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BI 860585 Dose Escalation Single Agent and in Combination With Exemestane or With Paclitaxel in Patients With Various Advanced and/or Metastatic Solid Tumors

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ClinicalTrials.gov Identifier: NCT01938846
Recruitment Status : Completed
First Posted : September 10, 2013
Results First Posted : January 4, 2019
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Neoplasms
Interventions Drug: BI 860585
Drug: exemestane
Drug: paclitaxel
Enrollment 90
Recruitment Details An open-label, Phase I, dose-finding study of BI 860585, a total of 90 patients received at least one dose of study medication.
Pre-assignment Details All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that all patients met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Period Title: Overall Study
Started [1] 41 25 24
Completed [2] 0 0 0
Not Completed 41 25 24
Reason Not Completed
Progressive disease             26             18             16
Adverse Event             8             4             3
Withdrawal by Subject             2             2             1
Other than listed             5             1             4
[1]
Entered/randomised
[2]
Not discontinued from last trial medication
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel Total
Hide Arm/Group Description Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses Total of all reporting groups
Overall Number of Baseline Participants 41 25 24 90
Hide Baseline Analysis Population Description
Treated set (TS): The treated set includes all patients who were administered at least one dose of any study medication (BI 860585, exemestane, or paclitaxel).
Age, Continuous   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 41 participants 25 participants 24 participants 90 participants
58.4  (13.8) 58.3  (9.5) 58.5  (10.2) 58.4  (11.7)
[1]
Measure Description: Age at the time of signing informed consent form is presented.
[2]
Measure Analysis Population Description: TS
Sex: Female, Male   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 25 participants 24 participants 90 participants
Female
13
  31.7%
23
  92.0%
12
  50.0%
48
  53.3%
Male
28
  68.3%
2
   8.0%
12
  50.0%
42
  46.7%
[1]
Measure Description: Number of subjects is categorized as Male or Female.
[2]
Measure Analysis Population Description: TS
1.Primary Outcome
Title The Number of Patients With Dose-Limiting Toxicities (DLTs) in the First Course of Each Treatment Arm
Hide Description The number of patients with Dose-Limiting Toxicities (DLTs) in the first course of each treatment arm to identify the Maximum Tolerated Dose (MTD) for BI 860585 monotherapy and BI 860585 in combination with exemestane of paclitaxel.
Time Frame 28 days (Maximum tolerated dose (MTD) evaluation period (First Treatment Cycle))
Hide Outcome Measure Data
Hide Analysis Population Description
Treated and Evaluable Set: The treated and evaluable set includes all patients who were administered at least one dose of study medication and who are evaluable with respect to DLT in the MTD evaluation period.
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description:
Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses
Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses
Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Overall Number of Participants Analyzed 36 21 18
Measure Type: Count of Participants
Unit of Measure: Participants
Total with dose limiting toxicities
4
  11.1%
4
  19.0%
2
  11.1%
2.Primary Outcome
Title The Maximum Tolerated Dose (MTD) for Each Treatment Arm
Hide Description The Maximum Tolerated Dose (MTD) for each treatment arm was the dose that was 1 dose cohort below that at which ≥2 of 6 patients had experienced DLT. i.e., the MTD was the highest dose studied for which the DLT incidence was no more than 17% (i.e. 1 of 6 patients) during the first treatment course.
Time Frame 28 days (Maximum tolerated dose (MTD) evaluation period (First Treatment Cycle))
Hide Outcome Measure Data
Hide Analysis Population Description
Treated and Evaluable Set: The treated and evaluable set includes all patients who were administered at least one dose of study medication and who are evaluable with respect to DLT in the MTD evaluation period.
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description:
Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses
Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses
Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Overall Number of Participants Analyzed 36 21 18
Measure Type: Number
Unit of Measure: Milligram (mg)
BI 860585 220 160 160
Exemestane NA [1]  25 NA [1] 
Paclitaxel NA [1]  NA [1]  80
[1]
Not applicable for this arm
3.Secondary Outcome
Title Objective Response Rate (Complete Response or Partial Response as Per the Response Evaluation Criteria In Solid Tumors Criteria [RECIST], Version 1.1)
Hide Description As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for objective response rate (Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions) for target lesions assessed by Magnetic resonance imaging (MRI) and Computed tomography (CT)
Time Frame From the date of first treatment administration until the earliest of disease progression, death, or last adequate tumour assessment before new anti-cancer therapy; data collected up to cut-off date 30 Jun 2017, Up to 1389 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set: The treated set includes all patients who were administered at least one dose of any study medication (BI 860585, exemestane or paclitaxel).
