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SELECT-1: Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC

Sponsor
AstraZeneca (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT01933932
Collaborator
(none)
510
Enrollment
196
Locations
2
Arms
111.1
Anticipated Duration (Months)
2.6
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy of selumetinib in combination with docetaxel (75mg/m2) vs placebo in combination with docetaxel (75mg/m2) in patients with locally advance or metastatic NSCLCs that harbor mutations of KRAS. This study will also assess the PK, safety, patient reported outcomes (PRO) and tolerability profile of the selumetinib/docetaxel combination, compared to placebo in combination with docetaxel

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

A Phase III, Double-Blind, Randomised, Placebo-Controlled Study to Assess the Efficacy and Safety of Selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate) in Combination with Docetaxel, in Patients receiving second line treatment for KRAS Mutation-Positive Locally Advanced or Metastatic Non Small Cell Lung Cancer (Stage IIIB - IV) (SELECT-1)

Study Design

Study Type:
Interventional
Actual Enrollment :
510 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase III, Double-Blind, Randomised, Placebo-Controlled Study to Assess the Efficacy and Safety of Selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate) in Combination With Docetaxel, in Patients Receiving Second Line Treatment for KRAS Mutation-Positive Locally Advanced or Metastatic Non Small Cell Lung Cancer (Stage IIIB - IV) (SELECT 1)
Actual Study Start Date :
Sep 25, 2013
Actual Primary Completion Date :
Jun 7, 2016
Anticipated Study Completion Date :
Dec 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Selumetinib + Docetaxel

Three 25mg Selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle

Drug: Selumetinib
Three 25 mg selumetinib capsules (Hyd-Sulfate) be administered orally, twice daily, (total dose 75 mg dose bd) on an uninterrupted schedule.
Other Names:
  • AZD6244; ARRY-142886

    • Drug: Docetaxel
    Docetaxel 75 mg/m2 will be administered intravenously on day 1 of each 21 day cycle.

    Drug: Pegylated G-CSF
    All patients will receive pegylated Granulocyte Colony Stimulating Factor (G-CSF) at least 24 hours after administration of every docetaxel dose and not within 14 days prior to the next docetaxel administration.
    Other Names:
  • Pegfilgrastim 6 mg

    		•
    Experimental: Placebo + Docetaxel

    Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.

    Drug: Docetaxel
    Docetaxel 75 mg/m2 will be administered intravenously on day 1 of each 21 day cycle.

    Drug: Placebo
    Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.

    Drug: Pegylated G-CSF
    All patients will receive pegylated Granulocyte Colony Stimulating Factor (G-CSF) at least 24 hours after administration of every docetaxel dose and not within 14 days prior to the next docetaxel administration.
    Other Names:
  • Pegfilgrastim 6 mg

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression-Free Survival (PFS) [Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)]

      Progression free survival is defined as the time from randomisation until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)

    Secondary Outcome Measures

    1. Overall Survival (OS) [Measured at baseline until date of death due to any cause. Estimated final completion : approximately 3.5 years after FSI]

      Overall Survival is defined as the time from the date of randomisation until death due to any cause.

    2. Objective Response Rate (ORR) [Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)]

      ORR is defined as the number (%) of subjects with at least one overall visit response of complete response (CR) or partial response (PR). Per RECIST v1.1 for target lesions and assessed by CT/MRI: CR - disappearance of all target lesions; PR - >=30% decrease in the sum of the longest diameter of target lesion. (Non-target lesion and new lesion results are also taken into account for the overall visit result)

    3. Duration of Response (DoR) [Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)]

      Duration of response is defined as the time from the date of first documented response until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)

    4. Symptom Improvement Rate Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) [Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI)]

      The symptom improvement rate will be defined as the number (%) of patients with two consecutive assessments at least 18 days apart (ie 21 days allowing a visit window of 3 days) which showed a clinically meaningful improvement in symptoms from baseline (defined as a decrease in the ASBI from baseline ≥10). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index.

    5. Time to Symptom Progression Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) [Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI)]

      Time to symptom progression will be defined as the time from randomization until the date of first clinically meaningful symptom deterioration (defined as an increase in the ASBI from baseline ≥10), or death (by any cause). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 130 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Provision of signed, written and dated informed consent prior to any study specific procedures

    • Male or female, aged 18 years or older

    • Histological or cytological confirmation of locally advanced or metastatic NSCLC (IIIB-IV)

    • KRAS mutation positive tumour sample as determined by the designated testing laboratory

    • Failure of 1st line anti-cancer therapy due to radiological documentation of disease progression in advanced disease or subsequent relapse of disease following 1st line therapy

    Exclusion Criteria:

    • Mixed small cell and non-small cell lung cancer histology.

    • Received >1 prior anti-cancer drug regimen for advanced or metastatic NSCLC. Patients who develop disease progression while on switch maintenance therapy (maintenance using an agent not in the first-line regimen) will not be eligible.

    • Receiving or have received systemic anti-cancer therapy within 30 days prior to starting study treatment

    • Other concomitant anti-cancer therapy agents excepts steroids

    • Prior treatment with a Mitogen-Activated protein Kinase (MEK) inhibitor or any docetaxel-containing regimen (prior treatment with paclitaxel is acceptable).

    • Last radiation therapy within 4 weeks prior starting study treatment, or limited field of radiation for palliation within 7 days of the first dose of study treatment

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Aurora Colorado United States 80045
    2 Research Site Pembroke Pines Florida United States 33028
    3 Research Site Atlanta Georgia United States 30318
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    157 Research Site Cluj Napoca Romania 400058
    158 Research Site Kazan Russian Federation 420012
    159 Research Site Moscow Russian Federation 105229
    160 Research Site Moscow Russian Federation 115478
    161 Research Site Saint Petersburg Russian Federation 197342
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    163 Research Site Saint-Petersburg Russian Federation 194291
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    165 Research Site Barcelona Spain 08003
    166 Research Site Barcelona Spain 08035
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    Sponsors and Collaborators

    • AstraZeneca

    Investigators

    • Study Chair: Gabriella Mariani, MD, AstraZeneca UK, MSD
    • Principal Investigator: Pasi Jänne, MD, Dana-Faber Cancer Institute, USA

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT01933932
    Other Study ID Numbers:
    • D1532C00079
    • 2013-001676-38
    First Posted:
    Sep 2, 2013
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by AstraZeneca
    Mitogen-Activated Protein Kinase Kinase inhibitor; Non Small Cell Lung Cancer; metastatic; second line treatment for Non Small Cell Lung Cancer; KRAS mutation
    Additional relevant MeSH terms:
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Docetaxel

    Study Results

    Participant Flow

    Recruitment Details This study started with an assessment visit where a tumour KRAS mutation assessment was performed, eligibility assessments were performed and informed consent obtained. Eligible patients were randomised at the next visit. Patients then received double-blinded study treatment, were seen and assessments performed until objective disease progression.
    Pre-assignment Detail Eligible patients randomised in a ratio of 1:1 to receive selumetinib (AZD6244; ARRY-142886) 75 mg bd in combination with docetaxel 75 mg/m2 or placebo in combination with docetaxel 75 mg/m2. They were stratified based on their WHO performance status and tumour histology. 510 patients enrolled and 510 randomised.
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Period Title: Overall Study
    STARTED 254 256
    COMPLETED 70 78
    NOT COMPLETED 184 178

    Baseline Characteristics

    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel Total
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle. Total of all reporting groups
    Overall Participants 254 256 510
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    61.9
    (8.48)
    60.9
    (8.08)
    61.4
    (8.30)
    Age, Customized (Number) [Number]
    >=65 years
    97
    38.2%
    83
    32.4%
    180
    35.3%
    <65 years
    157
    61.8%
    173
    67.6%
    330
    64.7%
    Sex: Female, Male (Count of Participants)
    Female
    96
    37.8%
    111
    43.4%
    207
    40.6%
    Male
    158
    62.2%
    145
    56.6%
    303
    59.4%
    Race (Number) [Number]
    White
    241
    94.9%
    243
    94.9%
    484
    94.9%
    Black or African American
    5
    2%
    1
    0.4%
    6
    1.2%
    Asian
    1
    0.4%
    4
    1.6%
    5
    1%
    American Indian or Alaska Native
    3
    1.2%
    2
    0.8%
    5
    1%
    Other
    4
    1.6%
    6
    2.3%
    10
    2%
    Ethnic group (Number) [Number]
    Hispanic or Latino
    14
    5.5%
    15
    5.9%
    29
    5.7%
    Not Hispanic or Latino
    240
    94.5%
    241
    94.1%
    481
    94.3%

