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    Clinical Trial Results:
    A Phase 1/2 Study Evaluating Intermittent and Continuous OSI 906 and Weekly Paclitaxel in Patients with Recurrent Epithelial Ovarian Cancer (and Other Solid Tumors)

    Summary
    EudraCT number
    2009-010319-34
    Trial protocol
    GB   PL   CZ   IT  
    Global end of trial date
    31 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    OSI-906-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00889382
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    International Study Number (ISN): 7487-CL-0202
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.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
    31 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary phase 1 objective of the study was to determine both the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of intermittent and continuous linsitinib in combination with weekly paclitaxel in patients with advanced solid tumors. The primary objective of the phase 2 portion of this study was to determine progression-free survival (PFS) evaluated by the investigator of 2 different schedules of linsitinib (Arm A and Arm B) in combination with weekly paclitaxel as compared with paclitaxel alone (Arm C) in recurrent/refractory ovarian cancer patients.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Switzerland: 23
    Country: Number of subjects enrolled
    United States: 39
    Worldwide total number of subjects
    210
    EEA total number of subjects
    100
    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)
    166
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    This multicenter study was conducted in the following locations: Phase 1: Switzerland, Canada, United Kingdom and United States. Phase 2: Australia, Canada, Czech Republic, Italy, Poland, Romania, Russia, Switzerland, United Kingdom, and United States. The principal investigator at each site was experienced in the therapeutic area of oncology.

    Pre-assignment
    Screening details
    Screening procedures included physical examination, vital signs and laboratory assessments. Patients were evaluated weekly at the study centers. Every 21 days will be considered 1 treatment period, except in phase 1, in which Treatment Period 1 was 28 days.

    Period 1
    Period 1 title
    Phase 1 and Phase 2 (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel
    Arm description
    Phase 1, Arm A – Intermittent OSI-906 300 mg quaque die (QD) (once daily) on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The starting dose of intermittent linsitinib was 300 mg daily on days 1 to 3 every 7 days. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 1 Arm A –Intermittent OSI-906 QD on Days 1 – 3, 8 – 10, and 15 – 17 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24. The starting dose of intermittent linsitinib was 300 mg daily on days 1 to 3 every 7 days. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to take the dose any time during that same day for intermittent schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. All patients were to receive paclitaxel premedication as per local practices. For phase 1, all A Arms, paclitaxel was given on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1, paclitaxel was given on Days 8, 15, and 22). On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion. Paclitaxel was administered on day 8 (not on day 1) for the first treatment period only in order to obtain single-agent pharmacokinetics for linsitinib and to assess any potential drug-drug interaction. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously, which was considered an acceptable standard based on available literature for the weekly administration of paclitaxel.

    Arm title
    Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel
    Arm description
    Phase 1, Arm A – Intermittent OSI-906 400 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 400 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 1 Arm A –Intermittent 400 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24. The intermittent linsitinib dose was 400 mg daily on days 1 to 3 every 7 days. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to take the dose any time during that same day for intermittent schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. All patients were to receive paclitaxel premedication as per local practices. For phase 1, all A Arms, paclitaxel was given on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1, paclitaxel was given on Days 8, 15, and 22). On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion. Paclitaxel was administered on day 8 (not on day 1) for the first treatment period only in order to obtain single-agent pharmacokinetics for linsitinib and to assess any potential drug-drug interaction. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously, which was considered an acceptable standard based on available literature for the weekly administration of paclitaxel.

    Arm title
    Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel
    Arm description
    Phase 1, Arm A – Intermittent OSI-906 450 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 450 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 1 Arm A –Intermittent 450 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24. The intermittent linsitinib dose was 450 mg daily on days 1 to 3 every 7 days. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to take the dose any time during that same day for intermittent schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. All patients were to receive paclitaxel premedication as per local practices. For phase 1, all A Arms, paclitaxel was given on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1, paclitaxel was given on Days 8, 15, and 22). On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion. Paclitaxel was administered on day 8 (not on day 1) for the first treatment period only in order to obtain single-agent pharmacokinetics for linsitinib and to assess any potential drug-drug interaction. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously, which was considered an acceptable standard based on available literature for the weekly administration of paclitaxel.