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description:
Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses
Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses
Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Overall Number of Participants Analyzed 41 25 24
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
4
  16.0%
5
  20.8%
4.Secondary Outcome
Title Disease Control Rate/Clinical Benefit Rate (Complete Response, Partial Response or Stable Disease as Per Response Evaluation Criteria In Solid Tumors Criteria [RECIST], Version 1.1)
Hide Description As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for disease control rate/clinical benefit rate (Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression) for target lesions assessed by Magnetic resonance imaging (MRI) and Computed tomography (CT)
Time Frame From the date of first treatment administration until the earliest of disease progression, death, or last adequate tumour assessment before new anti-cancer therapy.
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set: The treated set includes all patients who were administered at least one dose of any study medication (BI 860585, exemestane or paclitaxel).
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description:
Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses
Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses
Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Overall Number of Participants Analyzed 41 25 24
Measure Type: Count of Participants
Unit of Measure: Participants
8
  19.5%
7
  28.0%
14
  58.3%
5.Secondary Outcome
Title Duration of Clinical Benefit
Hide Description Duration of clinical benefit (Disease control) was defined as the time between first treatment administration until the earliest of disease progression or death, for patients with disease control.
Time Frame From the date of first treatment administration until the earliest of disease progression, death, or last adequate tumour assessment before new anti-cancer therapy; data collected up to cut-off date 30 Jun 2017, Up to 1389 days
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with disease control from the treated set (Treated Set: The treated set includes all patients who were administered at least one dose of any study medication (BI 860585, exemestane or paclitaxel)).
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description:
Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses
Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses
Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Overall Number of Participants Analyzed 8 7 14
Mean (Standard Deviation)
Unit of Measure: Months
8.31  (4.78) 10.06  (7.26) 7.79  (3.30)
6.Secondary Outcome
Title Duration of Objective Response
Hide Description Duration of objective response was defined as the time from first objective response until the earliest of progression or death, for patients with objective response.
Time Frame From the date of first treatment administration until the earliest of disease progression, death, or last adequate tumour assessment before new anti-cancer therapy; data collected up to cut-off date 30 Jun 2017, Up to 1389 days
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with objective response from the treated set (Treated Set: The treated set includes all patients who were administered at least one dose of any study medication (BI 860585, exemestane or paclitaxel)).
Arm/Group Title BI 860585 Monotherapy BI 860585 + Exemestane BI 860585 + Paclitaxel
Hide Arm/Group Description:
Patients were administered with BI 860585 daily oral dose of 5 milligram starting dose) over 28-day treatment courses
Patients were administered with daily oral dose of BI 860585 in combination with 25 milligram/day standard fixed dose of Exemestane over 28-day treatment courses
Patients were administered with BI 860585 in combination with Paclitaxel weekly intravenous infusion of 60 milligram/meter^2 for the first dose level/treatment cohort and 80 milligram/meter^2 (the standard combination dose) for subsequent dose levels/treatment cohorts over 28-day treatment courses
Overall Number of Participants Analyzed 0 4 5
Mean (Standard Deviation)
Unit of Measure: Months
9.16  (9.83) 4.42  (3.06)
7.Secondary Outcome
Title Area Under the Concentration-time Curve in Plasma of BI 860585 Over the Time Interval From 0 to Infinity (AUC0-∞)
Hide Description AUC0-∞, area under the concentration-time curve in plasma of BI 860585 over the time interval from 0 to infinity after single administration of BI 860585
