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    Clinical Trial Results:
    “Phase II clinical trial of doxycycline 50 mg or 100 mg daily for the prevention of skin toxicity in patients with metastatic colorectal cancer treated with Anti-EGFR and chemotherapy"

    Summary
    EudraCT number
    		 2017-004413-98
    Trial protocol
    		 ES  
    Global end of trial date
    06 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2021
    First version publication date
    14 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DERMIA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03448731
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    APICES SOLUCIONES S.L
    Sponsor organisation address
    Avenida Antonio López 16, 1ªA, Pinto, Madrid , Spain, 28320
    Public contact
    Clinical Operations Department, APICES, +34 918166804100, ana.moreno@apices.es
    Scientific contact
    Clinical Operations Department, APICES, +34 918166804100, ana.moreno@apices.es
    Sponsor organisation name
    Fundación CRIS de Investigación para Vencer el Cáncer
    Sponsor organisation address
    Avenida Manoteras, 22, 3º piso, Oficina 109, Madrid , Spain, 28050
    Public contact
    Marta Cardona, Fundación CRIS de Investigación para Vencer el Cáncer, +34 91 116 1312, mcardona@criscancer.org
    Scientific contact
    Marta Cardona, Fundación CRIS de Investigación para Vencer el Cáncer, +34 91 116 1312, mcardona@criscancer.org
    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 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to describe the efficacy of doxycycline 50 or 100 mg daily in the prevention of skin toxicity in patients with metastatic CRC (mCRC) treated with FOLFOX or FOLFIRI + anti-EGFR.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2018
    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
    Spain: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    19
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited in the study from 9th May 2018 until 22th january 2020

    Pre-assignment
    Screening details
    		 The patients underwent wild-type RAS tumor status analysys before signing the study informed consent form in order to check its eligibility. Patients undergoing FOLFOX or FOLFIRI + anti-EGFR treatment as first-line treatment of mCRC were eligible to receive study treatment.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Study treatment
    Arm description
    		 Patients received doxycycline 50 mg (or 100 mg, if applicable, in the second cohort) daily for 6 weeks beginning on Day -1 (one day before the administration of the first anti-EGFR dose). In a first stage, 10 patients entered the study at a dose of doxycycline 50 mg/day and an interim analysis were performed once 10 patients have finished the 6 weeks of treatment. If more than three patients presented ≥ grade 2 skin toxicities the dose of doxycycline will be increased to 100 mg/day for the next 30 patients to be recruited.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 or 100 mg (if applicable) daily for 6 weeks