    Arm title
    Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel
    Arm description
    Phase 1, Arm A – Intermittent OSI-906 600 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 600 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 1 Arm A –Intermittent 600 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24. The intermittent linsitinib dose was 600 mg daily on days 1 to 3 every 7 days. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to take the dose any time during that same day for intermittent schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. All patients were to receive paclitaxel premedication as per local practices. For phase 1, all A Arms, paclitaxel was given on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1, paclitaxel was given on Days 8, 15, and 22). On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion. Paclitaxel was administered on day 8 (not on day 1) for the first treatment period only in order to obtain single-agent pharmacokinetics for linsitinib and to assess any potential drug-drug interaction. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously, which was considered an acceptable standard based on available literature for the weekly administration of paclitaxel.

    Arm title
    Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel
    Arm description
    Phase 1, Arm B: Continuous OSI-906 bis in die (BID) (twice daily) from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 75 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 1, Arm B: Continuous OSI-906 BID (Days 1 – 28) (for TP 1); all other treatment period (TPs): continuous OSI-906 BID (Days 1 – 21). The starting dose of continuous linsitinib was 75 mg twice daily. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to skip the missed dose and take the next dose for continuous schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. All patients were to receive paclitaxel premedication as per local practices. For phase 1, all B Arms, paclitaxel was given on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1, paclitaxel was given on Days 8, 15, and 22). On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion. Paclitaxel was administered on day 8 (not on day 1) for the first treatment period only in order to obtain single-agent pharmacokinetics for linsitinib and to assess any potential drug-drug interaction. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously, which was considered an acceptable standard based on available literature for the weekly administration of paclitaxel.

    Arm title
    Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel
    Arm description
    Phase 1, Arm B: Continuous OSI-906 150 mg BID from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 150 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 1, Arm B: Continuous OSI-906 150 mg BID (Days 1 – 28) (for TP 1); all other treatment period (TPs): continuous OSI-906 BID (Days 1 – 21). The continuous linsitinib dose was 150 mg twice daily for this arm. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to skip the missed dose and take the next dose for continuous schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. All patients were to receive paclitaxel premedication as per local practices. For phase 1, all B Arms, paclitaxel was given on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1, paclitaxel was given on Days 8, 15, and 22). On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion. Paclitaxel was administered on day 8 (not on day 1) for the first treatment period only in order to obtain single-agent pharmacokinetics for linsitinib and to assess any potential drug-drug interaction. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously, which was considered an acceptable standard based on available literature for the weekly administration of paclitaxel.

    Arm title
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel
    Arm description
    Phase 2, Arm A – 600 mg intermittent linsitinib once daily on days 1 to 3, 8 to 10, and 15 to 17 with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 2, Arm A – Intermittent OSI-906 QD on Days 1 – 3, 8 – 10, and 15 – 17. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to take the dose any time during that same day for intermittent schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. For phase 2, Arm A, 80 mg/m^2 paclitaxel intravenously on days 1, 8, and 15 of every 21-day treatment period. On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion.

    Arm title
    Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel
    Arm description
    Phase 2, Arm B – 150 mg twice daily continuous linsitinib from day 1 onwards with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.
    Arm type
    Experimental

    Investigational medicinal product name
    OSI-906
    Investigational medicinal product code
    ASP7487
    Other name
    Linsitinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Sponsor supplied OSI-906/linsitinib as tablets. Linsitinib was to be taken with food and up to 200 mL of water. Patients were instructed to take the correct number of linsitinib tablets corresponding to the dose level to which they were enrolled. For phase 2, Arm B – 150 mg twice daily continuous linsitinib from day 1 onwards. Doses were to be taken at approximately the same time each day and at regular intervals (approximately every 12 hours). If a patient missed a dose of linsitinib, the missed dose should not have been taken with the subsequent dose. The patient was allowed to skip the missed dose and take the next dose for continuous schedule.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. For phase 2, Arm B, 80 mg/m^2 paclitaxel intravenously on days 1, 8, and 15 of every 21-day treatment period. On days when both study drugs were co-administered (linsitinib and paclitaxel), the linsitinib dose was to be taken 2 hours prior to initiating the paclitaxel infusion.