    Outcome Measures

    1. Primary Outcome
    Title Progression-Free Survival (PFS)
    Description Progression free survival is defined as the time from randomisation until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)
    Time Frame Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS) population comprised of all randomised patients.
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Measure Participants 254 256
    Median (Inter-Quartile Range) [Months]
    3.9
    2.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Selumetinib + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.4355
    Comments
    Method Log Rank
    Comments Analysis stratified by WHO performance status at randomisation.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.93
    Confidence Interval (2-Sided) 95%
    0.77 to 1.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Overall Survival (OS)
    Description Overall Survival is defined as the time from the date of randomisation until death due to any cause.
    Time Frame Measured at baseline until date of death due to any cause. Estimated final completion : approximately 3.5 years after FSI

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS) population comprised of all randomised patients.
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Measure Participants 254 256
    Median (Inter-Quartile Range) [Months]
    8.7
    7.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Selumetinib + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.6431
    Comments
    Method Log Rank
    Comments Analysis stratified by WHO performance status at randomisation.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.05
    Confidence Interval (2-Sided) 95%
    0.85 to 1.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Objective Response Rate (ORR)
    Description ORR is defined as the number (%) of subjects with at least one overall visit response of complete response (CR) or partial response (PR). Per RECIST v1.1 for target lesions and assessed by CT/MRI: CR - disappearance of all target lesions; PR - >=30% decrease in the sum of the longest diameter of target lesion. (Non-target lesion and new lesion results are also taken into account for the overall visit result)
    Time Frame Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS) population comprised of all randomised patients.
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Measure Participants 254 256
    Number [Number of responders]
    51
    35
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Selumetinib + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0515
    Comments
    Method Regression, Logistic
    Comments Analysis stratified by WHO performance status at randomisation
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.61
    Confidence Interval (2-Sided) 95%
    1.00 to 2.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Duration of Response (DoR)
    Description Duration of response is defined as the time from the date of first documented response until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)
    Time Frame Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS) population comprised of all randomised patients.
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Measure Participants 51 35
    Median (95% Confidence Interval) [Days]
    88.0
    136.0
    5. Secondary Outcome
    Title Symptom Improvement Rate Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS)
    Description The symptom improvement rate will be defined as the number (%) of patients with two consecutive assessments at least 18 days apart (ie 21 days allowing a visit window of 3 days) which showed a clinically meaningful improvement in symptoms from baseline (defined as a decrease in the ASBI from baseline ≥10). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index.
    Time Frame Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS) patients who have a baseline ASBI score >= 10
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Measure Participants 205 217
    Number [Number of patients with improvements]
    49
    46
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Selumetinib + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.5007
    Comments
    Method Regression, Logistic
    Comments Analysis stratified by WHO performance status at randomisation
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.17
    Confidence Interval (2-Sided) 95%
    0.74 to 1.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Time to Symptom Progression Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS)
    Description Time to symptom progression will be defined as the time from randomization until the date of first clinically meaningful symptom deterioration (defined as an increase in the ASBI from baseline ≥10), or death (by any cause). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index.
    Time Frame Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS) patients who have a baseline ASBI score <= 90
    Arm/Group Title Selumetinib + Docetaxel Placebo + Docetaxel
    Arm/Group Description Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
    Measure Participants 234 247
    Median (Inter-Quartile Range) [Months]
    1.6
    1.3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Selumetinib + Docetaxel, Placebo + Docetaxel
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.3438
    Comments
    Method Log Rank
    Comments Analysis stratified by WHO performance status at randomisation.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.90
    Confidence Interval (2-Sided) 95%
    0.74 to 1.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame AEs were collected from the time of signature of informed consent to the main study until 30 days (± 7 days) after the last dose of the last study treatment.
    Adverse Event Reporting Description The total number of patients at risk are taken from the number of patients in the safety analysis set. They are patients who received at least one dose of randomised investigational product (selumetinib/placebo). (The numbers in the participant flow module are randomised patients).
