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    Clinical Trial Results:
    CHANGE TO: A PILOT RANDOMISED STUDY TO COMPARE COMBINATION ANTIBIOTIC THERAPY (CIPROFLOXACIN AND DOXYCYCLINE) WITH STANDARD THERAPY (BUDESONIDE) IN THE TREATMENT OF ACTIVE CROHN'S DISEASE

    Summary
    EudraCT number
    		 2008-001137-99
    Trial protocol
    		 GB  
    Global end of trial date
    30 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2020
    First version publication date
    14 Jun 2020
    Other versions
    Summary report(s)
    		 End of Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    3591
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01783106
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    Brownlow Street, Liverpool, United Kingdom,
    Public contact
    Alex Astor, University of Liverpool, 0151 794 8373, sponsor@liverpool.ac.uk
    Scientific contact
    Alex Astor, University of Liverpool, 0151 794 8373, sponsor@liverpool.ac.uk
    Sponsor organisation name
    Royal Liverpool & Broadgreen University Hospitals
    Sponsor organisation address
    Prescot Street, Liverpool, United Kingdom,
    Public contact
    Heather Rogers, The Royal Liverpool & Broadgreen University Hospital NHS Trust, 0151 706 3702, Heather.Rogers@lhpspark.nhs.uk
    Scientific contact
    Heather Rogers, The Royal Liverpool & Broadgreen University Hospital NHS Trust, 0151 706 3702, Heather.Rogers@lhpspark.nhs.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
    27 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The Primary Objective •To compare the efficacy of a combination of antibiotics (Ciprofloxacin and Doxycycline) with standard therapy (oral Budesonide - Entocort CR) in the Treatment of Active Crohn’s Disease.
    Protection of trial subjects
    As well as the ongoing pharmacovigilance on this study, interim analysis was performed every 6 months to measure tolerability and efficacy. The design of the study, in respect to the frequency of the assessments and interventions, was done with input from patient and public involvement to ensure as little burden as possible was placed on subjects for their compliance with study protocol.
    Background therapy
    		 There was no set baseline medication per se, however patients who were receiving standard of care medication were required to maintain a stable dosage of it for their participation in the study. Prednisolone and Budesonide, as well as Azathioprine or marcaptopurine, were part of the inclusion factors providing the patients could maintain stable dose, the latter two drugs also being strafication factors in patients who had them administered prior to randomisation.
    Evidence for comparator
    		 The Comparison of the combination antibiotics with standard therapy for treating Active Crohn's Disease, taken from protocol: hydroxychloroquine enhances killing of intra-macrophage bacteria in other conditions and is used, as hydroxychloroquine 200mgs tds in combination with Doxycycline for up to 4 years as first-line therapy in Q-Fever. Our own data, has established in vitro efficacy of Hydroxychloroquine in combination with Doxyclycline and Ciprofloxacin in killing E. coli isolates within macrophages at a steady-state blood concentration of hydroxychloroquine 1-2 micrograms per ml. achievable with hydroxychloroquine 200mg tds dosing in an average adult. This study will be used to assess the efficacy and tolerability of six months' treatment of active Crohn's disease with antibiotics (Ciproflaxin, doxycycline and hydroxychloroquine) selected on the basis of their ability to kill Crrohns' disease E. coli isolates that have been internalised within macrophages in comparison with standard 3 months therapy with the low-side effect steroid, budesonide.
    Actual start date of recruitment
    25 Nov 2013
    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: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    52
    From 65 to 84 years
    8
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Sixty one patients were recruited across 8 sites in the United Kingdom. The first patient was recruited on 25 Nov 2013 and the last patient 05 Dec 2018