    Arm title
    Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Arm description
    Phase 2, Arm C – 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP. During phase 2, patients were stratified according to the following criteria: a) number of prior chemotherapy regimens (1 vs. 2); and b) outcome of most recent platinum-containing chemotherapy regimen – refractory (Progressive disease (PD) on most recent platinum-containing chemotherapy) vs. resistant (PD within 6 months of stopping most recent platinum-containing chemotherapy).
    Arm type
    Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Weekly paclitaxel was to be administered as an intravenous formulation over a 1-hour period according to institution practice. For phase 2, Arm C, 80 mg/m^2 paclitaxel intravenously on days 1, 8, and 15 of every 21-day treatment period.

    Number of subjects in period 1
    Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Started
    4
    3
    14
    6
    3
    28
    51
    51
    50
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    4
    3
    14
    6
    3
    28
    51
    51
    50
         Crossed over to continuous linsitinib 150 mg QD
    -
    -
    -
    -
    -
    -
    1
    5
    4
         Death
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Physician decision
    -
    -
    -
    -
    -
    -
    1
    3
    3
         Medical or ethical reasons
    -
    1
    1
    -
    -
    3
    -
    -
    -
         Adverse event
    1
    -
    3
    1
    -
    5
    5
    4
    8
         Other: Medical or ethical reasons
    -
    -
    -
    -
    -
    -
    -
    -
    1
         Withdrawal by subject
    -
    1
    -
    -
    -
    1
    -
    -
    -
         Other: Patient had travel plans
    -
    -
    -
    -
    -
    -
    -
    -
    1
         Other: clinical progression related to ascites
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Withdrew consent
    -
    -
    -
    -
    -
    -
    4
    3
    4
         Randomized but never received study drug
    -
    -
    -
    -
    -
    -
    1
    2
    1
         Disease progression
    3
    1
    10
    5
    3
    19
    39
    32
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 300 mg quaque die (QD) (once daily) on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The starting dose of intermittent linsitinib was 300 mg daily on days 1 to 3 every 7 days. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 400 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 400 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 450 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 450 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 600 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 600 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel
    Reporting group description
    Phase 1, Arm B: Continuous OSI-906 bis in die (BID) (twice daily) from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 75 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.

    Reporting group title
    Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel
    Reporting group description
    Phase 1, Arm B: Continuous OSI-906 150 mg BID from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 150 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.

    Reporting group title
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel
    Reporting group description
    Phase 2, Arm A – 600 mg intermittent linsitinib once daily on days 1 to 3, 8 to 10, and 15 to 17 with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.

    Reporting group title
    Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel
    Reporting group description
    Phase 2, Arm B – 150 mg twice daily continuous linsitinib from day 1 onwards with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.

    Reporting group title
    Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Reporting group description
    Phase 2, Arm C – 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP. During phase 2, patients were stratified according to the following criteria: a) number of prior chemotherapy regimens (1 vs. 2); and b) outcome of most recent platinum-containing chemotherapy regimen – refractory (Progressive disease (PD) on most recent platinum-containing chemotherapy) vs. resistant (PD within 6 months of stopping most recent platinum-containing chemotherapy).