    Arm/Group Title Placebo + Docetaxel Selumetinib + Docetaxel
    Arm/Group Description Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle. Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle
    All Cause Mortality
    Placebo + Docetaxel Selumetinib + Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Placebo + Docetaxel Selumetinib + Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 82/254 (32.3%) 124/251 (49.4%)
    Blood and lymphatic system disorders
    Anaemia 4/254 (1.6%) 4 3/251 (1.2%) 3
    Febrile neutropenia 2/254 (0.8%) 2 4/251 (1.6%) 4
    Neutropenia 1/254 (0.4%) 1 5/251 (2%) 5
    Thrombocytopenia 1/254 (0.4%) 1 0/251 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 0/254 (0%) 0 3/251 (1.2%) 3
    Cardiac failure 1/254 (0.4%) 1 2/251 (0.8%) 2
    Cardiac failure congestive 0/254 (0%) 0 1/251 (0.4%) 1
    Cardiovascular insufficiency 1/254 (0.4%) 1 0/251 (0%) 0
    Coronary artery dissection 0/254 (0%) 0 1/251 (0.4%) 1
    Pericardial effusion 2/254 (0.8%) 2 0/251 (0%) 0
    Pericarditis constrictive 0/254 (0%) 0 1/251 (0.4%) 1
    Sinus bradycardia 0/254 (0%) 0 1/251 (0.4%) 1
    Supraventricular tachycardia 0/254 (0%) 0 2/251 (0.8%) 2
    Eye disorders
    Retinal vein thrombosis 0/254 (0%) 0 1/251 (0.4%) 1
    Gastrointestinal disorders
    Abdominal pain 2/254 (0.8%) 2 2/251 (0.8%) 2
    Abdominal pain upper 1/254 (0.4%) 1 0/251 (0%) 0
    Colitis 2/254 (0.8%) 2 1/251 (0.4%) 1
    Constipation 1/254 (0.4%) 1 2/251 (0.8%) 2
    Diarrhoea 3/254 (1.2%) 3 10/251 (4%) 10
    Diverticular perforation 1/254 (0.4%) 1 0/251 (0%) 0
    Duodenal ulcer 1/254 (0.4%) 1 0/251 (0%) 0
    Dysphagia 0/254 (0%) 0 1/251 (0.4%) 1
    Gastric ulcer perforation 0/254 (0%) 0 1/251 (0.4%) 1
    Gastrooesophageal reflux disease 1/254 (0.4%) 1 0/251 (0%) 0
    Haemorrhoids 1/254 (0.4%) 1 0/251 (0%) 0
    Intestinal obstruction 0/254 (0%) 0 1/251 (0.4%) 1
    Lower gastrointestinal haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Proctitis 0/254 (0%) 0 1/251 (0.4%) 1
    Rectal haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Retroperitoneal haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Stomatitis 1/254 (0.4%) 1 0/251 (0%) 0
    Subileus 0/254 (0%) 0 1/251 (0.4%) 1
    Upper gastrointestinal haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Vomiting 1/254 (0.4%) 1 3/251 (1.2%) 3
    General disorders
    Asthenia 2/254 (0.8%) 2 1/251 (0.4%) 1
    Euthanasia 1/254 (0.4%) 1 0/251 (0%) 0
    Fatigue 1/254 (0.4%) 1 1/251 (0.4%) 1
    General physical health deterioration 0/254 (0%) 0 3/251 (1.2%) 3
    Malaise 0/254 (0%) 0 2/251 (0.8%) 2
    Oedema peripheral 1/254 (0.4%) 1 1/251 (0.4%) 1
    Pyrexia 5/254 (2%) 9 7/251 (2.8%) 8
    Immune system disorders
    Anaphylactic reaction 2/254 (0.8%) 2 0/251 (0%) 0
    Anaphylactic shock 1/254 (0.4%) 1 0/251 (0%) 0
    Hypersensitivity 0/254 (0%) 0 1/251 (0.4%) 1
    Infections and infestations
    Anal abscess 2/254 (0.8%) 2 0/251 (0%) 0
    Arthritis infective 0/254 (0%) 0 1/251 (0.4%) 1
    Bronchitis 0/254 (0%) 0 2/251 (0.8%) 2
    Device related infection 2/254 (0.8%) 2 0/251 (0%) 0
    Diverticulitis 1/254 (0.4%) 1 0/251 (0%) 0
    Herpes zoster 0/254 (0%) 0 1/251 (0.4%) 1
    Infected skin ulcer 0/254 (0%) 0 1/251 (0.4%) 1
    Infection 0/254 (0%) 0 1/251 (0.4%) 1
    Infectious pleural effusion 0/254 (0%) 0 1/251 (0.4%) 1
    Infective exacerbation of chronic obstructive airways disease 0/254 (0%) 0 1/251 (0.4%) 2
    Lower respiratory tract infection 5/254 (2%) 5 4/251 (1.6%) 4
    Lung abscess 0/254 (0%) 0 1/251 (0.4%) 1
    Lung infection 2/254 (0.8%) 2 3/251 (1.2%) 3
    Neutropenic sepsis 1/254 (0.4%) 1 0/251 (0%) 0
    Pneumocystis jirovecii pneumonia 1/254 (0.4%) 1 0/251 (0%) 0
    Pneumonia 11/254 (4.3%) 14 17/251 (6.8%) 20
    Pneumonia viral 0/254 (0%) 0 1/251 (0.4%) 1
    Respiratory tract infection 2/254 (0.8%) 3 6/251 (2.4%) 6
    Respiratory tract infection viral 1/254 (0.4%) 1 0/251 (0%) 0
    Sepsis 1/254 (0.4%) 1 7/251 (2.8%) 7
    Staphylococcal infection 1/254 (0.4%) 1 0/251 (0%) 0
    Streptococcal bacteraemia 0/254 (0%) 0 1/251 (0.4%) 1
    Urinary tract infection 1/254 (0.4%) 1 2/251 (0.8%) 2
    Urosepsis 0/254 (0%) 0 1/251 (0.4%) 1
    Injury, poisoning and procedural complications
    Femoral neck fracture 1/254 (0.4%) 1 0/251 (0%) 0
    Hip fracture 1/254 (0.4%) 1 1/251 (0.4%) 1
    Post procedural complication 1/254 (0.4%) 1 1/251 (0.4%) 1
    Radiation oesophagitis 1/254 (0.4%) 1 0/251 (0%) 0
    Toxicity to various agents 0/254 (0%) 0 1/251 (0.4%) 1
    Investigations
    C-reactive protein increased 0/254 (0%) 0 2/251 (0.8%) 3
    Ejection fraction decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Metabolism and nutrition disorders
    Cachexia 1/254 (0.4%) 1 0/251 (0%) 0
    Dehydration 3/254 (1.2%) 3 6/251 (2.4%) 6
    Hyperglycaemia 1/254 (0.4%) 1 0/251 (0%) 0
    Hyponatraemia 0/254 (0%) 0 2/251 (0.8%) 2
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/254 (0.4%) 1 0/251 (0%) 0
    Back pain 3/254 (1.2%) 3 0/251 (0%) 0
    Musculoskeletal chest pain 0/254 (0%) 0 1/251 (0.4%) 1
    Pathological fracture 0/254 (0%) 0 1/251 (0.4%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer 0/254 (0%) 0 1/251 (0.4%) 1
    Metastases to meninges 0/254 (0%) 0 1/251 (0.4%) 1
    Metastases to peritoneum 1/254 (0.4%) 1 0/251 (0%) 0
    Oesophageal adenocarcinoma 1/254 (0.4%) 1 0/251 (0%) 0
    Nervous system disorders
    Cerebral haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Cerebral ischaemia 0/254 (0%) 0 1/251 (0.4%) 1
    Cerebrovascular accident 1/254 (0.4%) 1 0/251 (0%) 0
    Cognitive disorder 1/254 (0.4%) 1 0/251 (0%) 0
    Dropped head syndrome 0/254 (0%) 0 1/251 (0.4%) 1
    Neurological decompensation 0/254 (0%) 0 1/251 (0.4%) 2
    Polyneuropathy 0/254 (0%) 0 1/251 (0.4%) 1
    Somnolence 1/254 (0.4%) 1 0/251 (0%) 0
    Syncope 0/254 (0%) 0 2/251 (0.8%) 3
    Psychiatric disorders
    Confusional state 2/254 (0.8%) 2 0/251 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/254 (0%) 0 2/251 (0.8%) 2
    Neurogenic bladder 1/254 (0.4%) 1 0/251 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/254 (0.4%) 1 2/251 (0.8%) 2
    Chronic obstructive pulmonary disease 0/254 (0%) 0 2/251 (0.8%) 2
