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    Clinical Trial Results:
    A phase I/II study to evaluate safety, tolerability, pharmacokinetics and efficacy of resminostat (4SC-201) in combination with a second-line treatment in patients with k-ras mutated advanced colorectal carcinoma

    Summary
    EudraCT number
    2010-020171-23
    Trial protocol
    DE  
    Global end of trial date
    28 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    13 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    4SC-201-3-2010
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01277406
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    4SC AG
    Sponsor organisation address
    Am Klopferspitz 19a, Planegg-Martinsried, Germany, 82152
    Public contact
    Corporate Communications, 4SC AG, +49 89 7007630, public@4sc.com
    Scientific contact
    Dr. Susanne Danhauser-Riedl, 4SC AG, Clinical Development, +49 89 7007630, susanne.danhauser-riedl@4sc.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase I: To determine the MTD of resminostat in combination with FOLFIRI by investigating safety, tolerability and pharmacokinetics of resminostat and FOLFIRI Phase II: Progression-free survival (PFS) - phase II of this study was not conducted!
    Protection of trial subjects
    The first patient in each cohort had to have completed the first treatment cycle of resminostat and FOLFIRI (14 days) before inclusion of further patients in the same cohort. Dose escalation decisions were made when safety and tolerability data from the first cycle were collected for all patients of a given cohort. A Data Safety Monitoring Board was involved in dose escalation decisions. In addition, patients did not receive placebo medication and all patients received full supportive care including antiemetics, antibiotics, and analgetics, as clinically indicated.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Dec 2010
    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
    Germany: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    11
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study participants were enrolled between 07 January 2011 and 11 January 2013 at 2 of 3 centers in Germany.

    Pre-assignment
    Screening details
    22 patients had been screened during a 7-day screening period prior to start of study drug. 5 patients were screening failures due to homozygous state of UGT1A1 (2 times), withdrawal of consent, worsening of general condition, and deterioration of bone marrow deficiency.

    Period 1
    Period 1 title
    Phase I (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    200 mg once daily
    Arm description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 200 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.
    Arm type
    Experimental

    Investigational medicinal product name
    Resminostat
    Investigational medicinal product code
    4SC-201
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At each treatment cycle, 200 mg resminostat were administered orally once daily in the morning on 5 consecutive days, followed by a 9-day rest period. Intake of resminostat tablets was at least 1 hour after a light breakfast. Tablets were not to be chewed or crushed and were swallowed with 200 mL of non-carbonated water at room temperature.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    5-FU
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use, Intravenous bolus use
    Dosage and administration details
    At each treatment cycle, 5-Fluorouracil was given as intravenous bolus injection (400 mg/m2) on Day 3, followed by an intravenous continuous infusion lasting until Day 4 (2,400 mg/m2 over 46 hours).

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Leucovorin, Calciumfolinat-GRY
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 400 mg/m2 folinic acid were given as 2-hour infusion during irinotecan infusion on Day 3.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    CPT-11
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 180 mg/m2 irinotecan were given as intravenous infusion over 90 minutes on Day 3.

    Arm title
    400 mg once daily
    Arm description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 400 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.
    Arm type
    Experimental

    Investigational medicinal product name
    Resminostat
    Investigational medicinal product code
    4SC-201
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At each treatment cycle, 400 mg resminostat were administered orally once daily in the morning on 5 consecutive days, followed by a 9-day rest period. Intake of resminostat tablets was at least 1 hour after a light breakfast. Tablets were not to be chewed or crushed and were swallowed with 200 mL of non-carbonated water at room temperature.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    5-FU
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    At each treatment cycle, 5-Fluorouracil was given as intravenous bolus injection (400 mg/m2) on Day 3, followed by an intravenous continuous infusion lasting until Day 4 (2,400 mg/m2 over 46 hours).

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Leucovorin, Calciumfolinat-GRY
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 400 mg/m2 folinic acid were given as 2-hour infusion during irinotecan infusion on Day 3.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    CPT-11
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 180 mg/m2 irinotecan were given as intravenous infusion over 90 minutes on Day 3.