    Reporting group values
    Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel Phase 2 Arm C - 80 mg/m^2 paclitaxel Total
    Number of subjects
    4 3 14 6 3 28 51 51 50 210
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    For phase 1 the age values were based on the Safety Analysis Set (SAF), the SAF consisted of all enrolled patients who received at least 1 dose of study drug. For phase 2 age values were based on the Full Analysis Set (FAS), the FAS consisted of all randomized patients.
    Units: years
        arithmetic mean (standard deviation)
    62.8 ± 7.59 61.7 ± 0.58 55.3 ± 9.35 58.5 ± 8.8 60.7 ± 2.08 56.9 ± 9.75 57.84 ± 10.68 57.96 ± 8.407 56.4 ± 9.198 -
    Gender categorical
    For phase 1 the gender values were based on the Safety Analysis Set (SAF), the SAF consisted of all enrolled patients who received at least 1 dose of study drug. For phase 2 gender values were based on the Full Analysis Set (FAS), the FAS consisted of all randomized patients.
    Units: Subjects
        Female
    3 2 13 5 3 23 51 51 50 201
        Male
    1 1 1 1 0 5 0 0 0 9

    End points

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    End points reporting groups
    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 300 mg quaque die (QD) (once daily) on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The starting dose of intermittent linsitinib was 300 mg daily on days 1 to 3 every 7 days. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 400 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 400 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 450 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 450 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 600 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 600 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel
    Reporting group description
    Phase 1, Arm B: Continuous OSI-906 bis in die (BID) (twice daily) from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 75 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.

    Reporting group title
    Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel
    Reporting group description
    Phase 1, Arm B: Continuous OSI-906 150 mg BID from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 150 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.

    Reporting group title
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel
    Reporting group description
    Phase 2, Arm A – 600 mg intermittent linsitinib once daily on days 1 to 3, 8 to 10, and 15 to 17 with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.

    Reporting group title
    Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel
    Reporting group description
    Phase 2, Arm B – 150 mg twice daily continuous linsitinib from day 1 onwards with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.

    Reporting group title
    Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Reporting group description
    Phase 2, Arm C – 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP. During phase 2, patients were stratified according to the following criteria: a) number of prior chemotherapy regimens (1 vs. 2); and b) outcome of most recent platinum-containing chemotherapy regimen – refractory (Progressive disease (PD) on most recent platinum-containing chemotherapy) vs. resistant (PD within 6 months of stopping most recent platinum-containing chemotherapy).

    Subject analysis set title
    Phase 1 Arm A- Intermittent OSI-906 once daily with paclitaxel
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The MTD Determination Analysis Set (MTDSET) was defined as all patients who were considered fully evaluable for assessment of Dose-limiting toxicity (DLT) or experienced DLTs. Patients who required a dose interruption or reduction during the initial 28-day treatment period remained evaluable for MTD determination if the reason for the reduction and/or interruption represented a DLT. A standard 3+3 dose escalation scheme was used. The dose-limiting toxicities were listed for the MTD determining patients. Patients were treated in either the intermittent or continuous linsitinib (in combination with weekly paclitaxel) arm.

    Subject analysis set title
    Phase 1 Arm B - Continuous OSI-906 twice daily with paclitaxel
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Population MTDSET.

    Primary: Phase 1: Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

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    End point title
    Phase 1: Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) [1]
    End point description
    The MTD Determination Analysis Set (MTDSET) was defined as all patients who were considered fully evaluable for assessment of Dose-limiting toxicity (DLT) or experienced DLTs. Patients who required a dose interruption or reduction during the initial 28-day treatment period remained evaluable for MTD determination if the reason for the reduction and/or interruption represented a DLT. A standard 3+3 dose escalation scheme was used. The dose-limiting toxicities were listed for the MTD determining patients. Patients were treated in either the intermittent or continuous linsitinib (in combination with weekly paclitaxel) arm.
    End point type
    Primary
    End point timeframe
    28 days.
    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 provided for Maximum Tolerated Dose (MTD), not applicable.
    End point values
    Phase 1 Arm A- Intermittent OSI-906 once daily with paclitaxel Phase 1 Arm B - Continuous OSI-906 twice daily with paclitaxel
    Number of subjects analysed
    24
    9
    Units: mg
    number (not applicable)
        MTD and RP2D [N= 12, 6]
    600
    150
    No statistical analyses for this end point

    Primary: Phase 2: Progression Free Survival (PFS)