    Dyspnoea 4/254 (1.6%) 5 7/251 (2.8%) 7
    Dyspnoea exertional 0/254 (0%) 0 1/251 (0.4%) 1
    Haemoptysis 0/254 (0%) 0 1/251 (0.4%) 1
    Hypoxia 0/254 (0%) 0 1/251 (0.4%) 1
    Interstitial lung disease 1/254 (0.4%) 1 4/251 (1.6%) 4
    Pleural effusion 3/254 (1.2%) 5 1/251 (0.4%) 1
    Pneumonitis 1/254 (0.4%) 1 3/251 (1.2%) 3
    Pneumothorax 1/254 (0.4%) 1 2/251 (0.8%) 2
    Pulmonary embolism 3/254 (1.2%) 3 4/251 (1.6%) 4
    Respiratory failure 1/254 (0.4%) 1 1/251 (0.4%) 1
    Sleep apnoea syndrome 0/254 (0%) 0 1/251 (0.4%) 1
    Vascular disorders
    Deep vein thrombosis 0/254 (0%) 0 2/251 (0.8%) 2
    Hypotension 0/254 (0%) 0 2/251 (0.8%) 2
    Internal haemorrhage 1/254 (0.4%) 1 0/251 (0%) 0
    Superior vena cava syndrome 0/254 (0%) 0 1/251 (0.4%) 1
    Venous thrombosis 0/254 (0%) 0 1/251 (0.4%) 1
    Other (Not Including Serious) Adverse Events
    Placebo + Docetaxel Selumetinib + Docetaxel
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 235/254 (92.5%) 244/251 (97.2%)
    Blood and lymphatic system disorders
    Anaemia 37/254 (14.6%) 40 46/251 (18.3%) 50
    Anaemia of malignant disease 0/254 (0%) 0 1/251 (0.4%) 1
    Febrile bone marrow aplasia 0/254 (0%) 0 1/251 (0.4%) 1
    Leukocytosis 4/254 (1.6%) 4 7/251 (2.8%) 7
    Leukopenia 4/254 (1.6%) 4 5/251 (2%) 7
    Lymphadenitis 1/254 (0.4%) 1 0/251 (0%) 0
    Lymphadenopathy 0/254 (0%) 0 1/251 (0.4%) 1
    Lymphopenia 2/254 (0.8%) 2 0/251 (0%) 0
    Neutropenia 14/254 (5.5%) 15 22/251 (8.8%) 24
    Neutrophilia 1/254 (0.4%) 1 0/251 (0%) 0
    Pancytopenia 1/254 (0.4%) 1 0/251 (0%) 0
    Thrombocytopenia 3/254 (1.2%) 4 1/251 (0.4%) 1
    Cardiac disorders
    Atrial fibrillation 4/254 (1.6%) 4 5/251 (2%) 5
    Bradycardia 0/254 (0%) 0 1/251 (0.4%) 1
    Bundle branch block left 0/254 (0%) 0 1/251 (0.4%) 1
    Cardiac failure 1/254 (0.4%) 1 5/251 (2%) 5
    Cardiac ventricular thrombosis 0/254 (0%) 0 1/251 (0.4%) 1
    Cardiomegaly 1/254 (0.4%) 1 0/251 (0%) 0
    Diastolic dysfunction 0/254 (0%) 0 1/251 (0.4%) 1
    Left ventricular dysfunction 0/254 (0%) 0 1/251 (0.4%) 1
    Mitral valve incompetence 0/254 (0%) 0 1/251 (0.4%) 1
    Palpitations 0/254 (0%) 0 1/251 (0.4%) 1
    Pericardial effusion 3/254 (1.2%) 3 0/251 (0%) 0
    Sinus tachycardia 3/254 (1.2%) 4 0/251 (0%) 0
    Tachycardia 7/254 (2.8%) 8 4/251 (1.6%) 4
    Ear and labyrinth disorders
    Cerumen impaction 1/254 (0.4%) 1 0/251 (0%) 0
    Deafness 0/254 (0%) 0 1/251 (0.4%) 1
    Ear pain 2/254 (0.8%) 2 1/251 (0.4%) 1
    Hypoacusis 2/254 (0.8%) 2 0/251 (0%) 0
    Tinnitus 1/254 (0.4%) 1 2/251 (0.8%) 2
    Vertigo 6/254 (2.4%) 6 8/251 (3.2%) 8
    Endocrine disorders
    Goitre 1/254 (0.4%) 1 0/251 (0%) 0
    Hyperthyroidism 1/254 (0.4%) 1 0/251 (0%) 0
    Oestrogen deficiency 1/254 (0.4%) 1 0/251 (0%) 0
    Eye disorders
    Cataract 0/254 (0%) 0 1/251 (0.4%) 1
    Chorioretinopathy 0/254 (0%) 0 1/251 (0.4%) 1
    Conjunctival irritation 0/254 (0%) 0 1/251 (0.4%) 1
    Conjunctivitis allergic 0/254 (0%) 0 1/251 (0.4%) 1
    Diplopia 2/254 (0.8%) 2 1/251 (0.4%) 1
    Dry eye 1/254 (0.4%) 1 4/251 (1.6%) 4
    Eye discharge 0/254 (0%) 0 1/251 (0.4%) 1
    Eye irritation 1/254 (0.4%) 1 3/251 (1.2%) 3
    Eye pain 2/254 (0.8%) 2 0/251 (0%) 0
    Eyelid oedema 0/254 (0%) 0 10/251 (4%) 10
    Eyelid skin dryness 0/254 (0%) 0 1/251 (0.4%) 1
    Hypermetropia 1/254 (0.4%) 1 0/251 (0%) 0
    Keratitis 0/254 (0%) 0 1/251 (0.4%) 1
    Lacrimation increased 13/254 (5.1%) 13 16/251 (6.4%) 16
    Macular oedema 0/254 (0%) 0 2/251 (0.8%) 2
    Ocular discomfort 1/254 (0.4%) 1 0/251 (0%) 0
    Ocular hyperaemia 0/254 (0%) 0 2/251 (0.8%) 2
    Ocular icterus 0/254 (0%) 0 1/251 (0.4%) 1
    Optic nerve compression 0/254 (0%) 0 1/251 (0.4%) 1
    Periorbital oedema 0/254 (0%) 0 11/251 (4.4%) 11
    Photopsia 1/254 (0.4%) 1 0/251 (0%) 0
    Presbyopia 1/254 (0.4%) 1 0/251 (0%) 0
    Retinal vascular disorder 1/254 (0.4%) 1 0/251 (0%) 0
    Retinal vein thrombosis 0/254 (0%) 0 1/251 (0.4%) 1
    Retinopathy 0/254 (0%) 0 1/251 (0.4%) 1
    Ulcerative keratitis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Vision blurred 4/254 (1.6%) 4 8/251 (3.2%) 8
    Visual acuity reduced 3/254 (1.2%) 3 3/251 (1.2%) 3
    Visual impairment 1/254 (0.4%) 1 3/251 (1.2%) 3
    Gastrointestinal disorders
    Abdominal discomfort 1/254 (0.4%) 1 3/251 (1.2%) 3
    Abdominal distension 3/254 (1.2%) 3 3/251 (1.2%) 3
    Abdominal pain 19/254 (7.5%) 25 23/251 (9.2%) 25
    Abdominal pain lower 0/254 (0%) 0 2/251 (0.8%) 2
    Abdominal pain upper 11/254 (4.3%) 12 12/251 (4.8%) 13
    Anal fissure 0/254 (0%) 0 2/251 (0.8%) 2
    Anal haemorrhage 0/254 (0%) 0 3/251 (1.2%) 3
    Anal inflammation 0/254 (0%) 0 1/251 (0.4%) 1
    Aphthous ulcer 2/254 (0.8%) 2 1/251 (0.4%) 1
    Ascites 1/254 (0.4%) 1 1/251 (0.4%) 1
    Colitis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Constipation 47/254 (18.5%) 57 39/251 (15.5%) 43
    Defaecation urgency 0/254 (0%) 0 1/251 (0.4%) 1
    Dental caries 1/254 (0.4%) 1 0/251 (0%) 0
    Diarrhoea 86/254 (33.9%) 126 149/251 (59.4%) 234
    Diverticulum 0/254 (0%) 0 1/251 (0.4%) 1
    Dry mouth 1/254 (0.4%) 1 15/251 (6%) 16
    Duodenitis 1/254 (0.4%) 1 0/251 (0%) 0
    Dyspepsia 12/254 (4.7%) 14 14/251 (5.6%) 14
    Dysphagia 5/254 (2%) 6 8/251 (3.2%) 8
    Enteritis 0/254 (0%) 0 1/251 (0.4%) 1
    Eructation 1/254 (0.4%) 1 0/251 (0%) 0
    Flatulence 2/254 (0.8%) 2 2/251 (0.8%) 2
    Gastritis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Gastrointestinal inflammation 1/254 (0.4%) 1 0/251 (0%) 0
    Gastrointestinal motility disorder 0/254 (0%) 0 1/251 (0.4%) 1
    Gastrointestinal pain 2/254 (0.8%) 2 2/251 (0.8%) 2
    Gastrooesophageal reflux disease 2/254 (0.8%) 3 8/251 (3.2%) 8
    Glossodynia 0/254 (0%) 0 2/251 (0.8%) 2
    Haematochezia 2/254 (0.8%) 3 1/251 (0.4%) 1
    Haemorrhoids 1/254 (0.4%) 1 3/251 (1.2%) 3
    Hiatus hernia 1/254 (0.4%) 1 0/251 (0%) 0
    Hyperchlorhydria 0/254 (0%) 0 1/251 (0.4%) 1
    Hypoaesthesia oral 1/254 (0.4%) 1 1/251 (0.4%) 1
    Lip blister 0/254 (0%) 0 1/251 (0.4%) 1
    Lip dry 0/254 (0%) 0 1/251 (0.4%) 1
    Lower gastrointestinal haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Melaena 1/254 (0.4%) 1 1/251 (0.4%) 1