    Number of subjects in period 1
    		Study treatment
    Started
    34
    Completed
    32
    Not completed
    2
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 34 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 15 15
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 60.8 (39 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 21 21
    ECOG-PS
    Units: Subjects
        ECOG-PS 0
    		 28 28
        ECPG-PS 1
    		 5 5
        ECPG-PS 2
    		 1 1
    Initial Diagnosis Per Patient according to location
    Units: Subjects
        Left colon
    		 13 13
        Rectum
    		 12 12
        Transverse colon
    		 6 6
        Right colon
    		 2 2
        Left colon + Rectum
    		 1 1
    Previous Treatments for Cancer: Surgery
    Units: Subjects
        Yes
    		 15 15
        No
    		 19 19
    Previous Treatments for Cancer: Radiotherapy
    Units: Subjects
        Yes
    		 4 4
        No
    		 30 30
    Previous Treatments for Cancer: Chemotherapy
    Units: Subjects
        XELOX
    		 8 8
        FOLFOX
    		 3 3
        Capecitabine
    		 3 3
        NO
    		 20 20
    Antineoplastic Treatment Administered
    Of the 34 patients with information on the antineoplastic treatment administered, 94.1% (32) indicated as anti-EGFR panitumumab.
    Units: Subjects
        FOLFOX + Panitumumab
    		 27 27
        FOLFIRI + Panitumumab
    		 5 5
        FOLFIRI + Cetuximab
    		 2 2
    Number of Patients Treated with Doxycycline According to Weeks of Treatment
    Units: Subjects
        Six (6)
    		 32 32
        Four (4)
    		 1 1
        Three (3)
    		 1 1
    Metastatic Diagnosis According to Location: Liver
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    		 27 27
        No
    		 7 7
    Metastatic Diagnosis According to Location: Distant Lymph Nodes
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    		 5 5
        No
    		 29 29
    Metastatic Diagnosis According to Location: Peritoneum
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    		 4 4
        No
    		 30 30
    Metastatic Diagnosis According to Location: Lung
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    		 7 7
        No
    		 27 27
    Weight
    Weight not available in two patients of Doxycycline 100 mg subject analysis set.
    Units: Kg
        median (full range (min-max))
    		 62.5 (51.0 to 120.0) -
    Height
    Height not available in 3 patients of Doxycycline 100 mg subject analysis set.
    Units: Cm
        median (full range (min-max))
    		 169.0 (155.0 to 181.0) -
    Respiratory Frequency
    Respiratory Frequency not available in two patients of Doxycycline 50 mg subject analysys set and four patients of Doxycycline 100 mg subject analysis set.
    Units: Breaths per minute
        median (full range (min-max))
    		 18.5 (12.0 to 28.0) -
    Temperature
    Temperature Not available in three patients of Doxycycline 100 mg subject analysis set.
    Units: °C
        median (full range (min-max))
    		 36.5 (35.5 to 37.0) -
    Systolic Blood Pressure
    Systolic Blood Pressure Not available in two patients of Doxycycline 100 mg subject analysis set.
    Units: mm Hg
        median (full range (min-max))
    		 130.5 (107.0 to 182.0) -
    Diastolic Blood Pressure
    Diastolic Blood Pressure Not available in two patients of doxycycline 100 mg subject analysis set.
    Units: mm Hg
        median (full range (min-max))
    		 74.0 (57.0 to 94.0) -
    Heart Rate
    Heart rate not available in three patients of Doxycycline 100 mg subject analysis set.
    Units: Bpm
        median (full range (min-max))
    		 74.0 (60.0 to 122.0) -
    Time Since Initial Diagnosis
    Units: Months
        median (full range (min-max))
    		 2.0 (0.4 to 53.9) -
    Time Since Metastic Diagnosis
    Time between the date of metastatic diagnosis and the date of informed consent.
    Units: Months
        median (full range (min-max))
    		 1.5 (0.3 to 39.8) -
    Subject analysis sets

    Subject analysis set title
    Doxycycline 50 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The 10 patients belonging to this subject analysys set received 50 mg of doxycycline.

    Subject analysis set title
    Doxycycline 100 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The 24 patients belonging to this subject analysys set received 100 mg of doxycycline.