Time Frame Pharmacokinetic samples were collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 23.917 hours after administration of BI 860585.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PKS): This patient set includes all evaluable patients in the treated set (TS) which provide at least one observation for at least one pharmacokinetic (PK) endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 2 2 3 3 0 5 4 3 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanomol*hour/ Litre [nmol*h/L]
21100
(27.3%)
51100
(65.4%)
70300
(26.4%)
126000
(17.7%)
425000
(28.5%)
680000
(38.9%)
791000
(12.3%)
1030000
(10.5%)
8.Secondary Outcome
Title Area Under the Concentration-time Curve in Plasma of BI 860585 Over the Time Interval From 0 to 24 Hours (AUC0-24)
Hide Description AUC0-24, area under the concentration-time curve in plasma of BI 860585 over the time interval from 0 to 24 hours after single administration of BI 860585
Time Frame Pharmacokinetic samples were collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 23.917 hours after administration of BI 860585.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 3 2 3 3 5 5 4 3 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanomol*hour/ Litre [nmol*h/L]
12900
(20.0%)
23400
(30.7%)
45400
(29.6%)
83200
(24.7%)
236000
(15.6%)
299000
(21.1%)
401000
(21.4%)
470000
(6.09%)
641000
(8.43%)
9.Secondary Outcome
Title Half Life of BI 860585 (t1/2)
Hide Description t ½, half-life of BI 860585 in plasma over a dosing interval after single administration of BI 860585
Time Frame Pharmacokinetic samples were collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 23.917 hours after administration of BI 860585.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 2 2 3 3 0 5 4 3 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Hour (h)
17.1
(14.5%)
21.6
(50.1%)
15.6
(11.8%)
14.2
(27.2%)
19.7
(28.0%)
17.2
(33.7%)
17.4
(11.0%)
16.9
(6.14%)
10.Secondary Outcome
Title Maximum Measured Concentration of BI 860585 (Cmax)
Hide Description Cmax, maximum measured concentration of BI 860585 in plasma over a dosing interval after single administration of BI 860585
Time Frame Pharmacokinetic samples were collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 23.917 hours after administration of BI 860585.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 3 3 3 3 4 6 4 3 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanomole/Litre [nmol/L]
995
(26.3%)
1590
(21.5%)
3330
(4.76%)
6770
(37.6%)
16900
(15.0%)
18800
(16.4%)
28000
(36.0%)
32400
(18.5%)
51500
(10.7%)
11.Secondary Outcome
Title Time to Maximum Concentration of BI 860585 (Tmax)
Hide Description Tmax, Time to maximum concentration of BI 860585 in plasma over a dosing interval after single administration of BI 860585
Time Frame Pharmacokinetic samples were collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 23.917 hours after administration of BI 860585.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 3 3 3 3 4 6 4 3 0 0 0 0 0 0 0 0
Median (Full Range)
Unit of Measure: Hour (h)
3.03
(1.98 to 3.03)
4.00
(2.00 to 8.00)
3.00
(1.07 to 3.17)
2.00
(1.00 to 5.98)
3.00
(1.05 to 3.00)
6.00
(3.00 to 8.02)
3.47
(2.00 to 8.00)
3.00
(2.00 to 6.00)
2.00
(2.00 to 3.20)
12.Secondary Outcome
Title Area Under the Concentration-time Curve of BI 860585 in Plasma Over a Dosing Interval at Steady State (AUCτ,ss)
Hide Description AUCτ,ss, area under the concentration-time curve of BI 860585 in plasma over the dosing interval at steady state after multiple administration of BI 860585 (Day 22) in BI 860585 monotherapy and in combination with exemestane and paclitaxel.
Time Frame Pharmacokinetic samples were collected at pre-dose and at 504.5, 505, 506, 507, 508, 510, 512, 527.917 hours after drug administration.
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Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 2 2 3 3 0 5 5 3 3 3 5 7 2 0 4 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanomol*hour/ Litre [nmol*h/L]
32000
(9.28%)
63100
(86.1%)
103000
(3.91%)
163000
(6.34%)
442000
(21.8%)
840000
(23.9%)
838000
(24.3%)
1350000
(12.3%)
271000
(12.9%)
281000
(31.8%)
676000
(30.7%)
988000
(19.1%)
374000
(4.69%)
630000
(54.8%)
730000
(20.3%)
13.Secondary Outcome
Title Half Life of BI 860585 at Steady State (t1/2,ss)
Hide Description t1/2,ss, half-life of BI 860585 in plasma at steady state after multiple administration of BI 860585 (Day 22) in BI 860585 monotherapy and in combination with exemestane and paclitaxel.