    Mouth ulceration 2/254 (0.8%) 2 4/251 (1.6%) 4
    Nausea 62/254 (24.4%) 81 94/251 (37.5%) 117
    Odynophagia 2/254 (0.8%) 2 0/251 (0%) 0
    Oesophageal pain 0/254 (0%) 0 1/251 (0.4%) 1
    Oesophagitis 2/254 (0.8%) 2 1/251 (0.4%) 1
    Oral discomfort 0/254 (0%) 0 1/251 (0.4%) 1
    Oral dysaesthesia 1/254 (0.4%) 1 0/251 (0%) 0
    Oral pain 2/254 (0.8%) 2 1/251 (0.4%) 1
    Paraesthesia oral 1/254 (0.4%) 1 1/251 (0.4%) 1
    Rectal haemorrhage 2/254 (0.8%) 2 3/251 (1.2%) 3
    Rectal tenesmus 1/254 (0.4%) 1 0/251 (0%) 0
    Stomatitis 33/254 (13%) 38 65/251 (25.9%) 82
    Swollen tongue 0/254 (0%) 0 1/251 (0.4%) 1
    Tooth loss 0/254 (0%) 0 1/251 (0.4%) 1
    Toothache 3/254 (1.2%) 3 1/251 (0.4%) 1
    Upper gastrointestinal haemorrhage 1/254 (0.4%) 1 0/251 (0%) 0
    Vomiting 31/254 (12.2%) 40 64/251 (25.5%) 87
    General disorders
    Asthenia 46/254 (18.1%) 54 66/251 (26.3%) 76
    Catheter site inflammation 0/254 (0%) 0 1/251 (0.4%) 1
    Chest pain 0/254 (0%) 0 3/251 (1.2%) 3
    Chills 3/254 (1.2%) 3 6/251 (2.4%) 6
    Device failure 0/254 (0%) 0 1/251 (0.4%) 1
    Extravasation 1/254 (0.4%) 1 1/251 (0.4%) 1
    Face oedema 4/254 (1.6%) 4 22/251 (8.8%) 26
    Fatigue 78/254 (30.7%) 96 69/251 (27.5%) 97
    Feeling cold 1/254 (0.4%) 2 1/251 (0.4%) 1
    Feeling hot 1/254 (0.4%) 1 0/251 (0%) 0
    Gait disturbance 0/254 (0%) 0 1/251 (0.4%) 1
    General physical health deterioration 3/254 (1.2%) 4 0/251 (0%) 0
    Generalised oedema 0/254 (0%) 0 8/251 (3.2%) 8
    Hyperthermia 1/254 (0.4%) 1 0/251 (0%) 0
    Inflammation 1/254 (0.4%) 1 0/251 (0%) 0
    Inflammatory pain 0/254 (0%) 0 1/251 (0.4%) 1
    Influenza like illness 9/254 (3.5%) 10 2/251 (0.8%) 2
    Infusion site extravasation 1/254 (0.4%) 1 0/251 (0%) 0
    Injection site pruritus 1/254 (0.4%) 1 0/251 (0%) 0
    Injection site reaction 1/254 (0.4%) 1 0/251 (0%) 0
    Local swelling 1/254 (0.4%) 1 1/251 (0.4%) 1
    Localised oedema 2/254 (0.8%) 2 1/251 (0.4%) 1
    Malaise 4/254 (1.6%) 4 1/251 (0.4%) 1
    Mucosal inflammation 2/254 (0.8%) 3 9/251 (3.6%) 10
    Mucosal toxicity 0/254 (0%) 0 1/251 (0.4%) 1
    Nodule 1/254 (0.4%) 1 0/251 (0%) 0
    Non-cardiac chest pain 5/254 (2%) 6 7/251 (2.8%) 7
    Oedema 7/254 (2.8%) 7 13/251 (5.2%) 14
    Oedema peripheral 38/254 (15%) 40 75/251 (29.9%) 98
    Pain 4/254 (1.6%) 4 9/251 (3.6%) 10
    Performance status decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Peripheral swelling 3/254 (1.2%) 3 6/251 (2.4%) 9
    Pyrexia 31/254 (12.2%) 42 47/251 (18.7%) 62
    Soft tissue inflammation 0/254 (0%) 0 1/251 (0.4%) 1
    Temperature intolerance 0/254 (0%) 0 1/251 (0.4%) 1
    Tenderness 2/254 (0.8%) 2 1/251 (0.4%) 1
    Xerosis 2/254 (0.8%) 2 2/251 (0.8%) 2
    Hepatobiliary disorders
    Bile duct obstruction 1/254 (0.4%) 1 0/251 (0%) 0
    Cholecystitis 0/254 (0%) 0 1/251 (0.4%) 1
    Cholestasis 0/254 (0%) 0 3/251 (1.2%) 3
    Hepatic function abnormal 1/254 (0.4%) 1 0/251 (0%) 0
    Hepatic pain 0/254 (0%) 0 1/251 (0.4%) 1
    Hepatocellular injury 0/254 (0%) 0 2/251 (0.8%) 2
    Hydrocholecystis 1/254 (0.4%) 1 0/251 (0%) 0
    Hyperbilirubinaemia 0/254 (0%) 0 1/251 (0.4%) 2
    Jaundice 0/254 (0%) 0 1/251 (0.4%) 1
    Immune system disorders
    Contrast media allergy 1/254 (0.4%) 1 1/251 (0.4%) 1
    Drug hypersensitivity 1/254 (0.4%) 1 1/251 (0.4%) 1
    Iodine allergy 0/254 (0%) 0 1/251 (0.4%) 1
    Infections and infestations
    Abdominal infection 1/254 (0.4%) 1 0/251 (0%) 0
    Anal abscess 0/254 (0%) 0 1/251 (0.4%) 1
    Anal fungal infection 0/254 (0%) 0 1/251 (0.4%) 1
    Anal infection 0/254 (0%) 0 1/251 (0.4%) 1
    Angular cheilitis 0/254 (0%) 0 1/251 (0.4%) 1
    Aspergillus infection 0/254 (0%) 0 1/251 (0.4%) 1
    Bacterial infection 1/254 (0.4%) 1 0/251 (0%) 0
    Bacteriuria 0/254 (0%) 0 1/251 (0.4%) 1
    Breast abscess 1/254 (0.4%) 1 0/251 (0%) 0
    Bronchitis 7/254 (2.8%) 8 8/251 (3.2%) 9
    Bullous impetigo 0/254 (0%) 0 1/251 (0.4%) 1
    Candida infection 0/254 (0%) 0 3/251 (1.2%) 3
    Cellulitis 0/254 (0%) 0 3/251 (1.2%) 3
    Clostridial infection 1/254 (0.4%) 1 0/251 (0%) 0
    Clostridium difficile infection 1/254 (0.4%) 1 0/251 (0%) 0
    Conjunctivitis 5/254 (2%) 7 12/251 (4.8%) 13
    Cystitis 6/254 (2.4%) 6 3/251 (1.2%) 4
    Device related infection 0/254 (0%) 0 1/251 (0.4%) 1
    Diverticulitis 2/254 (0.8%) 2 0/251 (0%) 0
    Ear infection 2/254 (0.8%) 2 1/251 (0.4%) 1
    Erysipelas 0/254 (0%) 0 2/251 (0.8%) 2
    Eye infection 2/254 (0.8%) 2 0/251 (0%) 0
    Folliculitis 1/254 (0.4%) 1 4/251 (1.6%) 6
    Fungal infection 4/254 (1.6%) 4 1/251 (0.4%) 1
    Fungal oesophagitis 1/254 (0.4%) 1 0/251 (0%) 0
    Fungal skin infection 0/254 (0%) 0 1/251 (0.4%) 1
    Gastroenteritis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Genital infection 1/254 (0.4%) 1 0/251 (0%) 0
    Gingivitis 0/254 (0%) 0 1/251 (0.4%) 1
    Helicobacter infection 1/254 (0.4%) 1 0/251 (0%) 0
    Herpes simplex 1/254 (0.4%) 1 0/251 (0%) 0
    Herpes virus infection 1/254 (0.4%) 1 2/251 (0.8%) 2
    Herpes zoster 1/254 (0.4%) 1 1/251 (0.4%) 1
    Hordeolum 1/254 (0.4%) 1 0/251 (0%) 0
    Impetigo 0/254 (0%) 0 1/251 (0.4%) 1
    Infected dermal cyst 0/254 (0%) 0 1/251 (0.4%) 1
    Influenza 3/254 (1.2%) 3 3/251 (1.2%) 3
    Injection site infection 0/254 (0%) 0 1/251 (0.4%) 1
    Localised infection 0/254 (0%) 0 1/251 (0.4%) 1
    Lower respiratory tract infection 7/254 (2.8%) 7 1/251 (0.4%) 1
    Lung infection 5/254 (2%) 6 5/251 (2%) 5
    Mucosal infection 1/254 (0.4%) 1 0/251 (0%) 0
    Nasopharyngitis 7/254 (2.8%) 8 10/251 (4%) 12
    Onychomycosis 0/254 (0%) 0 1/251 (0.4%) 1
    Oral candidiasis 5/254 (2%) 5 5/251 (2%) 5
    Oral fungal infection 2/254 (0.8%) 2 4/251 (1.6%) 4
    Oral herpes 2/254 (0.8%) 2 3/251 (1.2%) 4
    Oral infection 1/254 (0.4%) 1 1/251 (0.4%) 1
    Oropharyngeal candidiasis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Oropharyngitis fungal 0/254 (0%) 0 1/251 (0.4%) 1
    Otitis externa 0/254 (0%) 0 1/251 (0.4%) 1
    Otitis media 2/254 (0.8%) 2 0/251 (0%) 0
    Paronychia 6/254 (2.4%) 6 14/251 (5.6%) 14
    Pharyngitis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Pharyngotonsillitis 1/254 (0.4%) 1 0/251 (0%) 0
