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    Clinical Trial Results:
    Staining efficacy and safety of Methylene Blue enemas in patients undergoing flexible rectosigmoidoscopy

    Summary
    EudraCT number
    		 2013-000452-18
    Trial protocol
    		 IT  
    Global end of trial date
    24 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions
    Summary report(s)
    		 CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    CB-17-03/01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study protocol: CRO-13-111
    Sponsors
    Sponsor organisation name
    Cosmo Technologies
    Sponsor organisation address
    Riverside 2, 49 Sir John Rogerson's Quay, Grand Canal Dock, Dublin,, Dublin, Ireland, D02 KV60
    Public contact
    Study Management, CROSS S.A., +41 916300510, cbanyai@cosmopharma.com
    Scientific contact
    Study Management, CROSS S.A., 0867015703 916300510, cbanyai@cosmopharma.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
    25 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is the evaluation of the mucosal staining efficacy after single rectal dose of two Methylene Blue enema formulations containing, respectively, 0.002% methylene blue (Formulation A) and 0.02% methylene blue (Formulation B), in patients undergoing a rectosigmoidoscopy for various reasons.
    Protection of trial subjects
    Discrete measures of vital signs (blood pressure - BP, heart rate - HR, peripheral oxygen saturation - SpO2) were recorded prior to, during and after the end of the endoscopy.
    Background therapy
    		 The subjects, who received Formulation A, also received a commercial cleansing enema (Clisma-Lax 133 mL, by Sofar S.p.A., Italy; batch: R0330; expiry: MAY17) and took it at home following the instructions enclosed with the product.
    Evidence for comparator
    		 A total dose of 100 mL of Methylene Blue enema composition was selected for the present study. When administering formulation A, the dose contained methylene blue 0.002%. With formulation B, methylene blue was 0.02%. These new formulations were tested in order to verify the ability to stain the sigmoidal and rectal (distal) colonic mucosa when administered through an enema cleansing preparation before a rectosigmoidoscopy. Formulation A, with the lower methylene blue concentration, was designed to be administered after the cleansing enema with the aim of staining the mucosa after the gut is cleansed through a previously administered cleansing enema. Formulation B combines both the cleansing and the staining properties and was designed to be administered alone, without any additional cleansing enema. The concentration of methylene blue in formulation B was increased by 10 times, because the affinity of methylene blue for faeces is higher than that for the intestinal mucosa. Since formulation B is administered when the gut lumen is not yet cleansed from faeces, the higher methylene blue concentration aimed at obtaining the same mucosal staining efficacy as with formulation A.
    Actual start date of recruitment
    15 Mar 2013
    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
    Italy: 5
    Worldwide total number of subjects
    5
    EEA total number of subjects
    5
    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)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The subjects were assigned a consecutive study number. The subjects received their individual clinical supply package, including the investigational medicinal product (IMP) for their treatment.

    Pre-assignment
    Screening details
    		 From day -15 to day -1, out-patients scheduled for rectosigmoidoscopy were informed about the aims, procedures, benefits and possible risks of the study prior to sign the informed onsent form for inclusion in the trial. Their medical history was evaluated and recorded. The subjects underwent a physical examination.

    Period 1
    Period 1 title
    Day of Endoscopy (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded. Patients were assigned on their treatment based on a consecutive study number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Formulation A
    Arm description
    		 Methylene Blue enema
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylene Blue enema
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Enema
    Routes of administration
    Rectal use
    Dosage and administration details
    0.002% of methylene blue in 100 mL of product

    Arm title
    		 Formulation B
    Arm description
    		 Methylene Blue enema, 0.02% of methylene blue in 100 mL of product
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylene Blue enema
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Enema
    Routes of administration
    Rectal use
    Dosage and administration details
    0.02% of methylene blue in 100 mL of product

    Number of subjects in period 1
    		Formulation A Formulation B
    Started
    4
    1
    Completed
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Formulation A
    Reporting group description
    		 Methylene Blue enema

    Reporting group title
    Formulation B
    Reporting group description
    		 Methylene Blue enema, 0.02% of methylene blue in 100 mL of product

    Reporting group values
    		 Formulation A Formulation B Total
    Number of subjects
    		 4 1 5
    Age categorical
    Age: ≥18 year old;
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 2 1 3
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Age continuous
    Age: ≥18 year old;
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 63.0 (51 to 73) 46 (46 to 46) -
    Gender categorical
    Units: Subjects
        Female
    		 3 0 3
        Male
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Formulation A
    Reporting group description
    		 Methylene Blue enema

    Reporting group title
    Formulation B
    Reporting group description
    		 Methylene Blue enema, 0.02% of methylene blue in 100 mL of product

    Subject analysis set title
    Enrolled Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all enrolled subjects

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all subjects who received at least one dose of the IMP. This analysis set was used for safety analyses.

    Subject analysis set title
    Efficacy set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    the efficacy set was defined as all treated subjects who fulfilled the study protocol requirements in terms of IMP intake and efficacy measure collection, without major deviations that could affect the efficacy results. This analysis set was used for efficacy analysis.

    Primary: Evaluation of the mucosal staining efficacy of the two test Methylene Blue enema Formulations, named A and B.

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    End point title
    		 Evaluation of the mucosal staining efficacy of the two test Methylene Blue enema Formulations, named A and B. [1]
    End point description
    No analysis could be conducted on the efficacy variables of the study due to premature study discontinuation.
    End point type
    Primary
    End point timeframe
    No analysis could be conducted on the efficacy variables of the study due to premature study discontinuation.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No analysis could be conducted on the efficacy variables of the study due to premature study discontinuation.
    End point values
    		 Formulation A Formulation B Efficacy set
    Number of subjects analysed
    4 [2]
    1 [3]
    5 [4]
    Units: 5
        number (not applicable)
    4
    1
    5
    Notes
    [2] - No analysis could be conducted on the efficacy variables of the study due to premature study discont
    [3] - No analysis could be conducted on the efficacy variables of the study due to premature study discont
    [4] - No analysis could be conducted on the efficacy variables of the study due to premature study discont
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Day 1-Day of the endoscopy
    Adverse event reporting additional description
    No adverse events or serious adverse events occurred during the study. No discontinuation due to any treatment emergent adverse event occurred during the study. No clinically meaningful effect of methylene blue on vital signs or subjects’ health conditions was observed
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse events or serious adverse events occurred during the study. No discontinuation due to any treatment emergent adverse event occurred during the study. No clinically meaningful effect of methylene blue on vital signs or subjects’ health conditions was observed

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2013
    Protocol amendment 1 issued on 31JUL13 was reviewed and approved by the IEC on 16SEP13. Ref. nr. CE ICH 254/13.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Jun 2014
    A total of 40 patients was planned to be included in the study (20 patients in each treatment group). Altogether, 5 patients were enrolled in the study. The study was terminated prematurely by the Sponsor due to slow enrolment rate
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No analysis could be conducted on the efficacy variables of the study due to premature study discontinuation.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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