    Subject analysis sets values
    		 Doxycycline 50 mg Doxycycline 100 mg
    Number of subjects
    10
    24
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    6
    13
        From 65-84 years
    4
    11
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    57.7 (39.0 to 74.0)
    62.0 (43.0 to 79.0)
    Gender categorical
    Units: Subjects
        Female
    4
    9
        Male
    6
    15
    ECOG-PS
    Units: Subjects
        ECOG-PS 0
    7
    21
        ECPG-PS 1
    3
    2
        ECPG-PS 2
    0
    1
    Initial Diagnosis Per Patient according to location
    Units: Subjects
        Left colon
    3
    10
        Rectum
    5
    7
        Transverse colon
    1
    5
        Right colon
    1
    1
        Left colon + Rectum
    0
    1
    Previous Treatments for Cancer: Surgery
    Units: Subjects
        Yes
    5
    10
        No
    5
    14
    Previous Treatments for Cancer: Radiotherapy
    Units: Subjects
        Yes
    1
    3
        No
    9
    21
    Previous Treatments for Cancer: Chemotherapy
    Units: Subjects
        XELOX
    2
    6
        FOLFOX
    1
    2
        Capecitabine
    0
    3
        NO
    7
    13
    Antineoplastic Treatment Administered
    Of the 34 patients with information on the antineoplastic treatment administered, 94.1% (32) indicated as anti-EGFR panitumumab.
    Units: Subjects
        FOLFOX + Panitumumab
    7
    20
        FOLFIRI + Panitumumab
    3
    2
        FOLFIRI + Cetuximab
    0
    2
    Number of Patients Treated with Doxycycline According to Weeks of Treatment
    Units: Subjects
        Six (6)
    10
    22
        Four (4)
    0
    1
        Three (3)
    0
    1
    Metastatic Diagnosis According to Location: Liver
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    7
    27
        No
    3
    0
    Metastatic Diagnosis According to Location: Distant Lymph Nodes
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    1
    5
        No
    9
    19
    Metastatic Diagnosis According to Location: Peritoneum
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    0
    4
        No
    10
    28
    Metastatic Diagnosis According to Location: Lung
    Percentages calculated on total patients (N=34). Patients may have more than one metastatic site.
    Units: Subjects
        Yes
    2
    7
        No
    8
    17
    Weight
    Weight not available in two patients of Doxycycline 100 mg subject analysis set.
    Units: Kg
        median (full range (min-max))
    78.0 (63.0 to 105.0)
    78.5 (51.0 to 120)
    Height
    Height not available in 3 patients of Doxycycline 100 mg subject analysis set.
    Units: Cm
        median (full range (min-max))
    169.0 (160.0 to 181.0)
    165.0 (155.0 to 180.0)
    Respiratory Frequency
    Respiratory Frequency not available in two patients of Doxycycline 50 mg subject analysys set and four patients of Doxycycline 100 mg subject analysis set.
    Units: Breaths per minute
        median (full range (min-max))
    16.0 (12.0 to 26.0)
    18.5 (12.0 to 28.0)
    Temperature
    Temperature Not available in three patients of Doxycycline 100 mg subject analysis set.
    Units: °C
        median (full range (min-max))
    36.2 (35.5 to 37.0)
    36.5 (36.1 to 37.0)
    Systolic Blood Pressure
    Systolic Blood Pressure Not available in two patients of Doxycycline 100 mg subject analysis set.
    Units: mm Hg
        median (full range (min-max))
    124.5 (114.0 to 140.0)
    138.0 (107.0 to 182.0)
    Diastolic Blood Pressure
    Diastolic Blood Pressure Not available in two patients of doxycycline 100 mg subject analysis set.
    Units: mm Hg
        median (full range (min-max))
    72.0 (65.0 to 81.0)
    75.0 (57.0 to 94.0)
    Heart Rate
    Heart rate not available in three patients of Doxycycline 100 mg subject analysis set.
    Units: Bpm
        median (full range (min-max))
    70.0 (60.0 to 80.0)
    75.0 (62.0 to 122.0)
    Time Since Initial Diagnosis
    Units: Months
        median (full range (min-max))
    1.5 (0.4 to 46.0)
    2.2 (0.7 to 53.9)
    Time Since Metastic Diagnosis
    Time between the date of metastatic diagnosis and the date of informed consent.
    Units: Months
        median (full range (min-max))
    0.6 (0.3 to 1.9)
    1.9 (0.7 to 39.8)

    End points

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    End points reporting groups
    Reporting group title
    Study treatment
    Reporting group description
    		 Patients received doxycycline 50 mg (or 100 mg, if applicable, in the second cohort) daily for 6 weeks beginning on Day -1 (one day before the administration of the first anti-EGFR dose). In a first stage, 10 patients entered the study at a dose of doxycycline 50 mg/day and an interim analysis were performed once 10 patients have finished the 6 weeks of treatment. If more than three patients presented ≥ grade 2 skin toxicities the dose of doxycycline will be increased to 100 mg/day for the next 30 patients to be recruited.

    Subject analysis set title
    Doxycycline 50 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The 10 patients belonging to this subject analysys set received 50 mg of doxycycline.

    Subject analysis set title
    Doxycycline 100 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The 24 patients belonging to this subject analysys set received 100 mg of doxycycline.

    Primary: Percentage of patients who develop skin toxicity ( ≥ grade 2) during dermatological treatment

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    End point title
    		 Percentage of patients who develop skin toxicity ( ≥ grade 2) during dermatological treatment [1]
    End point description
    Efficacy of doxycycine to prevent skin toxicity in patients with metastatic colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI + anti-EGFR.
    End point type
    Primary
    End point timeframe
    After 6 weeks treatment doxycycline
    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: One arm non-controlled clinical trial. Only descriptive analyses performed. No comparisons.
    End point values
    		 Study treatment Doxycycline 50 mg Doxycycline 100 mg
    Number of subjects analysed
    34
    10
    24
    Units: Patients
        Grade 2
    9
    5
    4
        Grade 3
    2
    1
    1
        Grade ≥ 2
    11
    6
    5
    No statistical analyses for this end point

    Secondary: Median time to first occurrence of specific skin toxicity (≥ grade 2) during the skin treatment period

