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    Clinical Trial Results:
    Randomized multicenter, placebo-controlled, single blind study to assess the efficacy and tolerability of a combination of a cream containing ubidecarenone, dexpanthenol and chlorhexidine and a paste containing 2% diltiazem hydrochloride in the treatment of chronic anal fissure.

    Summary
    EudraCT number
    		 2005-005675-15
    Trial protocol
    		 PT   CZ   ES  
    Global end of trial date
    24 Apr 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Jun 2017
    First version publication date
    22 Sep 2016
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    wE would like to remove the summary results since is not mandatory.

    Trial information

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    Trial identification
    Sponsor protocol code
    DIL-UBI-DEX-CLO II/2003/003/PT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tecnimede, Sociedade Técnico Medicinal
    Sponsor organisation address
    Ru a da Tapada Grande, nº 2 , Abrunheira, Portugal, 2710-089
    Public contact
    Rita Neves, Tecnimede, Sociedade Técnico Medicinal, 0351 210 414 187, dmed.ct@tecnimede.pt
    Scientific contact
    Rita Neves, Tecnimede, Sociedade Técnico Medicinal, 0351 210 414 187, dmed.ct@tecnimede.pt
    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
    27 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this clinical trial was to assess the relative efficacy of the concomitant administration of UDC cream and DTZ 2% paste versus the administration of DTZ 2% paste + placebo of the UDC (PLC) after 8 weeks of CAF treatment.
    Protection of trial subjects
    To minimize Chronic Anal Fissure's pain patients were allowed to continue the conservative treatment and had access to rescue medication (paracetamol).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2009
    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
    Portugal: 117
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Czech Republic: 71
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    214
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment lasted 6 months after inclusion of the first patient in each country and per each study part.

    Pre-assignment
    Screening details
    		 Patients included signed the ICF, were able to comply with the study protocol, were aged 18 years or above, were diagnosed with idiopathic Chronic anal fissure unresponsive to previous therapy and did not present any exclusion criteria. From the 244 patients screened only 240 were randomized.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group I
    Arm description
    		 the DTZ 2% cutaneous paste and the PLC cutaneous cream
    Arm type
    		 Placebo

    Investigational medicinal product name
    Diltiazem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous paste
    Routes of administration
    Rectal use
    Dosage and administration details
    Total daily dose of 16 mg was planned for DTZ 2% and 400 mg for placebo.

    Arm title
    		 Group II
    Arm description
    		 DTZ 2% cutaneous paste and the UDC cutaneous cream
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diltiazem and UDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous emulsion, Cutaneous paste
    Routes of administration
    Rectal use
    Dosage and administration details
    Total daily dose of 16 mg was planned for DTZ 2% and 400 mg of UDC

    Number of subjects in period 1 [1]
    		Group I Group II
    Started
    112
    114
    Completed
    94
    93
    Not completed
    18
    21
         PP inclusion criteria violation
    18
    21
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The discrepancies are due to ITT analysis. There were subjects that not applied the medication

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 the DTZ 2% cutaneous paste and the PLC cutaneous cream

    Reporting group title
    Group II
    Reporting group description
    		 DTZ 2% cutaneous paste and the UDC cutaneous cream

    Reporting group values
    		 Group I Group II Total
    Number of subjects
    		 112 114 226
    Age categorical
    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)
    		 104 98 202
        From 65-84 years
    		 8 16 24
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.52 ± 14.79 47.43 ± 14.89 -
    Gender categorical
    Units: Subjects
        Female
    		 51 65 116
        Male
    		 61 49 110

    End points

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    End points reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 the DTZ 2% cutaneous paste and the PLC cutaneous cream

    Reporting group title
    Group II
    Reporting group description
    		 DTZ 2% cutaneous paste and the UDC cutaneous cream

    Primary: Chronic anal fissure cure after 8 weeks of treatment (intention to treat population)

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    End point title
    		 Chronic anal fissure cure after 8 weeks of treatment (intention to treat population)
    End point description
    End point type
    Primary
    End point timeframe
    After 8 weeks of treatment
    End point values
    		 Group I Group II
    Number of subjects analysed
    112
    114
    Units: Subjects
    65
    73
    Statistical analysis title
    		 Cure Proportion Comparision
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.413
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Changes in visual analogue scale for pain after 8 weeks of treatment (intention to treat population)

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    End point title
    		 Changes in visual analogue scale for pain after 8 weeks of treatment (intention to treat population)
    End point description
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment
    End point values
    		 Group I Group II
    Number of subjects analysed
    112
    114
    Units: mm
        arithmetic mean (standard deviation)
    46.7 ± 31.03
    46.87 ± 24.56
    Statistical analysis title
    		 VAS Means Comparision
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.873
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Changes in visual analogue scale for pain after 4 weeks of treatment (intention to treat population)

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    End point title
    		 Changes in visual analogue scale for pain after 4 weeks of treatment (intention to treat population)
    End point description
    End point type
    Secondary
    End point timeframe
    After 4 weeks of treatment
    End point values
    		 Group I Group II
    Number of subjects analysed
    112
    114
    Units: mm
        arithmetic mean (standard deviation)
    39.83 ± 27.42
    38.78 ± 25.41
    Statistical analysis title
    		 VAS Means Comparision
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.9
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Chronic anal fissure cure after 4 weeks of treatment (intention to treat population)

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    End point title
    		 Chronic anal fissure cure after 4 weeks of treatment (intention to treat population)
    End point description
    End point type
    Secondary
    End point timeframe
    After 4 weeks of treatment
    End point values
    		 Group I Group II
    Number of subjects analysed
    112
    114
    Units: Subjects
    14
    18
    Statistical analysis title
    		 Cure Proportion Comparision
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.568
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Chronic anal fissure relapse (intention to treat population)

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    End point title
    		 Chronic anal fissure relapse (intention to treat population)
    End point description
    End point type
    Secondary
    End point timeframe
    During the 24-week follow-up period
    End point values
    		 Group I Group II
    Number of subjects analysed
    65
    73
    Units: Subjects
    8
    14
    Statistical analysis title
    		 Relapse Proportion Comparision
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.351
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The investigator was responsible for notifying the sponsor no later than 24 hours of all serious adverse events, except those not requiring immediate notification. This expedited reporting was followed by a detailed report, no later than 5 (five) days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Group II
    Reporting group description
    		 -

    Reporting group title
    Group I
    Reporting group description
    		 -

    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: Details were given above
    Serious adverse events
    		 Group II Group I
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 121 (7.44%)
    6 / 117 (5.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood count abnormal
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal adenoma
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb traumatic amputation
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Intervertebral disc operation
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plastic surgery
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopaedic procedure
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Dysplasia
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group II Group I
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 117 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2008
    Clarification of the IMP circuit
    11 Sep 2009
    Clarification of the study procedures
    24 Jan 2012
    Alteration of the 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.
    None reported
    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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