    Pre-assignment
    Screening details
    		 83 patients were screened for the Apricot study, 61 of whom where randomised as they met the inclusion criteria. 17 patients did not meet the inclusion criteria, 4 declined to be a part of the trial and one patient was excluded for other reasons. Out of these 61 patients only 59 went on to receive the study drug.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label study with crossover once randomised, so no blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experiment arm
    Arm description
    		 4 weeks Combination Antibiotic Therapy (Oral Ciprofloxacin 500mg bd plus Doxycycline 100mg bd and Hydroxychloroquine 200mg tds) followed by a further 20 weeks continued therapy with Doxycycline 100mg bd and Hydroxychloroquine 200mg tds
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciprofloxacin
    Investigational medicinal product code
    Other name
    Ciloxan, Cipro, Neofloxin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg twice daily for 4 weeks. Tablets that can be swallowed with water and food

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Doryx, Doxyhexal, Doxylin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily for 4 weeks

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg three time daily for 4 weeks

    Arm title
    		 Control arm
    Arm description
    		 The Control group who received the standard of care regimen for study disease
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    9mg once daily for 8 weeks, then, 6mg once daily for 2 weeks, then, 3mg once daily for 2 weeks

    Number of subjects in period 1 [1]
    		Experiment arm Control arm
    Started
    28
    33
    Completed
    20
    28
    Not completed
    8
    5
         Consent withdrawn by subject
    -
    1
         Transferred to other arm/group
    7
    -
         Did not receive allocated intervention
    1
    1
         Lost to follow-up
    -
    3
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Crossover into and out of arms was done based on efficacy and not balance, there will therefore be a difference in these numbers
    Period 2
    Period 2 title
    Cross-over
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label study with crossover once randomised, so no blinding

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Experiment arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciprofloxacin
    Investigational medicinal product code
    Other name
    Ciloxan, Cipro, Neofloxin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg twice daily for 4 weeks. Tablets that can be swallowed with water and food

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Doryx, Doxyhexal, Doxylin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily for 4 weeks

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg three time daily for 4 weeks

    Arm title
    		 Control arm
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    9mg once daily for 8 weeks, then, 6mg once daily for 2 weeks, then, 3mg once daily for 2 weeks

    Number of subjects in period 2
    		Experiment arm Control arm
    Started
    39
    39
    Completed
    39
    39

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 61 61
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 61 61
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 36 36

    End points

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    End points reporting groups
    Reporting group title
    Experiment arm
    Reporting group description
    		 4 weeks Combination Antibiotic Therapy (Oral Ciprofloxacin 500mg bd plus Doxycycline 100mg bd and Hydroxychloroquine 200mg tds) followed by a further 20 weeks continued therapy with Doxycycline 100mg bd and Hydroxychloroquine 200mg tds

    Reporting group title
    Control arm
    Reporting group description
    		 The Control group who received the standard of care regimen for study disease
    Reporting group title
    Experiment arm
    Reporting group description
    		 -

    Reporting group title
    Control arm
    Reporting group description
    		 -

    Primary: Remission, defined as Crohn's disease activity index (CDAI) less than or equal to 150 at 10 weeks without addition of any other medication or treatment for their Crohn's disease

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    End point title
    		 Remission, defined as Crohn's disease activity index (CDAI) less than or equal to 150 at 10 weeks without addition of any other medication or treatment for their Crohn's disease
    End point description
    End point type
    Primary
    End point timeframe
    CDAI value of less than or equal to 150 at 10 weeks of intervention
    End point values
    		 Experiment arm Control arm Experiment arm Control arm
    Number of subjects analysed
    27
    32
    39
    39
    Units: Number of patients
    2
    8
    7
    10
    Statistical analysis title
    		 Primary Endpoint
    Comparison groups
    Experiment arm v Control arm
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.092
    Method
    		 Fisher exact
    Parameter type
    		 Proportions
    Confidence interval

    Primary: Remission, Defined as CDAI of less than or equal to 150 maintained through to 24 weeks

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    End point title
    		 Remission, Defined as CDAI of less than or equal to 150 maintained through to 24 weeks
    End point description
    End point type
    Primary
    End point timeframe
    CDAI less than or equal to 150 maintained after 24 weeks of intervention
    End point values
    		 Experiment arm Control arm Experiment arm Control arm
    Number of subjects analysed
    27
    32
    39
    39
    Units: Number of Patients
    2
    1
    6
    1
    Statistical analysis title
    		 Primary Endpoint
    Comparison groups
    Experiment arm v Control arm
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Fisher exact
    Confidence interval