    Pneumocystis jirovecii pneumonia 0/254 (0%) 0 1/251 (0.4%) 1
    Pneumonia 4/254 (1.6%) 4 8/251 (3.2%) 11
    Pneumonia bacterial 0/254 (0%) 0 1/251 (0.4%) 1
    Rash pustular 3/254 (1.2%) 3 6/251 (2.4%) 8
    Respiratory tract infection 8/254 (3.1%) 10 9/251 (3.6%) 10
    Respiratory tract infection viral 0/254 (0%) 0 2/251 (0.8%) 2
    Rhinitis 1/254 (0.4%) 1 2/251 (0.8%) 2
    Sepsis 1/254 (0.4%) 1 1/251 (0.4%) 1
    Sialoadenitis 0/254 (0%) 0 1/251 (0.4%) 1
    Sinusitis 5/254 (2%) 5 6/251 (2.4%) 7
    Skin candida 1/254 (0.4%) 1 0/251 (0%) 0
    Skin infection 4/254 (1.6%) 4 1/251 (0.4%) 1
    Staphylococcal infection 0/254 (0%) 0 1/251 (0.4%) 2
    Tonsillitis 0/254 (0%) 0 2/251 (0.8%) 2
    Tonsillitis bacterial 0/254 (0%) 0 1/251 (0.4%) 1
    Tooth abscess 2/254 (0.8%) 2 1/251 (0.4%) 2
    Upper respiratory tract infection 8/254 (3.1%) 11 1/251 (0.4%) 1
    Urinary tract infection 6/254 (2.4%) 11 16/251 (6.4%) 21
    Urinary tract infection bacterial 1/254 (0.4%) 1 1/251 (0.4%) 1
    Urosepsis 0/254 (0%) 0 1/251 (0.4%) 1
    Vaginal infection 0/254 (0%) 0 1/251 (0.4%) 1
    Viral infection 1/254 (0.4%) 1 1/251 (0.4%) 1
    Viral pharyngitis 0/254 (0%) 0 1/251 (0.4%) 1
    Vulvovaginal candidiasis 2/254 (0.8%) 2 0/251 (0%) 0
    Vulvovaginal mycotic infection 1/254 (0.4%) 1 1/251 (0.4%) 1
    Injury, poisoning and procedural complications
    Epiphyseal fracture 0/254 (0%) 0 1/251 (0.4%) 1
    Excoriation 1/254 (0.4%) 1 0/251 (0%) 0
    Fall 2/254 (0.8%) 2 4/251 (1.6%) 4
    Foot fracture 1/254 (0.4%) 1 0/251 (0%) 0
    Hip fracture 0/254 (0%) 0 1/251 (0.4%) 1
    Infusion related reaction 4/254 (1.6%) 4 0/251 (0%) 0
    Lumbar vertebral fracture 1/254 (0.4%) 1 0/251 (0%) 0
    Post procedural complication 1/254 (0.4%) 1 0/251 (0%) 0
    Procedural pain 2/254 (0.8%) 3 1/251 (0.4%) 1
    Procedural site reaction 1/254 (0.4%) 1 0/251 (0%) 0
    Pulmonary radiation injury 1/254 (0.4%) 1 0/251 (0%) 0
    Radiation pneumonitis 1/254 (0.4%) 1 0/251 (0%) 0
    Rib fracture 1/254 (0.4%) 1 0/251 (0%) 0
    Skin abrasion 0/254 (0%) 0 1/251 (0.4%) 1
    Skin injury 0/254 (0%) 0 1/251 (0.4%) 1
    Skin wound 0/254 (0%) 0 1/251 (0.4%) 1
    Ulna fracture 0/254 (0%) 0 1/251 (0.4%) 1
    Venous injury 1/254 (0.4%) 1 0/251 (0%) 0
    Wound 0/254 (0%) 0 1/251 (0.4%) 1
    Investigations
    Alanine aminotransferase increased 5/254 (2%) 5 6/251 (2.4%) 8
    Aspartate aminotransferase increased 3/254 (1.2%) 3 6/251 (2.4%) 7
    Blood albumin decreased 1/254 (0.4%) 1 2/251 (0.8%) 2
    Blood alkaline phosphatase increased 4/254 (1.6%) 4 1/251 (0.4%) 1
    Blood bilirubin increased 1/254 (0.4%) 1 2/251 (0.8%) 2
    Blood calcium increased 0/254 (0%) 0 1/251 (0.4%) 1
    Blood creatine phosphokinase MB increased 0/254 (0%) 0 1/251 (0.4%) 6
    Blood creatine phosphokinase increased 0/254 (0%) 0 6/251 (2.4%) 9
    Blood creatinine increased 2/254 (0.8%) 2 6/251 (2.4%) 10
    Blood glucose increased 0/254 (0%) 0 1/251 (0.4%) 1
    Blood lactate dehydrogenase increased 1/254 (0.4%) 1 1/251 (0.4%) 1
    Blood potassium decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Blood pressure decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Blood pressure increased 0/254 (0%) 0 1/251 (0.4%) 1
    Blood pressure systolic decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Blood thyroid stimulating hormone decreased 1/254 (0.4%) 1 0/251 (0%) 0
    Blood urea increased 1/254 (0.4%) 1 0/251 (0%) 0
    Body temperature increased 1/254 (0.4%) 1 0/251 (0%) 0
    Breath sounds abnormal 2/254 (0.8%) 2 0/251 (0%) 0
    C-reactive protein increased 2/254 (0.8%) 2 7/251 (2.8%) 9
    Carcinoembryonic antigen increased 1/254 (0.4%) 1 0/251 (0%) 0
    Eastern Cooperative Oncology Group performance status worsened 0/254 (0%) 0 1/251 (0.4%) 1
    Ejection fraction decreased 1/254 (0.4%) 1 5/251 (2%) 5
    Gamma-glutamyltransferase increased 6/254 (2.4%) 6 6/251 (2.4%) 6
    Inspiratory capacity decreased 0/254 (0%) 0 1/251 (0.4%) 1
    International normalised ratio increased 0/254 (0%) 0 1/251 (0.4%) 1
    Neutrophil count decreased 1/254 (0.4%) 2 1/251 (0.4%) 1
    Neutrophil count increased 0/254 (0%) 0 1/251 (0.4%) 1
    Oxygen saturation decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Platelet count decreased 1/254 (0.4%) 1 3/251 (1.2%) 4
    Platelet count increased 0/254 (0%) 0 1/251 (0.4%) 1
    Protein total decreased 1/254 (0.4%) 1 1/251 (0.4%) 1
    Transaminases increased 1/254 (0.4%) 1 0/251 (0%) 0
    Troponin I increased 0/254 (0%) 0 1/251 (0.4%) 2
    Troponin increased 1/254 (0.4%) 1 0/251 (0%) 0
    Urine output decreased 0/254 (0%) 0 1/251 (0.4%) 1
    Weight decreased 11/254 (4.3%) 12 21/251 (8.4%) 21
    Weight increased 2/254 (0.8%) 2 7/251 (2.8%) 7
    White blood cell count increased 0/254 (0%) 0 2/251 (0.8%) 2
    Metabolism and nutrition disorders
    Abnormal loss of weight 2/254 (0.8%) 2 1/251 (0.4%) 1
    Cachexia 1/254 (0.4%) 1 0/251 (0%) 0
    Decreased appetite 60/254 (23.6%) 76 56/251 (22.3%) 68
    Dehydration 6/254 (2.4%) 6 11/251 (4.4%) 12
    Electrolyte imbalance 0/254 (0%) 0 1/251 (0.4%) 1
    Fluid retention 0/254 (0%) 0 2/251 (0.8%) 2
    Hypercalcaemia 2/254 (0.8%) 2 1/251 (0.4%) 1
    Hyperglycaemia 3/254 (1.2%) 3 2/251 (0.8%) 4
    Hyperkalaemia 1/254 (0.4%) 1 1/251 (0.4%) 1
    Hyperphosphataemia 1/254 (0.4%) 1 0/251 (0%) 0
    Hyperproteinaemia 0/254 (0%) 0 1/251 (0.4%) 1
    Hypoalbuminaemia 4/254 (1.6%) 4 9/251 (3.6%) 11
    Hypocalcaemia 1/254 (0.4%) 1 5/251 (2%) 5
    Hypoglycaemia 0/254 (0%) 0 1/251 (0.4%) 2
    Hypokalaemia 3/254 (1.2%) 3 11/251 (4.4%) 11
    Hypomagnesaemia 6/254 (2.4%) 10 3/251 (1.2%) 3
    Hyponatraemia 2/254 (0.8%) 2 11/251 (4.4%) 11
    Hypophosphataemia 2/254 (0.8%) 2 2/251 (0.8%) 4
    Hypoproteinaemia 3/254 (1.2%) 3 0/251 (0%) 0
    Iron deficiency 1/254 (0.4%) 1 1/251 (0.4%) 1
    Magnesium deficiency 0/254 (0%) 0 1/251 (0.4%) 1
    Malnutrition 1/254 (0.4%) 1 0/251 (0%) 0
    Vitamin D deficiency 0/254 (0%) 0 1/251 (0.4%) 1
    Musculoskeletal and connective tissue disorders
    Amyotrophy 0/254 (0%) 0 1/251 (0.4%) 1
    Arthralgia 19/254 (7.5%) 23 23/251 (9.2%) 24
    Axillary mass 0/254 (0%) 0 1/251 (0.4%) 1