Time Frame Pharmacokinetic samples were collected at pre-dose and at 504.5, 505, 506, 507, 508, 510, 512, 527.917 hours after drug administration.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 2 2 3 3 0 5 5 0 3 3 5 7 0 0 4 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Hour (h)
31.5
(8.73%)
28.9
(47.4%)
33.1
(10.2%)
21.3
(20.0%)
29.8
(7.67%)
27.6
(18.3%)
24.9
(22.2%)
22.9
(13.8%)
24.7
(68.4%)
23.3
(7.82%)
25.3
(25.9%)
24.2
(37.2%)
14.Secondary Outcome
Title Time to Maximum Concentration of BI 860585 at Steady State (Tmax,ss)
Hide Description tmax,ss, Time to maximum concentration of BI 860585 at steady state after multiple administration of BI 860585 (Day 22) in BI 860585 monotherapy and in combination with exemestane and paclitaxel.
Time Frame Pharmacokinetic samples were collected at pre-dose and at 504.5, 505, 506, 507, 508, 510, 512, 527.917 hours after drug administration.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 3 3 3 3 6 5 5 2 3 3 5 7 2 4 4 4
Median (Full Range)
Unit of Measure: Hour (h)
6.00
(1.95 to 6.00)
2.02
(2.02 to 4.00)
2.00
(1.00 to 4.07)
3.00
(2.02 to 3.18)
2.00
(0.983 to 3.03)
3.61
(3.00 to 7.97)
3.10
(2.98 to 4.05)
3.03
(2.08 to 6.00)
5.00
(2.00 to 8.00)
3.98
(2.00 to 4.00)
2.00
(1.00 to 2.97)
3.00
(1.00 to 6.00)
2.02
(1.50 to 4.02)
2.03
(2.00 to 2.05)
4.92
(3.05 to 8.12)
2.50
(1.00 to 3.00)
6.00
(3.98 to 8.00)
15.Secondary Outcome
Title Maximum Measured Concentration of BI 860585 in Plasma at Steady State (Cmax,ss)
Hide Description Cmax,ss, maximum measured concentration at steady state after multiple administration of BI 860585 (Day 22) in BI 860585 monotherapy and in combination with exemestane and paclitaxel.
Time Frame Pharmacokinetic samples were collected at pre-dose and at 504.5, 505, 506, 507, 508, 510, 512, 527.917 hours after drug administration.
Hide Outcome Measure Data
Hide Analysis Population Description
PKS
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclita
Hide Arm/Group Description:
Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 40 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 80 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 120 mg BI 860585
Continuous daily oral dose of 25 mg/day standard fixed dose of exemestane over 28-day treatment courses combination with 160 mg BI 860585
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
Continuous daily oral dose of 160 mg BI 860585 in combination with once weekly iv infusion of 80 mg/m^2 paclitaxel
Overall Number of Participants Analyzed 3 3 3 3 3 6 5 5 2 3 3 5 7 2 4 4 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanomol/ Litre [nmol/L]
1730
(18.5%)
3720
(47%)
6630
(0.832%)
11600
(21.5%)
29700
(28.2%)
33700
(26.6%)
50100
(16.7%)
50500
(27.1%)
75700
(17.5%)
16700
(3.63%)
19600
(31.2%)
43800
(30.5%)
61400
(25.7%)
20500
(13.8%)
20700
(39.6%)
38900
(56.4%)
35400
(40.7%)
Time Frame From first drug administration until 28 days after last drug administration; up to 209 weeks
Adverse Event Reporting Description The treated set (includes all patients who were administered at least one dose of any study medication (BI 860585, exemestane, or paclitaxel)) was used for safety analysis.