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    End point title
    Phase 2: Progression Free Survival (PFS) [2]
    End point description
    The primary efficacy variable for this study was PFS based on the RECIST (v1.1), which only included the disease progression assessment from the radiological review. The hazard ratio of the treatment effect along with 95% CI was calculated using Cox proportional hazard model. The study analysis population consisted of the Full Analysis Set (FAS), the FAS consisted of all randomized patients.
    End point type
    Primary
    End point timeframe
    Up to 15 months.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was only applicable to the arms in the phase 2 portion of the trial.
    End point values
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Number of subjects analysed
    51
    51
    50
    Units: Percentage
        number (not applicable)
    76.5
    74.5
    66
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Unstratified hazard ratio for linsitinib/paclitaxel arm vs paclitaxel alone arm. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of linsitinib.
    Comparison groups
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel v Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2678
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    1.303
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.813
         upper limit
    2.089
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified hazard ratio for linsitinib/paclitaxel arm vs paclitaxel alone arm. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of linsitinib.
    Comparison groups
    Phase 2 Arm C - 80 mg/m^2 paclitaxel v Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4522
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    1.195
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.749
         upper limit
    1.909

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A Treatment Emergent Adverse Event (TEAE) was defined as any adverse event (i.e., a new event or an exacerbation of a pre-existing condition) that occurred after the patient was enrolled and up to 30 days after the last study drug administration.
    Adverse event reporting additional description
    An adverse event (AE) or adverse experience was defined as any untoward medical occurrence in a study patient who was administered a study drug that did not necessarily have a causal relationship with this treatment. All of the AEs with an onset date after the first dose of linsitinib for Arm C patients were considered as treatment emergent.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel
    Reporting group description
    Phase 2, Arm A – 600 mg intermittent linsitinib once daily on days 1 to 3, 8 to 10, and 15 to 17 with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day treatment period (TP).

    Reporting group title
    Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel
    Reporting group description
    Phase 2, Arm B – 150 mg twice daily continuous linsitinib from day 1 onwards with 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP.

    Reporting group title
    Phase 2 Arm C - 80 mg/m^2 paclitaxel
    Reporting group description
    Phase 2, Arm C – 80 mg/m^2 paclitaxel on days 1, 8, and 15 of every 21-day TP. During phase 2, patients were stratified according to the following criteria: a) number of prior chemotherapy regimens (1 vs. 2); and b) outcome of most recent platinum-containing chemotherapy regimen – refractory (Progressive disease (PD) on most recent platinum-containing chemotherapy) vs. resistant (PD within 6 months of stopping most recent platinum-containing chemotherapy).

    Reporting group title
    Phase 2 Arm C Crossover
    Reporting group description
    Twelve patients crossed over from treatment with paclitaxel alone in Arm C to be treated with single-agent linsitinib (150 mg continuous twice daily dosing). Of these 12 patients, 1 patient died before receiving treatment and a second patient was confirmed to have progressive disease and no treatment was given. Thus, 10 patients were actually treated with linsitinib in the crossover group. These patients were analyzed separately and are referred to as Arm C crossover patients.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 quaque die (QD) (once daily) on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except Treatment Period 1 (TP 1); in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The starting dose of intermittent linsitinib was 300 mg daily on days 1 to 3 every 7 days. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 400 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 400 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 450 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 450 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel
    Reporting group description
    Phase 1, Arm A – Intermittent OSI-906 600 mg QD on Days 1 – 3, 8 – 10, and 15 – 17 with paclitaxel on Days 1, 8, and 15 (except TP 1; in TP 1 OSI-906 on Days 1 – 3, 8 –10, 15 – 17, and 22 – 24 with paclitaxel on Days 8, 15, and 22). The intermittent linsitinib dose was 600 mg daily on days 1 to 3 every 7 days for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously.

    Reporting group title
    Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel
    Reporting group description
    Phase 1, Arm B: Continuous OSI-906 bis in die (BID) (twice daily) from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 75 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.