    Arm title
    600 mg once daily
    Arm description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 600 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.
    Arm type
    Experimental

    Investigational medicinal product name
    Resminostat
    Investigational medicinal product code
    4SC-201
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At each treatment cycle, 600 mg resminostat were administered orally once daily in the morning on 5 consecutive days, followed by a 9-day rest period. Intake of resminostat tablets was at least 1 hour after a light breakfast. Tablets were not to be chewed or crushed and were swallowed with 200 mL of non-carbonated water at room temperature.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    5-FU
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    At each treatment cycle, 5-Fluorouracil was given as intravenous bolus injection (400 mg/m2) on Day 3, followed by an intravenous continuous infusion lasting until Day 4 (2,400 mg/m2 over 46 hours).

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Leucovorin, Calciumfolinat-GRY
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 400 mg/m2 folinic acid were given as 2-hour infusion during irinotecan infusion on Day 3.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    CPT-11
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 180 mg/m2 irinotecan were given as intravenous infusion over 90 minutes on Day 3.

    Arm title
    400 mg twice daily
    Arm description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 400 mg resminostat twice daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.
    Arm type
    Experimental

    Investigational medicinal product name
    Resminostat
    Investigational medicinal product code
    4SC-201
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At each treatment cycle, 400 mg resminostat were administered orally twice daily in the morning and about 12 hours later in the evening on 5 consecutive days, followed by a 9-day rest period. Intake of resminostat tablets was at least 1 hour after a light breakfast or meal. Tablets were not to be chewed or crushed and were swallowed with 200 mL of non-carbonated water at room temperature.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    5-FU
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    At each treatment cycle, 5-Fluorouracil was given as intravenous bolus injection (400 mg/m2) on Day 3, followed by an intravenous continuous infusion lasting until Day 4 (2,400 mg/m2 over 46 hours).

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Leucovorin, Calciumfolinat-GRY
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 400 mg/m2 folinic acid were given as 2-hour infusion during irinotecan infusion on Day 3.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    CPT-11
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At each treatment cycle, 180 mg/m2 irinotecan were given as intravenous infusion over 90 minutes on Day 3.

    Number of subjects in period 1
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily
    Started
    3
    3
    3
    8
    Completed
    3
    3
    3
    7
    Not completed
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1

    Baseline characteristics

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

    Reporting group values
    Phase I Total
    Number of subjects
    17 17
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    11 11
        From 65-84 years
    6 6
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    5 5
        Male
    12 12

    End points

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    End points reporting groups
    Reporting group title
    200 mg once daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 200 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    400 mg once daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 400 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    600 mg once daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 600 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    400 mg twice daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 400 mg resminostat twice daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Primary: Pharmacokinetik (tmax)

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    End point title
    Pharmacokinetik (tmax) [1]
    End point description
    Time to maximum plasma concentration. Pharmacokinetic parameters were estimated by non-compartmental analysis, using the kinetic evaluation software WinNonlin. tmax was determined directly from the plasma concentration-time profiles.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 5
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily
    Number of subjects analysed
    3
    3
    2
    4
    Units: hour
        median (full range (min-max))
    2 (2 to 3)
    2 (2 to 2)
    1.5 (1 to 2)
    3 (2 to 5)
    No statistical analyses for this end point

    Primary: Pharmacokinetik (Cmax)

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    End point title
    Pharmacokinetik (Cmax) [2]
    End point description
    Maximum plasma concentration. Pharmacokinetic parameters were estimated by non-compartmental analysis, using the kinetic evaluation software WinNonlin. Cmax was determined directly from the plasma concentration-time profiles.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 5
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily
    Number of subjects analysed
    3
    3
    2
    4
    Units: mg/L
        geometric mean (full range (min-max))
    0.716 (0.35 to 1.18)
    1.92 (1.53 to 2.3)
    3.3 (2.32 to 4.68)
    1.52 (0.794 to 2.95)
    No statistical analyses for this end point

    Primary: Pharmacokinetik (AUClast)

