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    Clinical Trial Results:
    Peppermint oil for the treatment of Irritable Bowel Syndrome: optimizing therapeutic strategies using targeted delivery

    Summary
    EudraCT number
    		 2015-005467-16
    Trial protocol
    		 NL  
    Global end of trial date
    01 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2021
    First version publication date
    01 Dec 2021
    Other versions
    Summary report(s)
    		 Weerts_Gastroenterol_2020
    Weerts_JMU_2020
    Weerts_UEG_2021

    Trial information

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    Trial identification
    Sponsor protocol code
    55995
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02716285
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ABR form number (CCMO): 56000
    Sponsors
    Sponsor organisation name
    Maastricht university
    Sponsor organisation address
    Universiteitssingel 50, Maastricht, Netherlands, 6229 ER
    Public contact
    Coordinating investigator, Z Weerts, Maastricht University, 0031 3882284, z.weerts@maastrichtuniversity.nl
    Scientific contact
    Coordinating investigator, Z Weerts, Maastricht University, 0031 3882284, z.weerts@maastrichtuniversity.nl
    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
    01 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To assess the efficacy and safety profile of treatment of IBS symptoms with peppermint oil compared to placebo. Thereby superiority of peppermint oil can be scientifically supported, leading to increased recognition of this therapy in IBS. 2. To ascertain whether treatment of IBS symptoms with colon-targeted-delivery peppermint oil results in a greater reduction of IBS symptoms and reduction of side effects, compared to enteric-coated capsules delivering the oil in the small intestine.
    Protection of trial subjects
    Patients received treatment with peppermint oil or placebo. There were no invasive measurements. Side effects were monitored.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 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
    Netherlands: 190
    Worldwide total number of subjects
    190
    EEA total number of subjects
    190
    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)
    184
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients between 18 and 75 years of age, fulfilling the Rome IV criteria for IBS, and without alarm symptoms were recruited via primary care; via the outpatient clinics of the participating hospitals; or via self-referral through public advertisements, social media, and the Dutch IBS Patient Federation.

    Pre-assignment
    Screening details
    		 Prescreening (telephone interview) and a medical screening: history taking and a physical examination. After the screening, eligible patients entered a 14-day pretreatment period during which they scored their daily worst abdominal pain in a digital symptom diary, scored on an 11-point NRS. If mean abdominal pain>3. They were included.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Data analyst, Subject
    Blinding implementation details
    Capsules were over-encapsulated to ensure equal appearance of placebo and peppermint oil capsules. Packaging info only contained blinded information.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    182mg

    Arm title
    		 Small-intestinal release peppermint oil
    Arm description
    		 Small-intestinal release peppermint oil treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tempocol
    Investigational medicinal product code
    Other name
    Small-intestinal release peppermint oil
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    3 times daily 182mg

    Arm title
    		 Ileocolonic release peppermint oil
    Arm description
    		 Ileocolonic release peppermint oil
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tempocol-colopulse
    Investigational medicinal product code
    Other name
    Ileocolonic-release peppermint oil
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    3 times daily 182mg

    Number of subjects in period 1
    		Placebo Small-intestinal release peppermint oil Ileocolonic release peppermint oil
    Started
    64
    62
    64
    Completed
    61
    59
    59
    Not completed
    3
    3
    5
         personal reason
    1
    -
    -
         Adverse event, non-fatal
    1
    3
    5
         Lack of efficacy
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Small-intestinal release peppermint oil
    Reporting group description
    		 Small-intestinal release peppermint oil treatment

    Reporting group title
    Ileocolonic release peppermint oil
    Reporting group description
    		 Ileocolonic release peppermint oil

    Reporting group values
    		 Placebo Small-intestinal release peppermint oil Ileocolonic release peppermint oil Total
    Number of subjects
    		 64 62 64 190
    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)
    		 35.5 ± 15.2 32.0 ± 11.1 34.4 ± 13.1 -
    Gender categorical
    Units: Subjects
        Female
    		 49 51 48 148
        Male
    		 15 11 16 42
    IBS-SSS score
    The IBS-SSS consists of 5 items with a maximum score of 100; higher scores indicate more severe symptoms.
    Units: symptom severity score
        arithmetic mean (standard deviation)
    		 270.8 ± 74.2 277.0 ± 73.6 282.8 ± 68.7 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Small-intestinal release peppermint oil
    Reporting group description
    		 Small-intestinal release peppermint oil treatment

    Reporting group title
    Ileocolonic release peppermint oil
    Reporting group description
    		 Ileocolonic release peppermint oil

    Primary: Abdominal pain responder (FDA)