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    End point title
    		 Median time to first occurrence of specific skin toxicity (≥ grade 2) during the skin treatment period
    End point description
    Time to first onset of toxicity has been calculated as the number of days from the start of treatment with doxycycline to the onset of the first grade ≥ 2 skin toxicity during the 6-week treatment period.
    End point type
    Secondary
    End point timeframe
    After 6 weeks of treatment with doxycycline
    End point values
    		 Study treatment Doxycycline 50 mg Doxycycline 100 mg
    Number of subjects analysed
    8 [2]
    10
    24
    Units: Days
        median (full range (min-max))
    28.0 (14.0 to 34.0)
    21.5 (15.0 to 29.0)
    28.0 (14.0 to 34.0)
    Notes
    [2] - 8 patients experienced ≥ grade 2 skin toxicities
    No statistical analyses for this end point

    Secondary: Mean change from baseline in DLQI score at week 7

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    End point title
    		 Mean change from baseline in DLQI score at week 7
    End point description
    Evaluate the quality of life (QoL) of patients treated with doxycycline, 50 or 100 mg per day. QoL was evaluated using the dermatology life quality index (DLQI) at screening and at week 7. The following were considered: - Score 0-1: the skin problem has no effect on the patient's life. - Score 2-5: the skin problem has a slight effect on the patient's life. - Score 6-10: the skin problem has a moderate effect on the patient's life. - Score 11-20: the skin problem has a significant effect on the patient's life.  Score 21-30: the skin problem has an extremely important effect on the patient's life.
    End point type
    Secondary
    End point timeframe
    From baseline to week 7
    End point values
    		 Study treatment Doxycycline 50 mg Doxycycline 100 mg
    Number of subjects analysed
    30
    10
    20 [3]
    Units: Score
        median (full range (min-max))
    2.0 (0.0 to 10.0)
    2.0 (0.0 to 10.0)
    1.5 (0.0 to 5.0)
    Notes
    [3] - 4 patients of doxycycline 100 mg cohort did not have the DLQI questionnaire of week 7.
    No statistical analyses for this end point

    Secondary: Number of patients with grade 1-4 NCI-CTCAE adverse events related to doxycycline.

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    End point title
    		 Number of patients with grade 1-4 NCI-CTCAE adverse events related to doxycycline.
    End point description
    Safety and tolerability of doxycycline was based on all patients that received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline until week 7
    End point values
    		 Study treatment Doxycycline 50 mg Doxycycline 100 mg
    Number of subjects analysed
    34
    10
    34
    Units: Patients
        Epigastralgia Grade 1
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of patients who received topical, oral or IV antibiotics to treat skin or nail adverse reactions.

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    End point title
    		 Number of patients who received topical, oral or IV antibiotics to treat skin or nail adverse reactions.
    End point description
    Type of medication for skin or nail indications. Percentages for total number of patients in each group, doxycycline 50 mg/day (N=10), doxycycline 100 mg/day (N=24) and total analysed (N=34). Patients may have received more than one drug to treat skin or nail adverse reactions.
    End point type
    Secondary
    End point timeframe
    From baseline until week 7.
    End point values
    		 Study treatment Doxycycline 50 mg Doxycycline 100 mg
    Number of subjects analysed
    34
    10
    24
    Units: Skin adverse reaction
        Corticosteroid (Prednicarbate)
    5
    3
    2
        Corticosteroid (Hydrocortisone)
    2
    2
    0
        Corticosteroid (Clobetasol)
    1
    1
    0
        Corticosteroid (Betamethasone)
    1
    1
    0
        Antibacterial (Erythromycin)
    3
    1
    2
        Antibacterial (Mupirocin)
    1
    0
    1
        Antibacterial (Doxycycline)
    1
    0
    1
        Antibacterial (Clindamycin)
    1
    1
    0
        Antibacterial (Fusidic acid)
    1
    1
    0
        Antifungal (Nystatin)
    1
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline until end of treatment.
    Adverse event reporting additional description
    The analysis of adverse events was performed for total number of patients who received at least one dose of doxycycline treatment. Adverse events were coded using the latest available version of MedDRA dictionary and presented by system organ class (SOC) and preferred term (PT). To obtain adverse events by PT and patient, the maximum grades of each
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Doxycycline 50 mg
    Reporting group description
    		 -

    Reporting group title
    Doxycycline 100 mg
    Reporting group description
    		 -

    Reporting group title
    Doxycycline treatment
    Reporting group description
    		 -