    Reporting group title
    Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel
    Reporting group description
    Phase 1, Arm B: Continuous OSI-906 150 mg BID from Day 1 onwards with paclitaxel on Days 1, 8, and 15; (except TP 1; in TP 1 OSI-906 from Day 1 with paclitaxel on Days 8, 15, and 22). The continuous linsitinib dose was 150 mg twice daily for this arm. The planned starting dose of paclitaxel was 80 mg/m^2 intravenously. Arm B, continuous OSI-906 in combination with weekly paclitaxel, was divided into 3 subset groups: Arm B1 – TP 1: continuous OSI-906 BID (Days 1 – 21); Arm B2 – TP 1: Continuous OSI-906 BID (Days 1 – 28) (additional PK sampling on Day 9 or 13 or 14 for TP 1); Arm B3 – TP 1: continuous OSI-906 BID (Days 1 – 28) (OSI-906 dosing 2 hours prior to the initiation of paclitaxel infusion in TP 1 Day 8 only) all other TPs no separation in OSI-906 and paclitaxel dosing.

    Serious adverse events
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel Phase 2 Arm C - 80 mg/m^2 paclitaxel Phase 2 Arm C Crossover Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 50 (36.00%)
    19 / 49 (38.78%)
    17 / 49 (34.69%)
    3 / 10 (30.00%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    15 / 28 (53.57%)
         number of deaths (all causes)
    1
    8
    4
    0
    0
    0
    0
    1
    2
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Ovarian cancer recurrent
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Vaginal fistula
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent-graft malfunction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic stenosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 49 (8.16%)
    4 / 49 (8.16%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 6
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Small intestinal perforation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Obstructive uropathy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central line infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase 2 Arm A - 600 mg intermittent OSI-906 QD with paclitaxel Phase 2 Arm B - 150 mg BID continuous OSI-906 with paclitaxel Phase 2 Arm C - 80 mg/m^2 paclitaxel Phase 2 Arm C Crossover Phase 1 Arm A- Intermittent OSI-906 300 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 400 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 450 mg QD with paclitaxel Phase 1 Arm A- Intermittent OSI-906 600 mg QD with paclitaxel Phase 1 Arm B - Continuous OSI-906 75 mg BID with paclitaxel Phase 1 Arm B - Continuous OSI-906 150 mg BID with paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 50 (98.00%)
    47 / 49 (95.92%)
    48 / 49 (97.96%)
    9 / 10 (90.00%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    14 / 14 (100.00%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    28 / 28 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 28 (7.14%)
         occurrences all number
    3
    1
    15
    0
    1
    0
    1
    0
    2
    2
    Deep vein thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Flushing
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Hot flush
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    2
    1
    Hyperaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    2
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Food allergy
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 50 (22.00%)
    6 / 49 (12.24%)
    4 / 49 (8.16%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    4 / 28 (14.29%)
         occurrences all number
    23
    9
    5
    1
    0
    5
    2
    3
    0
    19
    Chills
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    3
    3
    0
    0
    0
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    23 / 50 (46.00%)
    26 / 49 (53.06%)
    26 / 49 (53.06%)
    1 / 10 (10.00%)
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    7 / 14 (50.00%)
    4 / 6 (66.67%)
    2 / 3 (66.67%)
    20 / 28 (71.43%)
         occurrences all number
    50
    56
    62
    1
    5
    7
    20
    10
    10
    63
    Mucosal inflammation
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 49 (6.12%)
    6 / 49 (12.24%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    7
    3
    10
    0
    0
    0
    0
    0
    0
    3
    Oedema peripheral
         subjects affected / exposed
    8 / 50 (16.00%)
    4 / 49 (8.16%)
    10 / 49 (20.41%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    8 / 28 (28.57%)
         occurrences all number
    11
    7
    15
    2
    0
    3
    3
    1
    8
    8
    Pain
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    0
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    2 / 50 (4.00%)
    8 / 49 (16.33%)
    6 / 49 (12.24%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    8
    9
    2
    0
    0
    0
    1
    0
    4
    Influenza like illness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Catheter related complication
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Early satiety
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    2