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    End point title
    Pharmacokinetik (AUClast) [3]
    End point description
    Area under the plasma concentration-time curve from time zero to last measurable concentration time point. Pharmacokinetic parameters were estimated by non-compartmental analysis, using the kinetic evaluation software WinNonlin. AUClast values were calculated by linear/log trapezoidal rule from time zero to the last measurable concentration time point.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 5
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily
    Number of subjects analysed
    3
    3
    2
    4
    Units: mg x h/L
        geometric mean (full range (min-max))
    2.04 (1.05 to 3.19)
    6.06 (4.87 to 7.74)
    9.99 (7.62 to 13.1)
    4.73 (2.61 to 7.55)
    No statistical analyses for this end point

    Primary: Maximum tolerated dose (number of subjects with DLTs)

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    End point title
    Maximum tolerated dose (number of subjects with DLTs) [4]
    End point description
    Dose-limiting toxicity was defined as any of the following conditions occurring in Cycle 1: • ≥ Grade 3 non-hematological toxicity (excluding alopecia; ALT/AST < 10x ULN; gamma GGT and AP levels, fatigue only Grade 4); • ≥ Grade 3 nausea, uncontrolled vomiting, or diarrhea over more than 48 h; • Grade 3 elevated troponin levels if other evidence of cardiac damage is present; • Grade 4 granulocytopenia lasting ≥ 7 days, febrile neutropenia, thrombocytopenia, or anemia; • Inability to receive the scheduled regimen of resminostat and FOLFIRI due to toxicity, and to begin the next dosing within two weeks; • ≥ Grade 2 non-hematological toxicity persisting beyond first cycle, juged by the investigator/sponsor as dose limiting; • Toxicities which in the judgment of the investigator/sponsor are dose limiting;
    End point type
    Primary
    End point timeframe
    Only DLTs proclaimed in Cyle 1 (14 days) were used for the purpose of MTD decisions.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily
    Number of subjects analysed
    3
    3
    3
    8
    Units: Number of subjects with DLTs
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period of observation for collection of adverse events extended from the first dose of resminostat through 30 days following the last dose of resminostat.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    200 mg once daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 200 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    400 mg once daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 400 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    600 mg once daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 600 mg resminostat once daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    400 mg twice daily
    Reporting group description
    In 14-day treatment cycles, patients were dosed on 5 consecutive days (Days 1-5) with 400 mg resminostat twice daily, followed by a 9-day rest period (Days 6-14). On Days 3 and 4 compounds of FOLFIRI regimen (5-fluorouracil, folinic acid, irinotecan) were administered according to the respective summary of product characteristics.

