5.8 to 17.0) -
    FEV1
    Forced expiratory volume in 1 second
    Units: % predicted
        arithmetic mean (standard deviation)
    95 ± 14.6 -
    FVC
    Forced vital capacity
    Units: % predicted
        arithmetic mean (standard deviation)
    110 ± 20.7 -
    24 hour cough frequency
    Baseline cough rate measured over 24 hours during simultaneous impedance pH monitoring
    Units: coughs per hour
        median (inter-quartile range (Q1-Q3))
    24 (12 to 32) -
    LCQ Score
    Leicester cough questionnaire total score
    Units: numeric score
        arithmetic mean (standard deviation)
    14.2 ± 3.8 -
    Daytime cough severity VAS
    100mm visual analogue score
    Units: mm
        arithmetic mean (standard deviation)
    43 ± 25.6 -
    Night-time cough severity VAS
    100mm visual analogue scale
    Units: mm
        median (inter-quartile range (Q1-Q3))
    17 (8 to 25) -
    Symptom Index (SI)
    The symptom index represents the percentage of cough events that correlate with reflux events
    Units: percent
        arithmetic mean (standard deviation)
    ± -
    Total reflux episodes
    Units: number
        median (inter-quartile range (Q1-Q3))
    -
    Lower oesophageal sphincter pressure (LOSP)
    Normal pressure - 26mmHg
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    -
    Subject analysis sets

    Subject analysis set title
    SAP Analysis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All patients for whom reflux symptom association data were available (n=19)

    Subject analysis set title
    Reflux Analysis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with fully available reflux data (n=20)

    Subject analysis sets values
    SAP Analysis Reflux Analysis
    Number of subjects
    19
    20
    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
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    Smoking Status
    Units: Subjects
        Never Smoked
        Ex Smoker
    Symptom Association Probability (SAP)
    SAP describes the association between coughing and preceding reflux events. Patients are described being either SAP positive or SAP negative.
    Units: Subjects
        SAP Positive
        SAP Negative
        Not recorded
    Classification of reflux events
    Units: Subjects
        Normal
        Abnormal
        Not recorded
    Peristalsis Strength
    Units: Subjects
        Weak
        Normal
        Not recorded
    Smoking History
    Units: Pack Years
        median (inter-quartile range (Q1-Q3))
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    ±
    ±
    Cough Duration
    Units: Years
        median (inter-quartile range (Q1-Q3))
    FEV1
    Forced expiratory volume in 1 second
    Units: % predicted
        arithmetic mean (standard deviation)
    ±
    ±
    FVC
    Forced vital capacity
    Units: % predicted
        arithmetic mean (standard deviation)
    ±
    ±
    24 hour cough frequency
    Baseline cough rate measured over 24 hours during simultaneous impedance pH monitoring
    Units: coughs per hour
        median (inter-quartile range (Q1-Q3))
    LCQ Score
    Leicester cough questionnaire total score
    Units: numeric score
        arithmetic mean (standard deviation)
    ±
    ±
    Daytime cough severity VAS
    100mm visual analogue score
    Units: mm
        arithmetic mean (standard deviation)
    ±
    ±
    Night-time cough severity VAS
    100mm visual analogue scale
    Units: mm
        median (inter-quartile range (Q1-Q3))
    Symptom Index (SI)
    The symptom index represents the percentage of cough events that correlate with reflux events
    Units: percent
        arithmetic mean (standard deviation)
    14 ± 8.4
    ±
    Total reflux episodes
    Units: number
        median (inter-quartile range (Q1-Q3))
    48.9 (23.5 to 68.8)
    Lower oesophageal sphincter pressure (LOSP)
    Normal pressure - 26mmHg
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    22.2 (6.7 to 26.2)

    End points

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    End points reporting groups
    Reporting group title
    Lesogaberan
    Reporting group description
    120mg Lesogaberan MR BD for 2 weeks.

    Reporting group title
    Placebo
    Reporting group description
    2 weeks treatment with matched placebo.

    Subject analysis set title
    SAP Analysis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All patients for whom reflux symptom association data were available (n=19)

    Subject analysis set title
    Reflux Analysis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Patients with fully available reflux data (n=20)

    Primary: 24-hour Cough Frequency

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    End point title
    24-hour Cough Frequency
    End point description
    End point type
    Primary
    End point timeframe
    Cough frequency over 24 hours measured after two weeks treatment with Lesogaberan or matched placebo
    End point values
    Lesogaberan Placebo
    Number of subjects analysed
    21
    18
    Units: coughs/hour
        median (inter-quartile range (Q1-Q3))
    22.7 (6.7 to 38.8)
    22.6 (11.4 to 29.2)
    Statistical analysis title
    Cough Frequency Analysis
    Statistical analysis description
    Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Based on previous cough frequency data in an unselected chronic cough group, the study had approximately 80% power to detect a 43% reduction in cough with lesogaberan over placebo, assuming a SD of log cough frequency of 0.42. Sig level p<0.05.
    Comparison groups
    Lesogaberan v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.119 [1]
    Method
    GEE model
    Confidence interval
    Notes
    [1] - Significance set at p<0.05