    Serious adverse events
    		 Doxycycline 50 mg Doxycycline 100 mg Doxycycline treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 24 (4.17%)
    3 / 34 (8.82%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Overdose
    Additional description: Overdose grade 1
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic thrombosis
    Additional description: Aortic thrombosis grade 4
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Diarrhoea grade 3
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Doxycycline 50 mg Doxycycline 100 mg Doxycycline treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    24 / 24 (100.00%)
    34 / 34 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
    Additional description: Lipoma grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Vascular disorders
    Hypotension
    Additional description: Hypotension grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Epistaxis
    Additional description: Epistaxis grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Xerosis
    Additional description: 2 Xerosis grade 1
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 24 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    Mucosal inflammation
    Additional description: Doxycycline 50 mg: 4 mucosal inflammation grade 1, 2 grade 2 and 1 grade 3. Doxycycline 100 mg: 5 mucosal inflammation grade 1 and 5 grade 2.
         subjects affected / exposed
    7 / 10 (70.00%)
    11 / 24 (45.83%)
    18 / 34 (52.94%)
         occurrences all number
    7
    11
    18
    Asthenia
    Additional description: Doxycycline 50 mg: 3 Asthenia grade 1, 2 grade 2 and 1 grade 3. Doxycycline 100 mg: 13 Asthenia grade 1 and 2 grade 2.
         subjects affected / exposed
    6 / 10 (60.00%)
    15 / 24 (62.50%)
    21 / 34 (61.76%)
         occurrences all number
    6
    15
    21
    Chest pain
    Additional description: Chest pain grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
    Additional description: Oropharyngeal pain grade 1
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Bronchospasm
    Additional description: Bronchospasm grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Investigations
    Reduced platelet count
    Additional description: Reduced platelet count grade 2.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Elevated blood creatinine
    Additional description: Elevated blood creatinine grade 2.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Weight loss
    Additional description: Weight loss grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Accidental exposure to product
    Additional description: Accidental exposure to product grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Nervous system disorders
    Neurotoxicity
    Additional description: Doxycycline 50 mg: 2 neurotoxicity grade 1. Doxycycline 100 mg: 8 neurotoxicity grade 1 and 1 grade 1.
         subjects affected / exposed
    2 / 10 (20.00%)
    8 / 24 (33.33%)
    10 / 34 (29.41%)
         occurrences all number
    2
    8
    10
    Peripheral neuropathy
    Additional description: Doxycycline 50 mg: Peripheral neuropathy grade 1. Doxycycline 100 mg: Peripheral neuropathy grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 24 (4.17%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    2
    Dysgeusia
    Additional description: 1 dysgeusia grade 1 and 1 grade 3.
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 24 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    Dysaesthesia
    Additional description: 3 Dysaesthesia grade 1.
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 24 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    3
    0
    3
    Syncope
    Additional description: Syncope grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
    Additional description: Thrombocytopenia grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Neutropenia
    Additional description: 4 neutropenia grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 24 (16.67%)
    4 / 34 (11.76%)
         occurrences all number
    0
    4
    4
    Anaemia
    Additional description: 2 anaemia grade 1 and 1 grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 24 (12.50%)
    3 / 34 (8.82%)
         occurrences all number
    0
    3
    3
    Eye disorders
    Increased fluid production
    Additional description: Increased fluid production grade 1
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Eyelid oedema
    Additional description: Eyelid oedema grade 1
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Vomiting
    Additional description: Doxycycline 50 mg: 2 Vomiting grade 1, 1 grade 2 and 1 grade 3. Doxycycline 100 mg: Vomiting grade 1
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 24 (4.17%)
    5 / 34 (14.71%)
         occurrences all number
    4
    1
    1
    Aphthous ulcer
    Additional description: Doxycycline 50 mg: Aphthous ulcer grade 1 Doxycycline 100 mg: 1 Aphthous ulcer grade 1 and 1 grade 2.
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 24 (8.33%)
    3 / 34 (8.82%)
         occurrences all number
    1
    2
    3
    Nausea
    Additional description: Doxycycline 50 mg: 2 Nausea grade 1 and 2 grade 2. Doxycycline 100 mg: 8 Nausea grade 1.
         subjects affected / exposed
    4 / 10 (40.00%)
    8 / 24 (33.33%)
    12 / 34 (35.29%)
         occurrences all number
    4
    8
    12
    Constipation
    Additional description: Doxycycline 50 mg: 3 constipation grade 1. Doxycycline 100 mg: 6 constipation grade 1.