    Back pain 28/254 (11%) 32 19/251 (7.6%) 22
    Bone pain 20/254 (7.9%) 21 18/251 (7.2%) 23
    Coccydynia 1/254 (0.4%) 1 0/251 (0%) 0
    Fistula discharge 0/254 (0%) 0 1/251 (0.4%) 1
    Flank pain 2/254 (0.8%) 2 1/251 (0.4%) 1
    Fracture pain 0/254 (0%) 0 1/251 (0.4%) 1
    Groin pain 1/254 (0.4%) 1 1/251 (0.4%) 1
    Hypercreatinaemia 0/254 (0%) 0 1/251 (0.4%) 1
    Intervertebral disc protrusion 1/254 (0.4%) 1 0/251 (0%) 0
    Joint stiffness 0/254 (0%) 0 1/251 (0.4%) 1
    Joint swelling 0/254 (0%) 0 2/251 (0.8%) 2
    Limb discomfort 1/254 (0.4%) 1 0/251 (0%) 0
    Muscle atrophy 0/254 (0%) 0 2/251 (0.8%) 2
    Muscle spasms 7/254 (2.8%) 8 3/251 (1.2%) 3
    Muscle twitching 1/254 (0.4%) 1 0/251 (0%) 0
    Muscular weakness 7/254 (2.8%) 8 10/251 (4%) 10
    Musculoskeletal chest pain 12/254 (4.7%) 12 11/251 (4.4%) 11
    Musculoskeletal discomfort 1/254 (0.4%) 1 0/251 (0%) 0
    Musculoskeletal pain 13/254 (5.1%) 15 5/251 (2%) 5
    Myalgia 37/254 (14.6%) 49 23/251 (9.2%) 24
    Myopathy 1/254 (0.4%) 1 0/251 (0%) 0
    Myositis 0/254 (0%) 0 1/251 (0.4%) 1
    Neck pain 5/254 (2%) 6 4/251 (1.6%) 4
    Osteoarthritis 1/254 (0.4%) 1 0/251 (0%) 0
    Osteonecrosis 0/254 (0%) 0 1/251 (0.4%) 1
    Osteopenia 2/254 (0.8%) 2 0/251 (0%) 0
    Pain in extremity 15/254 (5.9%) 20 9/251 (3.6%) 11
    Pain in jaw 0/254 (0%) 0 1/251 (0.4%) 1
    Rheumatic disorder 1/254 (0.4%) 1 0/251 (0%) 0
    Rheumatoid arthritis 1/254 (0.4%) 1 0/251 (0%) 0
    Spinal pain 1/254 (0.4%) 1 1/251 (0.4%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 1/254 (0.4%) 1 1/251 (0.4%) 1
    Endometrial sarcoma 0/254 (0%) 0 1/251 (0.4%) 1
    Tumour associated fever 2/254 (0.8%) 2 0/251 (0%) 0
    Tumour necrosis 0/254 (0%) 0 1/251 (0.4%) 1
    Tumour pain 2/254 (0.8%) 2 1/251 (0.4%) 1
    Nervous system disorders
    Ageusia 2/254 (0.8%) 3 1/251 (0.4%) 1
    Amnesia 1/254 (0.4%) 1 2/251 (0.8%) 2
    Aphasia 2/254 (0.8%) 2 0/251 (0%) 0
    Aphonia 0/254 (0%) 0 1/251 (0.4%) 1
    Apraxia 1/254 (0.4%) 1 0/251 (0%) 0
    Balance disorder 2/254 (0.8%) 2 0/251 (0%) 0
    Burning sensation 1/254 (0.4%) 1 1/251 (0.4%) 1
    Cerebellar syndrome 0/254 (0%) 0 1/251 (0.4%) 1
    Cerebral ischaemia 0/254 (0%) 0 1/251 (0.4%) 1
    Coordination abnormal 1/254 (0.4%) 1 0/251 (0%) 0
    Disturbance in attention 0/254 (0%) 0 3/251 (1.2%) 3
    Dizziness 10/254 (3.9%) 11 15/251 (6%) 15
    Dizziness postural 1/254 (0.4%) 1 0/251 (0%) 0
    Dysarthria 0/254 (0%) 0 1/251 (0.4%) 1
    Dysgeusia 23/254 (9.1%) 25 17/251 (6.8%) 17
    Extrapyramidal disorder 1/254 (0.4%) 1 0/251 (0%) 0
    Facial neuralgia 0/254 (0%) 0 1/251 (0.4%) 1
    Headache 26/254 (10.2%) 30 9/251 (3.6%) 10
    Hyperaesthesia 1/254 (0.4%) 1 0/251 (0%) 0
    Hypersomnia 1/254 (0.4%) 1 0/251 (0%) 0
    Hypoaesthesia 3/254 (1.2%) 5 1/251 (0.4%) 1
    Lethargy 5/254 (2%) 5 1/251 (0.4%) 1
    Memory impairment 1/254 (0.4%) 1 1/251 (0.4%) 1
    Monoparesis 1/254 (0.4%) 1 0/251 (0%) 0
    Neuralgia 5/254 (2%) 5 0/251 (0%) 0
    Neuropathy peripheral 10/254 (3.9%) 10 12/251 (4.8%) 12
    Neurotoxicity 1/254 (0.4%) 1 2/251 (0.8%) 2
    Paraesthesia 17/254 (6.7%) 23 18/251 (7.2%) 18
    Paresis 0/254 (0%) 0 1/251 (0.4%) 1
    Parosmia 1/254 (0.4%) 1 1/251 (0.4%) 1
    Partial seizures 1/254 (0.4%) 1 0/251 (0%) 0
    Peripheral motor neuropathy 2/254 (0.8%) 2 0/251 (0%) 0
    Peripheral sensorimotor neuropathy 1/254 (0.4%) 1 0/251 (0%) 0
    Peripheral sensory neuropathy 7/254 (2.8%) 9 9/251 (3.6%) 9
    Polyneuropathy 5/254 (2%) 5 4/251 (1.6%) 4
    Psychomotor hyperactivity 0/254 (0%) 0 1/251 (0.4%) 1
    Sciatica 2/254 (0.8%) 2 0/251 (0%) 0
    Seizure 2/254 (0.8%) 2 1/251 (0.4%) 1
    Somnolence 1/254 (0.4%) 1 2/251 (0.8%) 2
    Syncope 0/254 (0%) 0 6/251 (2.4%) 7
    VIIth nerve paralysis 1/254 (0.4%) 1 0/251 (0%) 0
    Vocal cord paralysis 0/254 (0%) 0 1/251 (0.4%) 1
    Psychiatric disorders
    Abnormal dreams 1/254 (0.4%) 1 0/251 (0%) 0
    Agitation 1/254 (0.4%) 1 1/251 (0.4%) 1
    Anxiety 5/254 (2%) 5 10/251 (4%) 10
    Confusional state 3/254 (1.2%) 3 5/251 (2%) 6
    Delusion 0/254 (0%) 0 1/251 (0.4%) 1
    Depression 4/254 (1.6%) 4 4/251 (1.6%) 4
    Disorientation 1/254 (0.4%) 1 2/251 (0.8%) 2
    Hallucination 0/254 (0%) 0 1/251 (0.4%) 1
    Illusion 1/254 (0.4%) 1 0/251 (0%) 0
    Insomnia 10/254 (3.9%) 11 9/251 (3.6%) 9
    Irritability 1/254 (0.4%) 1 0/251 (0%) 0
    Panic attack 0/254 (0%) 0 1/251 (0.4%) 1
    Sleep disorder 1/254 (0.4%) 1 2/251 (0.8%) 2
    Stress 0/254 (0%) 0 1/251 (0.4%) 1
    Tension 1/254 (0.4%) 1 0/251 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/254 (0%) 0 1/251 (0.4%) 1
    Chromaturia 0/254 (0%) 0 1/251 (0.4%) 1
    Chronic kidney disease 0/254 (0%) 0 1/251 (0.4%) 2
    Costovertebral angle tenderness 1/254 (0.4%) 1 0/251 (0%) 0
    Cystitis noninfective 0/254 (0%) 0 1/251 (0.4%) 1
    Dysuria 1/254 (0.4%) 1 4/251 (1.6%) 4
    Haematuria 2/254 (0.8%) 2 0/251 (0%) 0
    Haemoglobinuria 0/254 (0%) 0 1/251 (0.4%) 1
    Micturition urgency 1/254 (0.4%) 1 0/251 (0%) 0
    Pollakiuria 0/254 (0%) 0 1/251 (0.4%) 1
    Proteinuria 1/254 (0.4%) 1 2/251 (0.8%) 3
    Renal failure 0/254 (0%) 0 1/251 (0.4%) 1
    Strangury 1/254 (0.4%) 1 0/251 (0%) 0
    Urinary incontinence 2/254 (0.8%) 2 1/251 (0.4%) 1
    Urinary retention 1/254 (0.4%) 1 3/251 (1.2%) 3
    Urinary tract pain 0/254 (0%) 0 1/251 (0.4%) 1
    Urine odour abnormal 0/254 (0%) 0 1/251 (0.4%) 1
    Reproductive system and breast disorders
    Acquired hydrocele 0/254 (0%) 0 1/251 (0.4%) 1
    Breast discomfort 0/254 (0%) 0 1/251 (0.4%) 1
    Dysmenorrhoea 0/254 (0%) 0 1/251 (0.4%) 1
    Erectile dysfunction 1/254 (0.4%) 1 0/251 (0%) 0
    Pelvic pain 1/254 (0.4%) 1 2/251 (0.8%) 2
    Polymenorrhoea 1/254 (0.4%) 1 0/251 (0%) 0
    Prostatism 0/254 (0%) 0 1/251 (0.4%) 1
    Pruritus genital 1/254 (0.4%) 1 0/251 (0%) 0
    Vaginal discharge 1/254 (0.4%) 1 0/251 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/254 (0%) 0 2/251 (0.8%) 2
    Asthma 1/254 (0.4%) 1 0/251 (0%) 0
    Atelectasis 2/254 (0.8%) 2 0/251 (0%) 0
    Bronchial secretion retention 1/254 (0.4%) 1 0/251 (0%) 0
    Bronchospasm 1/254 (0.4%) 1 1/251 (0.4%) 2
    Chronic obstructive pulmonary disease 1/254 (0.4%) 1 1/251 (0.4%) 1