 
Arm/Group Title 5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 220 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclitaxel 220 mg BI 860585+80 mg/m^2 Paclitaxel
Hide Arm/Group Description Continuous daily oral dose of 5 milligram/day (starting dose) over 28-day treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 10 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 20 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 40 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 80 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 120 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 160 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 220 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Continuous daily oral dose of 300 milligram/day over 28-days treatment courses of BI 860585 Monotherapy Patients were administered with daily oral dose of 40 mg BI 860585 in combination with 25 mg exemestane standard fixed dose over 28-day treatment courses Patients were administered with daily oral dose of 80 mg BI 860585 in combination with 25 mg exemestane standard fixed dose over 28-day treatment courses Patients were administered with daily oral dose of 120 mg BI 860585 in combination with 25 mg exemestane standard fixed dose over 28-day treatment courses Patients were administered with daily oral dose of 160 mg BI 860585 in combination with 25 mg exemestane standard fixed dose over 28-day treatment courses Patients were administered with daily oral dose of 220 mg BI 860585 in combination with 25 mg exemestane standard fixed dose over 28-day treatment courses Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 60 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses Patients were administered with 80 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses Patients were administered with 120 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses Patients were administered with 160 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses Patients were administered with 220 mg BI 860585 in combination with weekly intravenous infusion of 80 mg/m^2 the standard combination dose of paclitaxel for the first dose level/treatment for subsequent dose levels/treatment cohorts over 28-day treatment courses
All-Cause Mortality
5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 220 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclitaxel 220 mg BI 860585+80 mg/m^2 Paclitaxel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/3 (33.33%)   1/3 (33.33%)   1/3 (33.33%)   0/3 (0.00%)   0/3 (0.00%)   1/7 (14.29%)   1/7 (14.29%)   0/9 (0.00%)   0/3 (0.00%)   0/3 (0.00%)   3/4 (75.00%)   1/7 (14.29%)   0/8 (0.00%)   0/3 (0.00%)   0/3 (0.00%)   0/4 (0.00%)   0/7 (0.00%)   0/7 (0.00%)   0/3 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 220 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclitaxel 220 mg BI 860585+80 mg/m^2 Paclitaxel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/3 (66.67%)   1/3 (33.33%)   2/3 (66.67%)   1/3 (33.33%)   2/3 (66.67%)   4/7 (57.14%)   4/7 (57.14%)   4/9 (44.44%)   2/3 (66.67%)   0/3 (0.00%)   4/4 (100.00%)   3/7 (42.86%)   2/8 (25.00%)   1/3 (33.33%)   2/3 (66.67%)   3/4 (75.00%)   3/7 (42.86%)   4/7 (57.14%)   1/3 (33.33%) 
Blood and lymphatic system disorders                                       
Thrombocytopenia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastrointestinal disorders                                       
Abdominal pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Abdominal pain upper  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Colonic fistula  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Diarrhoea  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Dysphagia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Haemorrhoidal haemorrhage  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Intestinal obstruction  1  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Nausea  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Oesophagitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Vomiting  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
General disorders                                       
Chest pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Condition aggravated  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Fatigue  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
General physical health deterioration  1  0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Oedema peripheral  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Hepatobiliary disorders                                       
Bile duct obstruction  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Hepatic failure  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Infections and infestations                                       
Biliary tract infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Perihepatic abscess  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Peritonitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Pneumonia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Sepsis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Urinary tract infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Viral oesophagitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Injury, poisoning and procedural complications                                       
Anaesthetic complication pulmonary  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Craniocerebral injury  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Overdose  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Investigations                                       
Alanine aminotransferase increased  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Aspartate aminotransferase increased  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Metabolism and nutrition disorders                                       
Decreased appetite  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  0/3 (0.00%) 
Dehydration  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Hypercalcaemia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Hyperglycaemia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Hypokalaemia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Hypomagnesaemia  1  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Hyponatraemia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Musculoskeletal and connective tissue disorders                                       
Back pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Bone pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Flank pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                                       