         subjects affected / exposed
    3 / 10 (30.00%)
    6 / 24 (25.00%)
    9 / 34 (26.47%)
         occurrences all number
    3
    6
    9
    Dyspepsia
    Additional description: Doxycycline 50 mg: dyspepsia grade 1 Doxycycline 100 mg: dyspepsia grade 1
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 24 (4.17%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    2
    Diarrhoea
    Additional description: Doxycycline 50 mg: 4 Diarrhoea grade 1 and 1 grade 2. Doxycycline 100 mg: 8 Diarrhoea grade 1 and 2 grade 2.
         subjects affected / exposed
    6 / 10 (60.00%)
    10 / 24 (41.67%)
    16 / 34 (47.06%)
         occurrences all number
    6
    10
    16
    Rectal tenesmus
    Additional description: Rectal tenesmus grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Stomatitis
    Additional description: Stomatitis grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Abdominal pain
    Additional description: 4 Abdominal pain grade 1 and 1 grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 24 (20.83%)
    5 / 34 (14.71%)
         occurrences all number
    0
    5
    5
    Bloating
    Additional description: Bloating grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Frequent defecation
    Additional description: Frequent defecation grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Dry skin
    Additional description: Doxycycline 50 mg: 1 Dry skin grade 2. Doxycycline 100 mg: 2 Dry skin grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 24 (8.33%)
    3 / 34 (8.82%)
         occurrences all number
    1
    2
    3
    Skin fissures
    Additional description: Doxycycline 100 mg: 2 Skin fissures grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 24 (8.33%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    Rash
    Additional description: Doxycycline 50 mg: 2 Rash grade 2. Doxycycline 100 mg: 3 Rash grade 1 and 3 grade 2.
         subjects affected / exposed
    2 / 10 (20.00%)
    6 / 24 (25.00%)
    8 / 34 (23.53%)
         occurrences all number
    2
    6
    8
    Acneiform dermatitis
    Additional description: 2 Acneiform dermatitis grade 2 and 1 grade 3.
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 24 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    3
    0
    3
    Skin toxicity
    Additional description: 2 Skin toxicity grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 24 (8.33%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    Vulvovaginal pruritus
    Additional description: Vulvovaginal pruritus grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
    Additional description: 2 Pruritus grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 24 (8.33%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    Skin exfoliation
    Additional description: Skin exfoliation grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Erythema
    Additional description: Erythema grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Eczema
    Additional description: Eczema grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Perioral dermatitis
    Additional description: Perioral dermatitis grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Scab
    Additional description: Scab grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Acne
    Additional description: 2 Acne grade 1 and 1 grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 24 (12.50%)
    3 / 34 (8.82%)
         occurrences all number
    0
    3
    3
    Paronychia
    Additional description: Paronychia grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Folliculitis
    Additional description: 4 Folliculitis grade 1, 1 grade 2 and 1 grade 3.
         subjects affected / exposed
    0 / 10 (0.00%)
    6 / 24 (25.00%)
    6 / 34 (17.65%)
         occurrences all number
    0
    6
    6
    Cellulitis
    Additional description: Cellulitis grade 3.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Back pain
    Additional description: Back pain grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Rhinitis
    Additional description: Rhinitis grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Oral candidiasis
    Additional description: Oral candidiasis grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Conjunctivitis
    Additional description: 2 Conjunctivitis grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 24 (8.33%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    Metabolism and nutrition disorders
    Hyposideraemia
    Additional description: Hyposideraemia grade 1.
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 24 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Decreased appetite
    Additional description: Doxycycline 50 mg: 1 Decreased appetite grade 1 and 1 grade 2. Doxycycline 100 mg: 5 Decreased appetite grade 1.
         subjects affected / exposed
    2 / 10 (20.00%)
    5 / 24 (20.83%)
    7 / 34 (20.59%)
         occurrences all number
    2
    5
    7
    Hypomagnesaemia
    Additional description: Hypomagnesaemia grade 1.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Hypokalaemia
    Additional description: Hypokalaemia grade 2.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 24 (4.17%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1

    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.
    Estimated sample size was not reached, which may affect the accuracy of the study results. Not controlled study design.
    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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