    Infusion site pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    1
    Thirst
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 49 (6.12%)
    5 / 49 (10.20%)
    0 / 10 (0.00%)
    3 / 4 (75.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    5 / 28 (17.86%)
         occurrences all number
    5
    3
    7
    0
    3
    0
    2
    2
    0
    5
    Abnormal dreams
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Affect lability
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    1
    1
    3
    Confusional state
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    2
    Excoriation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Periorbital haematoma
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    6
    1
    0
    2
    0
    0
    1
    1
    0
    7
    Electrocardiogram QT prolonged
         subjects affected / exposed
    16 / 50 (32.00%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    28
    2
    1
    0
    0
    2
    1
    1
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    1
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Blood amylase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    3
    Blood urine present
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    8
    1
    0
    3
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Lipase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    Weight decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Splinter haemorrhages
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 50 (22.00%)
    12 / 49 (24.49%)
    17 / 49 (34.69%)
    0 / 10 (0.00%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    3 / 6 (50.00%)
    2 / 3 (66.67%)
    4 / 28 (14.29%)
         occurrences all number
    25
    17
    26
    0
    2
    5
    9
    4
    3
    8
    Leukopenia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    3
    5
    3
    0
    0
    0
    6
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    12 / 50 (24.00%)
    3 / 49 (6.12%)
    4 / 49 (8.16%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    4 / 14 (28.57%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    4 / 28 (14.29%)
         occurrences all number
    21
    4
    4
    0
    0
    0
    9
    1
    2
    4
    Bone marrow failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 49 (10.20%)
    12 / 49 (24.49%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    10 / 28 (35.71%)
         occurrences all number
    4
    14
    14
    0
    1
    1
    4
    0
    3
    10
    Dyspnoea
         subjects affected / exposed
    7 / 50 (14.00%)
    7 / 49 (14.29%)
    6 / 49 (12.24%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    8 / 28 (28.57%)
         occurrences all number
    8
    19
    7
    0
    0
    0
    7
    1
    0
    8
    Epistaxis
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 49 (14.29%)
    5 / 49 (10.20%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    6 / 14 (42.86%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    3 / 28 (10.71%)
         occurrences all number
    5
    8
    6
    0
    1
    0
    9
    1
    3
    3
    Nasal congestion
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    2
    3
    0
    1
    0
    0
    0
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    4 / 28 (14.29%)
         occurrences all number
    5
    2
    3
    0
    0
    0
    2
    0
    3
    5
    Dysphonia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    4
    4
    Haemoptysis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    Nasal dryness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    3
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    1
    1
    Productive cough
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Pulmonary congestion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    1
    Sinus congestion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    1
    1
    Throat irritation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    5 / 49 (10.20%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    3
    1
    5
    0
    1
    0
    4
    2
    0
    4
    Dysgeusia
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 49 (10.20%)
    9 / 49 (18.37%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    8 / 28 (28.57%)
         occurrences all number
    2
    5
    17
    1
    0
    0
    6
    1
    1
    9
    Headache
         subjects affected / exposed
    6 / 50 (12.00%)
    8 / 49 (16.33%)
    7 / 49 (14.29%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    6 / 14 (42.86%)
    0 / 6 (0.00%)
    3 / 3 (100.00%)
    7 / 28 (25.00%)
         occurrences all number
    8
    8
    17
    0
    4
    0
    12
    0
    3
    10
    Neuropathy peripheral
         subjects affected / exposed
    7 / 50 (14.00%)
    8 / 49 (16.33%)
    17 / 49 (34.69%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
    2 / 3 (66.67%)
    6 / 28 (21.43%)
         occurrences all number
    10
    15
    31
    0
    1
    0
    14
    1
    5
    13
    Paraesthesia