    Secondary: Capsaicin evoked Emax

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    End point title
    Capsaicin evoked Emax
    End point description
    Incremental concentrations of capsaicin were inhaled through a dose controlled nebuliser up to the maximum tolerated dose or the end of the challenge. Emax is defined as the maximum number of coughs evoked by any concentration of capsaicin.
    End point type
    Secondary
    End point timeframe
    Capsaicin challenge was performed at screening and at baseline and at the end of both treatment periods. The challenge was administered at 2 hours post final dose of medication intended to capture peak drug plasma levels.
    End point values
    Lesogaberan Placebo
    Number of subjects analysed
    16
    16
    Units: Number of coughs
        arithmetic mean (confidence interval 95%)
    27.4 (22.7 to 32.1)
    34.3 (28.0 to 40.7)
    Statistical analysis title
    Effect of treatment on maximum cough responses
    Statistical analysis description
    Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.
    Comparison groups
    Lesogaberan v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    GEE model
    Confidence interval

    Secondary: Capsaicin evoked ED50

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    End point title
    Capsaicin evoked ED50
    End point description
    Capsaicin challenge was performed at screening and at baseline and at the end of both treatment periods. The challenge was administered at 2 hours post final dose of medication intended to capture peak drug plasma levels. Incremental concentrations of capsaicin solution were inhaled through a dose controlled nebuliser up to the maximum tolerated dose or the end of the challenge. ED50 is defined as the dose or concentration of capsaicin that elicits half of the maximum cough response (Emax).
    End point type
    Secondary
    End point timeframe
    ED50 dose compared after 2 weeks treatment with lesogaberan or matched placebo.
    End point values
    Lesogaberan Placebo
    Number of subjects analysed
    16 [2]
    16 [3]
    Units: micromole(s)
        geometric mean (confidence interval 95%)
    45.3 (31.6 to 59.0)
    27.7 (15.4 to 39.9)
    Notes
    [2] - 16 out of 22 patients completed the capsaicin challenges due to supply issue.
    [3] - 16 out of 22 patients completed the capsaicin challenges due to supply issue.
    Statistical analysis title
    Effect of treatment on capsaicin evoked ED50
    Statistical analysis description
    Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model.
    Comparison groups
    Lesogaberan v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03 [4]
    Method
    GEE model
    Confidence interval
    Notes
    [4] - Significance set at p<0.05

    Secondary: Daytime cough severity VAS

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    End point title
    Daytime cough severity VAS
    End point description
    100mm visual analogue scale where patients are asked to draw a vertical line to indicate their perceived cough severity during daytime hours on any particular day.
    End point type
    Secondary
    End point timeframe
    Measured pre and post 2 weeks of treatment with lesogaberan or matched placebo.
    End point values
    Lesogaberan Placebo
    Number of subjects analysed
    18
    20
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    31.5 (22.4 to 61.9)
    35.5 (18.3 to 63.5)
    Statistical analysis title
    Effect of treatment on daytime VAS
    Statistical analysis description
    Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.
    Comparison groups
    Lesogaberan v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5
    Method
    GEE model
    Confidence interval

    Secondary: Night-time cough severity VAS

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    End point title
    Night-time cough severity VAS
    End point description
    100mm visual analogue scale where patients are asked to draw a vertical line to indicate their perceived cough severity during overnight hours on any particular day.
    End point type
    Secondary
    End point timeframe
    Measured pre and post 2 weeks of treatment with lesogaberan or matched placebo.
    End point values
    Lesogaberan Placebo
    Number of subjects analysed
    18
    20
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    12.0 (0.9 to 38.1)
    14.5 (2.0 to 36.3)
    Statistical analysis title
    Effect of treatment on night-time VAS
    Statistical analysis description
    Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.
    Comparison groups
    Lesogaberan v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.768
    Method
    GEE model
    Confidence interval

    Secondary: LCQ

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    End point title
    LCQ
    End point description
    Self-reported quality of life outcome measure - Leicester Cough Questionnaire (LCQ). 19 items with likert scale (1-7) reflecting on cough for previous 2 weeks.
    End point type
    Secondary
    End point timeframe
    Measured pre and post 2 weeks of treatment with lesogaberan or matched placebo
    End point values
    Lesogaberan Placebo
    Number of subjects analysed
    21
    20
    Units: total score
        arithmetic mean (standard deviation)
    14.9 ± 3.0
    14.7 ± 3.5
    Statistical analysis title
    Effect of treatment on total LCQ score
    Statistical analysis description
    Generalised Estimating Equation (GEE) models were used to analyze the data assessing the influence of treatment period and sequence. We adjusted for period specific baseline. Potential carryover effects were examined by the sequence in the model. Significance was set at p <0.05.
    Comparison groups
    Lesogaberan v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    GEE model
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported from administration of the first dose of study medication, throughout both dosing periods (2 weeks each), a 1-2 week washout period and until the final follow up visit (1-2 weeks after final dose of study medication).
    Adverse event reporting additional description
    AEs were assessed by the investigator at each study visit via patient reporting, routine safety blood testing, vital signs and ECGs
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo treatment
    Reporting group description
    AEs during placebo treatment period

    Reporting group title
    Lesogaberan treatment
    Reporting group description
    -

    Serious adverse events
    Placebo treatment Lesogaberan treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo treatment Lesogaberan treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 22 (54.55%)
    12 / 21 (57.14%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 21 (14.29%)
         occurrences all number
    2
    3
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Dizziness
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Rhinorrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2017
    Substantial Amendment number 1: Section 9.1, page 29, of the protocol was updated to reduce the total number of patients recruited to the study from 50 to 25. As recruitment commenced the investigators noticed a self-selection bias in the study, with only the patients who have reflux agreeing to take part. Thus the vast majority of the patients recruited and tested being SAP positive. If SAP positive vs SAP negative patients were compared as part of the secondary outcome of the study, a very large number of patients would have been needed. Whereas if only SAP positive patients were studied, only need 25 patients would be required (based on previous studies calculations).

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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