    Primary: Remission, defined as CDAI of less than or equal to 150 maintained through to 52 weeks

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    End point title
    		 Remission, defined as CDAI of less than or equal to 150 maintained through to 52 weeks
    End point description
    End point type
    Primary
    End point timeframe
    Number of patients maintaining remission through to 52 weeks
    End point values
    		 Experiment arm Control arm Experiment arm Control arm
    Number of subjects analysed
    27
    32
    39
    39
    Units: Number of patients
    1
    1
    3
    1
    Statistical analysis title
    		 Primary Ednpoint
    Comparison groups
    Experiment arm v Control arm
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Remission and/or Response, defined as a fall in CDAI of more than 70 points at 10 weeks

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    End point title
    		 Remission and/or Response, defined as a fall in CDAI of more than 70 points at 10 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Response: Number of patients in whom the CDAI falls by greater than 70 points at 4 week and 10 weeks of intervention, Remission defined as less than or equal to CDAI of 150
    End point values
    		 Experiment arm Control arm Experiment arm Control arm
    Number of subjects analysed
    27
    32
    39
    39
    Units: Number of patients
    9
    11
    15
    13
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Experiment arm v Control arm
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.01
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Remission, Defined as CDAI of less than or equal to 150 at 4 weeks

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    End point title
    		 Remission, Defined as CDAI of less than or equal to 150 at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    CDAI less than or equal to 150 maintained at 4 weeks of intervention
    End point values
    		 Experiment arm Control arm Experiment arm Control arm
    Number of subjects analysed
    27
    32
    39
    39
    Units: Number of patients
    4
    8
    8
    9
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Experiment arm v Control arm
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.01
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Patient global assessment of symptom severity by visual analogue score

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    End point title
    		 Patient global assessment of symptom severity by visual analogue score
    End point description
    The summaries reported refer to VAS median and IQR at baseline. See Supplementary Figure 3 on the End of Study Report for summaries across all time points.
    End point type
    Secondary
    End point timeframe
    Value of VAS reported by patients at Baseline, 4 weeks, 10 weeks, 24 weeks, 52 weeks
    End point values
    		 Experiment arm Control arm
    Number of subjects analysed
    39
    39
    Units: Scale 1-10
        median (inter-quartile range (Q1-Q3))
    3.3 (2.1 to 4.9)
    4.1 (2.2 to 5.3)
    No statistical analyses for this end point

    Secondary: Fall in Faecal Calprotectin

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    End point title
    		 Fall in Faecal Calprotectin
    End point description
    The summaries reported refer to faecal calprotein median and IQR at baseline. See Supplementary Figure 5 on the End of Study Report for summaries across all time points.
    End point type
    Secondary
    End point timeframe
    Faecal Calprotein levels at baseline and week 10.
    End point values
    		 Experiment arm Control arm
    Number of subjects analysed
    39
    39
    Units: ug/g
        median (inter-quartile range (Q1-Q3))
    497 (265 to 726)
    574 (307 to 924)
    No statistical analyses for this end point

    Secondary: Adverse Events and possible drug-related side effects - Nausea

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    End point title
    		 Adverse Events and possible drug-related side effects - Nausea
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse Events and possible drug-related side effects were assessed at each visit.
    End point values
    		 Experiment arm Control arm
    Number of subjects analysed
    39
    39
    Units: Number of events
    24
    6
    No statistical analyses for this end point

    Secondary: Adverse Events and possible drug-related side effects - Diarrhoea

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    End point title
    		 Adverse Events and possible drug-related side effects - Diarrhoea
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse Events and possible drug-related side effects were assessed at each visit.
    End point values
    		 Experiment arm Control arm
    Number of subjects analysed
    39
    39
    Units: Number of patients
    9
    7
    No statistical analyses for this end point

    Secondary: Adverse Events and possible drug-related side effects - Mood disturbance