         subjects affected / exposed
    7 / 50 (14.00%)
    7 / 49 (14.29%)
    4 / 49 (8.16%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    15
    12
    9
    1
    0
    0
    3
    1
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 49 (6.12%)
    5 / 49 (10.20%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 14 (21.43%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    6 / 28 (21.43%)
         occurrences all number
    8
    4
    12
    0
    0
    1
    9
    5
    0
    9
    Somnolence
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Ataxia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    4
    Balance disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    2
    0
    Lethargy
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    0
    2
    Memory impairment
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Parosmia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    5
    Restless legs syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Sinus headache
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    Speech disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    3
    0
    0
    0
    0
    0
    0
    0
    Blepharospasm
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Deafness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Hearing impaired
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    5
    1
    0
    0
    0
    1
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    7 / 50 (14.00%)
    5 / 49 (10.20%)
    7 / 49 (14.29%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    8
    5
    7
    1
    0
    0
    3
    0
    0
    3
    Abdominal pain
         subjects affected / exposed
    10 / 50 (20.00%)
    11 / 49 (22.45%)
    20 / 49 (40.82%)
    2 / 10 (20.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    4 / 14 (28.57%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    7 / 28 (25.00%)
         occurrences all number
    17
    12
    50
    6
    2
    1
    7
    4
    0
    10
    Abdominal pain lower
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    6 / 50 (12.00%)
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    14
    2
    12
    4
    0
    1
    2
    2
    0
    0
    Ascites
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    4
    3
    3
    0
    0
    0
    1
    4
    0
    1
    Constipation
         subjects affected / exposed
    14 / 50 (28.00%)
    17 / 49 (34.69%)
    16 / 49 (32.65%)
    2 / 10 (20.00%)
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    3 / 14 (21.43%)
    4 / 6 (66.67%)
    0 / 3 (0.00%)
    9 / 28 (32.14%)
         occurrences all number
    23
    29
    26
    4
    2
    4
    5
    4
    0
    11
    Dyspepsia
         subjects affected / exposed
    8 / 50 (16.00%)
    3 / 49 (6.12%)
    6 / 49 (12.24%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    6 / 14 (42.86%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 28 (7.14%)
         occurrences all number
    11
    3
    6
    0
    0
    0
    8
    0
    1
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    30 / 50 (60.00%)
    16 / 49 (32.65%)
    23 / 49 (46.94%)
    1 / 10 (10.00%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    12 / 14 (85.71%)
    4 / 6 (66.67%)
    3 / 3 (100.00%)
    15 / 28 (53.57%)
         occurrences all number
    60
    28
    41
    1
    6
    4
    20
    9
    10
    23
    Stomatitis
         subjects affected / exposed
    7 / 50 (14.00%)
    3 / 49 (6.12%)
    4 / 49 (8.16%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    5 / 28 (17.86%)
         occurrences all number
    8
    3
    5
    0
    3
    0
    2
    1
    4
    7
    Vomiting
         subjects affected / exposed
    17 / 50 (34.00%)
    7 / 49 (14.29%)
    16 / 49 (32.65%)
    2 / 10 (20.00%)
    3 / 4 (75.00%)
    2 / 3 (66.67%)
    6 / 14 (42.86%)
    1 / 6 (16.67%)
    3 / 3 (100.00%)
    9 / 28 (32.14%)
         occurrences all number
    40
    10
    43
    4
    5
    2
    8
    2
    9
    15
    Diarrhoea
         subjects affected / exposed
    23 / 50 (46.00%)
    15 / 49 (30.61%)
    13 / 49 (26.53%)
    2 / 10 (20.00%)
    2 / 4 (50.00%)
    3 / 3 (100.00%)
    8 / 14 (57.14%)
    4 / 6 (66.67%)
    2 / 3 (66.67%)
    16 / 28 (57.14%)
         occurrences all number
    35
    25
    29
    4
    6
    4
    15
    13
    9
    28
    Haemorrhoids
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    0
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Breath odour
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    1
    Eructation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gingival pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hyperchlorhydria
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Melaena
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tongue discolouration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    2
    0
    Umbilical hernia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Bladder spasm
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0