    Reporting group title
    Total
    Reporting group description
    -

    Serious adverse events
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 8 (25.00%)
    6 / 17 (35.29%)
         number of deaths (all causes)
    3
    3
    3
    6
    15
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Somnolence
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Portal venous gas
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    200 mg once daily 400 mg once daily 600 mg once daily 400 mg twice daily Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    8 / 8 (100.00%)
    17 / 17 (100.00%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    1
    1
    3
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    1
    1
    2
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Thrombophlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Surgical and medical procedures
    Nutritional supplementation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Stent placement
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    0
    0
    2
    Device leakage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    4 / 8 (50.00%)
    10 / 17 (58.82%)
         occurrences all number
    3
    3
    2
    5
    13
    Feeling hot
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    2
    0
    3
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Local swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    0
    2
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
         occurrences all number
    1
    4
    1
    0
    6
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    3 / 8 (37.50%)
    7 / 17 (41.18%)
         occurrences all number
    1
    2
    2
    4
    9
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    0
    1
    1
    1
    3
    Sleep disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Sleep disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    3
    0
    3
    Acute stress disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Investigations
    Amino acid level increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    0
    2
    Blood calcium decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Blood creatinine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Blood testosterone decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    0
    1
    2
    Electrocardiogram PQ interval
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    0
    2
    5
    4
    11
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    0
    3
    1
    1
    5
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    3
    0
    3
    Lmyphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    3
    3
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Thyroxine free decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Tri-iodothyronine free decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    1
    1
    2
    Weight decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 8 (12.50%)
    5 / 17 (29.41%)
         occurrences all number
    1
    1
    3
    1
    6
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    2
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 8 (12.50%)
    4 / 17 (23.53%)
         occurrences all number
    0
    1
    3
    1
    5
    Sinus bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    2
    2
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    2
    2
    Dysaesthesia pharynx
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    1
    1
    3
    Hiccups
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    0
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    2
    2
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Wheezing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    1 / 8 (12.50%)
    8 / 17 (47.06%)
         occurrences all number
    2
    3
    4
    1
    10
    Leukopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    1
    0
    2
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    2
    2
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    3 / 17 (17.65%)
         occurrences all number
    0
    0
    1
    5
    6
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    1
    2
    3
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    3 / 17 (17.65%)
         occurrences all number
    0
    1
    0
    2
    3
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Polyneuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Vocal cord paralysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Cholinergic syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    0
    2
    3
    Aphthous stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    0
    1
    2
    Ascites
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    3
    0
    0
    4
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    4 / 17 (23.53%)
         occurrences all number
    1
    2
    0
    1
    4
    Diarrhoea
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    4 / 8 (50.00%)
    12 / 17 (70.59%)
         occurrences all number
    4
    5
    3
    8
    20
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 8 (25.00%)
    3 / 17 (17.65%)
         occurrences all number
    0
    0
    1
    2
    3
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    1
    1
    2
    Eructation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    0
    2
    3
    Haematemesis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Melaena
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    5 / 8 (62.50%)
    11 / 17 (64.71%)
         occurrences all number
    3
    3
    3
    7
    16
    Oral mucosal erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Tongue dry
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Varices oesophageal
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    5 / 8 (62.50%)
    8 / 17 (47.06%)
         occurrences all number
    7
    6
    0
    8
    21
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 8 (25.00%)
    5 / 17 (29.41%)
         occurrences all number
    0
    1
    2
    2
    5
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    1
    1
    2
    Eczema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Hyperhydrosis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    1
    2
    0
    1
    4
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 8 (0.00%)
    4 / 17 (23.53%)
         occurrences all number
    0
    2
    2
    0
    4
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 8 (25.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    2
    2
    Rosacea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Scab
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    1
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    1
    0
    2
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    1
    0
    0
    2
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    3
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Proctalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    2
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 8 (50.00%)
    4 / 17 (23.53%)
         occurrences all number
    0
    0
    0
    4
    4
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    0
    1
    3
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    2
    0
    0
    0
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 8 (25.00%)
    7 / 17 (41.18%)
         occurrences all number
    1
    2
    2
    4
    9
    Hypomagnesaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 8 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    5
    0
    6
    Polydipsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Vitamin K deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    1
    0
    2
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    4
    0
    0
    4
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Endometritis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 8 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    1
    Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 8 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2011
    Documentation of change of LKP and Principal Investigator at one site.
    21 Jul 2011
    To improve patient recruitment in phase I of the study, an additional participating site was submitted. Furthermore the protocol and patient informed consent were adapted regarding the in- and exclusion criteria of phase I of the clinical trial: o Patients in ≥ 2nd line treatment were allowed to participate in phase I of the clinical trial. o Patients without k-ras mutation were included in phase I of the study. o The inclusion and exclusion criteria of phase II of the study were not changed.
    15 Dec 2011
    During study conduct it was observed that a special focus on the serum electrolyte levels of the patients was needed. In order to increase the safety of the study participants, the recommendation of prophylactic and interventional substitution of electrolytes was added to the study protocol. Furthermore, the definition of dose-limiting toxicities was adjusted according to current knowledge of the safety profile of the resminostat/FOLFIRI combination. The points amended were: o Addition of advice in case of serum electrolyte deviations o Update information about study duration o Adaption of the definition of dose limiting toxicities o Other formal changes and clarifications
    28 Jan 2013
    Implementation of administrative changes, and prolongation of the recruiting phase. The points amended were: o Update information about study team members o Update information about study duration o Other formal changes, e.g. punctuation

    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.
    After completion of phase I, and even though the phase I part raised no safety concerns, 4SC AG decided to primarily focus on the development of resminostat in other indications. Therefore, the SHORE study was terminated without conducting phase II.
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