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    End point title
    		 Abdominal pain responder (FDA)
    End point description
    An abdominal pain responder is someone who has a >30% in mean daily worst abdominal pain, scored on a 11 point NRS, in at least 50% of the time in which treatment is given.
    End point type
    Primary
    End point timeframe
    0-8 weeks
    End point values
    		 Placebo Small-intestinal release peppermint oil Ileocolonic release peppermint oil
    Number of subjects analysed
    64
    62
    63 [1]
    Units: Responders
        Abdominal pain responder
    22
    29
    26
        Abdominal pain non-responder
    42
    33
    37
    Notes
    [1] - 1 person excluded from analysis due to unjustified randomization
    Statistical analysis title
    		 Abdominal Pain responder (FDA)
    Statistical analysis description
    The responder outcomes were analyzed by using multiple logistic regression, with correction for the minimization variables of sex, center, IBS subtype, age. Ors, 2-sided 95% CIs, and corresponding P values are reported. Patients with fewer than 4 weekly diary entries were considered to be nonresponders for that week, regardless of their score. To account for multiple comparison 2-sided P values of 0.05/4 1⁄4 0.0125 were considered statistically significant for the primary outcome.
    Comparison groups
    Placebo v Small-intestinal release peppermint oil v Ileocolonic release peppermint oil
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.0125 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Notes
    [2] - To account for multiple comparisons (both intervention groups with placebo and 2 primary outcomes), 2-sided P values of 0.05/4 1⁄4 0.0125 were considered statistically significant for the primary outcomes.
    Statistical analysis title
    		 Global relief
    Statistical analysis description
    The responder outcomes were analyzed by using multiple logistic regression, with correction for the minimization variables of sex, center, IBS subtype, age. Ors, 2-sided 95% CIs, and corresponding P values are reported. Patients with fewer than 4 weekly diary entries were considered to be nonresponders for that week, regardless of their score. To account for multiple comparison 2-sided P values of 0.05/4 1⁄4 0.0125 were considered statistically significant for the primary outcome.
    Comparison groups
    Placebo v Small-intestinal release peppermint oil v Ileocolonic release peppermint oil
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.0125 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Notes
    [3] - To account for multiple comparisons (both intervention groups with placebo and 2 primary outcomes), 2-sided P values of 0.05/4 1⁄4 0.0125 were considered statistically significant for the primary outcomes.

    Primary: Global relief responder

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    End point title
    		 Global relief responder
    End point description
    A global relief responder was defined as a patient with a weekly relief of threshold 6 or 7 on the 11 point NRS in at least 50% of the treatment period, that is, 4 weeks.
    End point type
    Primary
    End point timeframe
    0-8 weeks
    End point values
    		 Placebo Small-intestinal release peppermint oil Ileocolonic release peppermint oil
    Number of subjects analysed
    64
    62
    63 [4]
    Units: Global relief responder
        Global Relief responder
    3
    6
    1
        Global Relief non-responder
    61
    56
    62
    Notes
    [4] - 1 person was excluded from the ITT analysis due to unjustified randomization
    Statistical analysis title
    		 Global relief responder
    Comparison groups
    Small-intestinal release peppermint oil v Ileocolonic release peppermint oil v Placebo
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.0125 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Notes
    [5] - To account for multiple comparisons (both intervention groups with placebo and 2 primary outcomes), 2-sided P values of 0.05/4 1⁄4 0.0125 were considered statistically significant for the primary outcomes.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    0-8 weeks
    Adverse event reporting additional description
    Patients were asked to score any side effects daily into the daily symptom diary (digital application) (question: did you experience any side effects today?). In addition, at the end of the week - prespecified questions were asked about side effects such as belching, nausea, etc.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Own codebook
    Dictionary version
    x
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Small-intestinal release peppermint oil
    Reporting group description
    		 Small-intestinal release peppermint oil treatment

    Reporting group title
    Ileocolonic release peppermint oil
    Reporting group description
    		 Ileocolonic release peppermint oil

    Serious adverse events
    		 Placebo Small-intestinal release peppermint oil Ileocolonic release peppermint oil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placebo Small-intestinal release peppermint oil Ileocolonic release peppermint oil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 64 (78.13%)
    59 / 62 (95.16%)
    61 / 63 (96.83%)
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    21 / 64 (32.81%)
    25 / 62 (40.32%)
    26 / 63 (41.27%)
         occurrences all number
    21
    25
    26
    Gastrointestinal disorders
    Heartburn
         subjects affected / exposed
    18 / 64 (28.13%)
    31 / 62 (50.00%)
    23 / 63 (36.51%)
         occurrences all number
    18
    31
    23
    Belching
         subjects affected / exposed
    15 / 64 (23.44%)
    28 / 62 (45.16%)
    12 / 63 (19.05%)
         occurrences all number
    15
    28
    12
    Belching with minty taste
         subjects affected / exposed
    1 / 64 (1.56%)
    36 / 62 (58.06%)
    14 / 63 (22.22%)
         occurrences all number
    1
    36
    14
    Abdominal cramps
         subjects affected / exposed
    12 / 64 (18.75%)
    13 / 62 (20.97%)
    29 / 63 (46.03%)
         occurrences all number
    12
    13
    29
    Altered anal sensation/sensitive urethra
         subjects affected / exposed
    9 / 64 (14.06%)
    22 / 62 (35.48%)
    39 / 63 (61.90%)
         occurrences all number
    9
    22
    39
    Peppermint oil-scented stool
         subjects affected / exposed
    1 / 64 (1.56%)
    18 / 62 (29.03%)
    18 / 63 (28.57%)
         occurrences all number
    1
    18
    18

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31470006
    http://www.ncbi.nlm.nih.gov/pubmed/34468079
    http://www.ncbi.nlm.nih.gov/pubmed/33030150
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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