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    End point title
    		 Adverse Events and possible drug-related side effects - Mood disturbance
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse Events and possible drug-related side effects were assessed at each visit.
    End point values
    		 Experiment arm Control arm
    Number of subjects analysed
    39
    39
    Units: Number of events
    3
    5
    No statistical analyses for this end point

    Secondary: Adverse Events and possible drug-related side effects - Sleep disturbance

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    End point title
    		 Adverse Events and possible drug-related side effects - Sleep disturbance
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse Events and possible drug-related side effects were assessed at each visit.
    End point values
    		 Experiment arm Control arm
    Number of subjects analysed
    39
    39
    Units: Number of events
    8
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time the patient commenced the study drug, until end of study (week 52 or early withdrawal)
    Adverse event reporting additional description
    AEs were identified during patients clinic visits with specific questioning as appropriate
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Experiment arm
    Reporting group description
    		 4 weeks Combination Antibiotic Therapy (Oral Ciprofloxacin 500mg bd plus Doxycycline 100mg bd and Hydroxychloroquine 200mg tds) followed by a further 20 weeks continued therapy with Doxycycline 100mg bd and Hydroxychloroquine 200mg tds

    Reporting group title
    Control
    Reporting group description
    		 The Control group who received the standard of care regimen for study disease

    Serious adverse events
    		 Experiment arm Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 39 (12.82%)
    1 / 39 (2.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Intestinal obstruction
    Additional description: Small bowel obstruction for conservative management (CRP262). Follow up with surgical operation
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
    Additional description: Worsening of patient's underlying Crohn's disease to warrant discontinuation of the study intervention.
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abcess
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
    Additional description: Rhabdomyolsis secondary to fall Sepsis? source
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (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: 0%
    Non-serious adverse events
    		 Experiment arm Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    30 / 39 (76.92%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Poor peripheral circulation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 39 (5.13%)
         occurrences all number
    2
    2
    Pyrexia
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Swelling
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Respiratory symptom
         subjects affected / exposed
    3 / 39 (7.69%)
    6 / 39 (15.38%)
         occurrences all number
    3
    8
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Depression
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Mood altered
         subjects affected / exposed
    4 / 39 (10.26%)
    6 / 39 (15.38%)
         occurrences all number
    4
    7
    Sleep disorder
         subjects affected / exposed
    8 / 39 (20.51%)
    9 / 39 (23.08%)
         occurrences all number
    8
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Incisional hernia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiovascular symptom
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    5 / 39 (12.82%)
    5 / 39 (12.82%)
         occurrences all number
    5
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Taste disorder
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Asthenopia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    4 / 39 (10.26%)
    2 / 39 (5.13%)
         occurrences all number
    6
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Anal fissure
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Anal incontinence
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Anal ulcer
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Defaecation urgency
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    9 / 39 (23.08%)
    6 / 39 (15.38%)
         occurrences all number
    9
    7
    Dry mouth
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 39 (12.82%)
    2 / 39 (5.13%)
         occurrences all number
    5
    2
    Glossodynia
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Haematemesis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 39 (2.56%)
    5 / 39 (12.82%)
         occurrences all number
    1
    6
    Nausea
         subjects affected / exposed
    19 / 39 (48.72%)
    7 / 39 (17.95%)
         occurrences all number
    24
    7
    Proctalgia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Rectal tenesmus
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Alopecia