    Cough 35/254 (13.8%) 44 37/251 (14.7%) 39
    Dry throat 1/254 (0.4%) 1 0/251 (0%) 0
    Dysphonia 7/254 (2.8%) 7 11/251 (4.4%) 12
    Dyspnoea 40/254 (15.7%) 41 55/251 (21.9%) 57
    Dyspnoea at rest 0/254 (0%) 0 1/251 (0.4%) 1
    Dyspnoea exertional 7/254 (2.8%) 7 6/251 (2.4%) 6
    Epistaxis 8/254 (3.1%) 10 13/251 (5.2%) 13
    Haemoptysis 8/254 (3.1%) 14 8/251 (3.2%) 12
    Hiccups 2/254 (0.8%) 2 3/251 (1.2%) 3
    Hypoxia 3/254 (1.2%) 3 2/251 (0.8%) 2
    Increased bronchial secretion 1/254 (0.4%) 1 0/251 (0%) 0
    Interstitial lung disease 1/254 (0.4%) 1 0/251 (0%) 0
    Laryngeal inflammation 1/254 (0.4%) 1 0/251 (0%) 0
    Lung consolidation 0/254 (0%) 0 1/251 (0.4%) 1
    Lung infiltration 0/254 (0%) 0 1/251 (0.4%) 1
    Nasal congestion 4/254 (1.6%) 4 2/251 (0.8%) 2
    Nasal discomfort 1/254 (0.4%) 1 1/251 (0.4%) 1
    Oropharyngeal pain 8/254 (3.1%) 8 7/251 (2.8%) 8
    Pleural disorder 0/254 (0%) 0 1/251 (0.4%) 1
    Pleural effusion 9/254 (3.5%) 12 11/251 (4.4%) 14
    Pleuritic pain 2/254 (0.8%) 2 0/251 (0%) 0
    Pneumonitis 2/254 (0.8%) 2 0/251 (0%) 0
    Pneumothorax 0/254 (0%) 0 1/251 (0.4%) 1
    Productive cough 10/254 (3.9%) 11 8/251 (3.2%) 8
    Pulmonary congestion 0/254 (0%) 0 1/251 (0.4%) 1
    Pulmonary embolism 1/254 (0.4%) 1 3/251 (1.2%) 3
    Pulmonary haemorrhage 0/254 (0%) 0 2/251 (0.8%) 2
    Pulmonary oedema 0/254 (0%) 0 1/251 (0.4%) 1
    Pulmonary pain 1/254 (0.4%) 1 0/251 (0%) 0
    Rales 1/254 (0.4%) 1 1/251 (0.4%) 1
    Respiratory distress 0/254 (0%) 0 1/251 (0.4%) 1
    Respiratory failure 2/254 (0.8%) 2 2/251 (0.8%) 2
    Rhinitis allergic 0/254 (0%) 0 1/251 (0.4%) 1
    Rhinorrhoea 6/254 (2.4%) 7 5/251 (2%) 5
    Rhonchi 0/254 (0%) 0 1/251 (0.4%) 1
    Sinus congestion 0/254 (0%) 0 1/251 (0.4%) 1
    Sleep apnoea syndrome 1/254 (0.4%) 1 0/251 (0%) 0
    Throat irritation 1/254 (0.4%) 1 0/251 (0%) 0
    Upper respiratory tract inflammation 1/254 (0.4%) 1 0/251 (0%) 0
    Upper-airway cough syndrome 1/254 (0.4%) 1 1/251 (0.4%) 1
    Wheezing 2/254 (0.8%) 2 1/251 (0.4%) 1
    Skin and subcutaneous tissue disorders
    Acne 2/254 (0.8%) 2 7/251 (2.8%) 7
    Alopecia 64/254 (25.2%) 65 49/251 (19.5%) 49
    Blister 0/254 (0%) 0 2/251 (0.8%) 2
    Dermatitis 0/254 (0%) 0 2/251 (0.8%) 2
    Dermatitis acneiform 2/254 (0.8%) 2 30/251 (12%) 34
    Dermatitis bullous 1/254 (0.4%) 1 1/251 (0.4%) 1
    Dermatitis diaper 0/254 (0%) 0 1/251 (0.4%) 1
    Dry skin 14/254 (5.5%) 19 30/251 (12%) 31
    Eczema 0/254 (0%) 0 2/251 (0.8%) 3
    Erythema 8/254 (3.1%) 8 7/251 (2.8%) 7
    Erythema multiforme 0/254 (0%) 0 4/251 (1.6%) 4
    Exfoliative rash 0/254 (0%) 0 1/251 (0.4%) 1
    Hand dermatitis 0/254 (0%) 0 1/251 (0.4%) 1
    Hyperhidrosis 4/254 (1.6%) 4 2/251 (0.8%) 2
    Hyperkeratosis 2/254 (0.8%) 2 1/251 (0.4%) 1
    Hypertrichosis 0/254 (0%) 0 1/251 (0.4%) 1
    Ingrowing nail 1/254 (0.4%) 1 0/251 (0%) 0
    Nail bed disorder 0/254 (0%) 0 1/251 (0.4%) 1
    Nail bed inflammation 0/254 (0%) 0 1/251 (0.4%) 1
    Nail discolouration 5/254 (2%) 5 8/251 (3.2%) 8
    Nail disorder 2/254 (0.8%) 2 1/251 (0.4%) 1
    Nail ridging 1/254 (0.4%) 1 1/251 (0.4%) 1
    Nail toxicity 0/254 (0%) 0 2/251 (0.8%) 2
    Night sweats 2/254 (0.8%) 3 0/251 (0%) 0
    Onychalgia 0/254 (0%) 0 1/251 (0.4%) 1
    Onychoclasis 3/254 (1.2%) 3 4/251 (1.6%) 4
    Onycholysis 7/254 (2.8%) 7 12/251 (4.8%) 12
    Onychomadesis 0/254 (0%) 0 3/251 (1.2%) 3
    Pain of skin 1/254 (0.4%) 1 1/251 (0.4%) 1
    Palmar-plantar erythrodysaesthesia syndrome 2/254 (0.8%) 2 7/251 (2.8%) 7
    Petechiae 1/254 (0.4%) 1 0/251 (0%) 0
    Photosensitivity reaction 0/254 (0%) 0 1/251 (0.4%) 1
    Pigmentation disorder 2/254 (0.8%) 2 0/251 (0%) 0
    Pruritus 12/254 (4.7%) 12 16/251 (6.4%) 21
    Pruritus generalised 0/254 (0%) 0 2/251 (0.8%) 3
    Psoriasis 2/254 (0.8%) 2 1/251 (0.4%) 1
    Rash 28/254 (11%) 29 85/251 (33.9%) 114
    Rash erythematous 2/254 (0.8%) 2 7/251 (2.8%) 10
    Rash generalised 0/254 (0%) 0 4/251 (1.6%) 4
    Rash macular 2/254 (0.8%) 2 7/251 (2.8%) 10
    Rash maculo-papular 0/254 (0%) 0 8/251 (3.2%) 9
    Rash papular 1/254 (0.4%) 1 2/251 (0.8%) 2
    Rash pruritic 0/254 (0%) 0 2/251 (0.8%) 2
    Scar pain 1/254 (0.4%) 1 0/251 (0%) 0
    Skin discolouration 0/254 (0%) 0 2/251 (0.8%) 2
    Skin exfoliation 3/254 (1.2%) 4 2/251 (0.8%) 2
    Skin fissures 0/254 (0%) 0 5/251 (2%) 5
    Skin hyperpigmentation 0/254 (0%) 0 1/251 (0.4%) 1
    Skin hypopigmentation 0/254 (0%) 0 1/251 (0.4%) 1
    Skin irritation 0/254 (0%) 0 1/251 (0.4%) 1
    Skin plaque 0/254 (0%) 0 1/251 (0.4%) 1
    Skin toxicity 0/254 (0%) 0 2/251 (0.8%) 3
    Skin ulcer 1/254 (0.4%) 1 1/251 (0.4%) 1
    Solar dermatitis 0/254 (0%) 0 1/251 (0.4%) 1
    Swelling face 0/254 (0%) 0 3/251 (1.2%) 3
    Telangiectasia 0/254 (0%) 0 1/251 (0.4%) 1
    Urticaria 0/254 (0%) 0 2/251 (0.8%) 2
    Vascular disorders
    Deep vein thrombosis 2/254 (0.8%) 2 2/251 (0.8%) 2
    Embolism 1/254 (0.4%) 1 0/251 (0%) 0
    Flushing 2/254 (0.8%) 2 3/251 (1.2%) 3
    Haematoma 4/254 (1.6%) 4 2/251 (0.8%) 2
    Haemorrhage 0/254 (0%) 0 1/251 (0.4%) 1
    Hot flush 5/254 (2%) 5 0/251 (0%) 0
    Hypertension 3/254 (1.2%) 5 4/251 (1.6%) 5
    Hypotension 8/254 (3.1%) 8 13/251 (5.2%) 16
    Inferior vena cava syndrome 1/254 (0.4%) 1 0/251 (0%) 0
    Jugular vein thrombosis 1/254 (0.4%) 1 0/251 (0%) 0
    Lymphoedema 0/254 (0%) 0 1/251 (0.4%) 1
    Orthostatic hypotension 1/254 (0.4%) 1 2/251 (0.8%) 2
    Peripheral coldness 1/254 (0.4%) 1 1/251 (0.4%) 1
    Phlebitis 1/254 (0.4%) 1 0/251 (0%) 0
    Thrombophlebitis superficial 1/254 (0.4%) 1 0/251 (0%) 0
    Thrombosis 1/254 (0.4%) 1 0/251 (0%) 0
    Varicose vein 0/254 (0%) 0 1/251 (0.4%) 1
    Vena cava thrombosis 0/254 (0%) 0 1/251 (0.4%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr Gabriella Mariani
    Organization AstraZeneca Research and Development
    Phone +44 (0)1763 263801
    Email ClinicalTrialTransparency@astrazeneca.com
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT01933932
    Other Study ID Numbers:
    • D1532C00079
    • 2013-001676-38
    First Posted:
    Sep 2, 2013
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022