Cancer pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Malignant neoplasm progression  1  1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  2/4 (50.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Metastases to central nervous system  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Nervous system disorders                                       
Ischaemic stroke  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/3 (33.33%) 
Neurological decompensation  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Neurotoxicity  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Paraparesis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Syncope  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Psychiatric disorders                                       
Suicidal ideation  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Renal and urinary disorders                                       
Acute kidney injury  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Renal failure  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Respiratory, thoracic and mediastinal disorders                                       
Dyspnoea  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Dyspnoea exertional  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Haemoptysis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Pneumonitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Pulmonary embolism  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Pulmonary oedema  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Respiratory failure  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Skin and subcutaneous tissue disorders                                       
Rash  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Vascular disorders                                       
Aorto-duodenal fistula  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Deep vein thrombosis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Shock  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
5 mg BI 860585 10 mg BI 860585 20 mg BI 860585 40 mg BI 860585 80 mg BI 860585 120 mg BI 860585 160 mg BI 860585 220 mg BI 860585 300 mg BI 860585 40 mg BI 860585+25 mg Exemestane 80 mg BI 860585+25 mg Exemestane 120 mg BI 860585+25 mg Exemestane 160 mg BI 860585+25 mg Exemestane 220 mg BI 860585+25 mg Exemestane 80 mg BI 860585+60 mg/m^2 Paclitaxel 80 mg BI 860585+80 mg/m^2 Paclitaxel 120 mg BI 860585+80 mg/m^2 Paclitaxel 160 mg BI 860585+80 mg/m^2 Paclitaxel 220 mg BI 860585+80 mg/m^2 Paclitaxel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   7/7 (100.00%)   7/7 (100.00%)   9/9 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   4/4 (100.00%)   7/7 (100.00%)   8/8 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   4/4 (100.00%)   7/7 (100.00%)   7/7 (100.00%)   3/3 (100.00%) 
Blood and lymphatic system disorders                                       
Anaemia  1  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/7 (14.29%)  0/7 (0.00%)  2/9 (22.22%)  0/3 (0.00%)  1/3 (33.33%)  2/4 (50.00%)  2/7 (28.57%)  2/8 (25.00%)  1/3 (33.33%)  2/3 (66.67%)  3/4 (75.00%)  3/7 (42.86%)  4/7 (57.14%)  0/3 (0.00%) 
Leukopenia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/3 (0.00%) 
Lymphopenia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/3 (33.33%) 
Neutropenia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  2/3 (66.67%)  0/4 (0.00%)  3/7 (42.86%)  1/7 (14.29%)  1/3 (33.33%) 
Thrombocytopenia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Cardiac disorders                                       
Bradycardia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Sinus tachycardia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Tachycardia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Ear and labyrinth disorders                                       
Ear pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Tinnitus  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/3 (0.00%) 
Vertigo  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Eye disorders                                       
Cataract  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Dry eye  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  0/3 (0.00%) 
Lacrimation increased  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Maculopathy  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Vision blurred  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Visual acuity reduced  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Xerophthalmia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Gastrointestinal disorders                                       
Abdominal distension  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Abdominal pain  1  3/3 (100.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/7 (0.00%)  2/7 (28.57%)  1/9 (11.11%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  2/7 (28.57%)  2/8 (25.00%)  0/3 (0.00%)  2/3 (66.67%)  3/4 (75.00%)  4/7 (57.14%)  2/7 (28.57%)  0/3 (0.00%) 
Abdominal pain lower  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Abdominal pain upper  1  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  2/7 (28.57%)  0/3 (0.00%) 
Abnormal faeces  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Anal haemorrhage  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Aphthous ulcer  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Ascites  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Constipation  1  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/7 (14.29%)  2/7 (28.57%)  0/9 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  1/7 (14.29%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  2/7 (28.57%)  0/7 (0.00%)  0/3 (0.00%) 
Diarrhoea  1  1/3 (33.33%)  0/3 (0.00%)  3/3 (100.00%)  0/3 (0.00%)  1/3 (33.33%)  3/7 (42.86%)  3/7 (42.86%)  6/9 (66.67%)  3/3 (100.00%)  1/3 (33.33%)  0/4 (0.00%)  3/7 (42.86%)  6/8 (75.00%)  2/3 (66.67%)  1/3 (33.33%)  3/4 (75.00%)  4/7 (57.14%)  5/7 (71.43%)  3/3 (100.00%) 
Dry mouth  1  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  2/4 (50.00%)  2/7 (28.57%)  1/8 (12.50%)  1/3 (33.33%)  2/3 (66.67%)  1/4 (25.00%)  1/7 (14.29%)  2/7 (28.57%)  0/3 (0.00%) 
Duodenal stenosis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Duodenogastric reflux  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Dyspepsia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/4 (50.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Dysphagia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  0/3 (0.00%) 
Enterocolitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Faecaloma  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Faeces soft  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastritis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastrointestinal disorder  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastrointestinal haemorrhage  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastrooesophageal reflux disease  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/8 (25.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/3 (33.33%) 
Glossitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Glossodynia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Haematemesis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Haemorrhoidal haemorrhage  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  2/9 (22.22%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Haemorrhoids  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Melaena  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Mouth ulceration  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Nausea  1  1/3 (33.33%)  0/3 (0.00%)  2/3 (66.67%)  2/3 (66.67%)  1/3 (33.33%)  3/7 (42.86%)  4/7 (57.14%)  4/9 (44.44%)  2/3 (66.67%)  0/3 (0.00%)  3/4 (75.00%)  4/7 (57.14%)  2/8 (25.00%)  1/3 (33.33%)  2/3 (66.67%)  2/4 (50.00%)  3/7 (42.86%)  2/7 (28.57%)  1/3 (33.33%) 
Odynophagia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Oesophagitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Periodontal disease  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Proctalgia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Proctitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Stomatitis  1  0/3 (0.00%)  2/3 (66.67%)  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  3/7 (42.86%)  2/7 (28.57%)  0/9 (0.00%)  2/3 (66.67%)  0/3 (0.00%)  0/4 (0.00%)  3/7 (42.86%)  5/8 (62.50%)  2/3 (66.67%)  2/3 (66.67%)  1/4 (25.00%)  1/7 (14.29%)  2/7 (28.57%)  1/3 (33.33%) 
Swollen tongue  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Tongue ulceration  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Umbilical hernia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Vomiting  1  3/3 (100.00%)  0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  4/7 (57.14%)  3/7 (42.86%)  4/9 (44.44%)  1/3 (33.33%)  0/3 (0.00%)  3/4 (75.00%)  3/7 (42.86%)  0/8 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/4 (25.00%)  2/7 (28.57%)  1/7 (14.29%)  1/3 (33.33%) 
General disorders                                       
Asthenia  1  2/3 (66.67%)  1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  1/3 (33.33%)  1/4 (25.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/4 (25.00%)  1/7 (14.29%)  1/7 (14.29%)  0/3 (0.00%) 
Chest pain  1  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  1/9 (11.11%)  1/3 (33.33%)  1/3 (33.33%)  1/4 (25.00%)  2/7 (28.57%)  0/8 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Chills  1  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Cyst  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Disease progression  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Facial pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Fatigue  1  1/3 (33.33%)  2/3 (66.67%)  2/3 (66.67%)  1/3 (33.33%)  2/3 (66.67%)  1/7 (14.29%)  2/7 (28.57%)  5/9 (55.56%)  3/3 (100.00%)  2/3 (66.67%)  2/4 (50.00%)  3/7 (42.86%)  4/8 (50.00%)  2/3 (66.67%)  2/3 (66.67%)  3/4 (75.00%)  5/7 (71.43%)  6/7 (85.71%)  1/3 (33.33%) 
Gait disturbance  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
General physical health deterioration  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Generalised oedema  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Hyperpyrexia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Impaired healing  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Influenza like illness  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Localised oedema  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Malaise  1  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Mucosal inflammation  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  1/3 (33.33%) 
Oedema peripheral  1  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  1/9 (11.11%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  3/7 (42.86%)  2/8 (25.00%)  1/3 (33.33%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Pain  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Pyrexia  1  1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  1/7 (14.29%)  2/7 (28.57%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/8 (25.00%)  0/3 (0.00%)  1/3 (33.33%)  2/4 (50.00%)  2/7 (28.57%)  2/7 (28.57%)  0/3 (0.00%) 
Hepatobiliary disorders                                       
Hepatitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Immune system disorders                                       
Hypersensitivity  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Infections and infestations                                       
Body tinea  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Bronchiolitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Bronchitis  1  1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Conjunctivitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Cystitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/3 (33.33%) 
Erysipelas  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Escherichia urinary tract infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Eye infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Folliculitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/3 (33.33%) 
Fungal skin infection  1  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastroenteritis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Gastroenteritis viral  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Herpes zoster  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/3 (33.33%) 
Influenza  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/3 (0.00%) 
Lip infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Lung infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Nail infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Oral fungal infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Paronychia  1  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  2/3 (66.67%)  0/4 (0.00%)  1/7 (14.29%)  1/7 (14.29%)  0/3 (0.00%) 
Pneumonia  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Rash pustular  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Respiratory tract infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/3 (33.33%) 
Rhinitis  1  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/3 (0.00%) 
Sinusitis  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Skin infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  0/7 (0.00%)  0/3 (0.00%) 
Tooth infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/9 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/7 (0.00%)  0/3 (0.00%) 
Upper respiratory tract infection  1  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/9 (11.11%)  0/3 (0.00%)  0/3 (0.00%)  0/4 (0.00%)