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Blister
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Erythema
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Hair disorder
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    7 / 39 (17.95%)
    1 / 39 (2.56%)
         occurrences all number
    7
    1
    Pruritus
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
         occurrences all number
    3
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Dysuria
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 39 (12.82%)
    1 / 39 (2.56%)
         occurrences all number
    5
    1
    Back pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Rhabdomyolysis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Tendon pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Anal candidiasis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
         occurrences all number
    3
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 39 (0.00%)
         occurrences all number
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Dec 2008
    An Amended Protocol/Substantial amendment was required by MHRA so that clinical trial authorisation could be obtained on trial. Amended protocol should be submitted to address the following: - As patients might be elderly and/or have been on corticosteroid therapy, exclusion criteria should include a history of tendon disorders related to fluroquinolone administration in accordance with the SmPC
    02 Apr 2009
    An Amended Protocol/Substantial amendment is required to make some essential changes to clarify trial procedures, making changes where necessary to ensure trial is not bias, trial data is credible, patients safety maintained by adding Data Monitoring committee and finally to correct a number of administration errors. Amended protocol should be submitted to address the following: - Addition of Data Monitoring Committee - Addition of Study Team - Change in Secondary End-point Endoscopy changed from 12 weeks to 10 weeks - Change from Single Blind to open label trial
    31 Mar 2010
    NO PATIENTS WERE RECRUITED WITH THE GIVEN PROTOCOL, MAINLY DUE TO THE NEED TO STOP AZATHIOPRINE TO ALLOW TRIMETHOPRIM TREATMENT, THERE WAS ALSO RELUCTANCE TO TAKE METRONIDAZOLE FOR 3 MONTHS. FOLLOWING ADVICE FROM AN INDEPENDENT DATA MONITORING COMMITTEE AND THE TRUST GOVERNANCE ADVISOR (PROFESSOR TOM WALLEY) WE DECIDED TO CHANGE THE ANTIBIOTIC COMBINATION TO CIPROFLOXACIN AND DOXYCYCLINE A COMBINATION THAT HAS BEEN USED LONG TERM FOR OTHER INDICATIONS AND THAT IS EQUALLY SUPPORTED (COMPARED WITH CIPROFLOXACIN, TRIMETHOPRIM, METRONIDAZOLE) BY IN VITRO DATA OF EFFICACY AGAINST E. COLI IN MACROPHAGES (THAT TARGET ORGANSIMS IN THIS TRIAL). 1. CHANGE IN ANTIBIOTIC FROM CIPROFLOXACIN, METRONIDAZOLE AND TRIMETHOPRIM TO CIPROFLOXACIN AND DOXYCYCLINE 2. FOR ALL PATIENTS ENTERING THE STUDY, 1 ADDITIONAL BLOOD SAMPLE WILL BE TAKEN, THE SERUM WILL BE STORED AND USED FOR E-COLI ANTIBODY TESTING IN THE UNITED STATES OF AMERICA. INFORMATION HAS BEEN ADDED IN PROTOCOL, PATIENT INFORMATION SHEET AND CONSENT FORM 3. ADDITION OF STUDY TEAM MEMBERS
    06 Dec 2011
    Addition of hydroxychloroquine. Update of the primary endpoint - To compare the efficacy of a combination of antibiotics (ciproflaxin and doxycicline together with hydroxychloroquine) with standard therapy (oral budesonide) in the treatment of active crohn's disease. Update to primary outcome measures. Change of medication schedule, with an additional 20 weeks of continued therapy of Doxyclcine and Hydroxychloroquine. Option of patients who are randomised to Budenoside to cross over after lack of favourable response. added exclusion criteria related to hydroxychloroquine tolerance.
    04 Jan 2013
    Update of protocol to exclude patients who are receiving methotrexate due to concerns over the safety in interactions with this drug and Ciprofloxacin and Doxycycline.
    01 Aug 2013
    Added extra biopsies to the protocol for faecal calprotectin. Adoption of study by LCTU and so update to the Pharmacovigilance section in line with their systems/SOPs. Change to consent form to confirm patients are happy with copy being sent to the RLBUHT (new co-sponsor)
    04 Apr 2014
    change of CI - Professor Chris Probert took over from Prof. Probert Update of inclusion criteria related to acceptable levels of C reactive protein in patients entering the study. Changes to the sites running the study.
    03 Aug 2016
    Addition of new sites to the study. Change of appendix to specify tricylcic antidepressants that are not permitted (previous just stated "trycyclic antidepressants"). addition of windows before or after schedule assessment to allow for scheduling issues at sites. update on definition of source documentation in the light of recent changes in local practices to reduce physical/paper records.

    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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    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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