Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, International Study of durvalumab as Sequential Therapy in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy (PACIFIC)

    Summary
    EudraCT number
    		 2014-000336-42
    Trial protocol
    		 SK   IT   DE   HU   GB   ES   NL   BE   PL   GR  
    Global end of trial date
    24 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Oct 2023
    First version publication date
    18 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D4191C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02125461
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, SE 151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of durvalumab treatment compared with placebo in terms of overall survival (OS) and progression-free survival (PFS).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation / Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 Patients must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 42 days prior to randomization in the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 May 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Spain: 61
    Country: Number of subjects enrolled
    Australia: 42
    Country: Number of subjects enrolled
    Turkey: 36
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    United States: 170
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    Japan: 112
    Country: Number of subjects enrolled
    Korea, Republic of: 46
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Viet Nam: 3
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Peru: 3
    Worldwide total number of subjects
    713
    EEA total number of subjects
    226
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    391
    From 65 to 84 years
    320
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were randomized between 09 May 2014 and 22 Apr 2016 in 235 study centers across 26 countries. Data cut-off (DCO) date for analysis of PFS and PFS rates at 12 and 18 months: 13 Feb 2017; DCO date for analysis of OS and all other secondary endpoints: 22 Mar 2018; DCO date for study completion: 11 Jan 2021.

    Pre-assignment
    Screening details
    		 Eligible patients with locally advanced, unresectable Stage III non-small cell lung cancer were randomized in a 2:1 ratio to receive either durvalumab (MEDI4736) 10 milligrams (mg) / kilogram (kg) every 2 weeks (Q2W) or placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Durvalumab (MEDI4736)
    Arm description
    		 Patients in the durvalumab (MEDI4736) monotherapy group were to receive durvalumab 10 mg/kg Q2W via intravenous infusion for up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    Other name
    MEDI4736
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received durvalumab 10 mg/kg via intravenous infusion Q2W.

    Arm title
    		 Placebo
    Arm description
    		 Patients in the placebo group were to receive matching placebo for intravenous infusion Q2W for up to 12 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received placebo matching durvalumab via intravenous infusion Q2W.

    Number of subjects in period 1
    		Durvalumab (MEDI4736) Placebo
    Started
    476
    237
    Full analysis set (FAS)
    476
    237
    Received treatment
    473
    236
    Safety analysis set
    475
    234
    Completed 12 months of treatment
    232
    82
    Completed
    178
    68
    Not completed
    298
    169
         Adverse event, serious fatal
    260
    149
         Consent withdrawn by subject
    30
    16
         Missing Termination Reason
    -
    1
         Lost to follow-up
    8
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Durvalumab (MEDI4736)
    Reporting group description
    		 Patients in the durvalumab (MEDI4736) monotherapy group were to receive durvalumab 10 mg/kg Q2W via intravenous infusion for up to 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in the placebo group were to receive matching placebo for intravenous infusion Q2W for up to 12 months.

    Reporting group values
    		 Durvalumab (MEDI4736) Placebo Total
    Number of subjects
    		 476 237 713
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 215 105 320
        From 65-84 years
    		 261 130 391
        85 years and over
    		 0 2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.0 ± 8.66 62.6 ± 9.64 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 142 71 213
        Male
    		 334 166 500
    Smoking History
    Units: Subjects
        Non-smoker
    		 43 21 64
        Ex-smoker
    		 354 178 532
        Current smoker
    		 79 38 117
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 337 157 494
        Black or African American
    		 12 2 14
        Asian
    		 120 72 192
        Native Hawaiian or Pacific Islander
    		 1 1 2
        American Indian or Alaska Native
    		 4 5 9
        Other
    		 1 0 1
        Missing
    		 1 0 1

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Durvalumab (MEDI4736)
    Reporting group description
    		 Patients in the durvalumab (MEDI4736) monotherapy group were to receive durvalumab 10 mg/kg Q2W via intravenous infusion for up to 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in the placebo group were to receive matching placebo for intravenous infusion Q2W for up to 12 months.

    Primary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival
    End point description
    OS was defined as the time from the date of randomization until death due to any cause. OS was calculated using the Kaplan-Meier technique. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Primary
    End point timeframe
    From baseline until death due to any cause. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476 [1]
    237 [2]
    Units: Months
        median (confidence interval 95%)
    99999 (34.7 to 99999)
    28.7 (22.9 to 99999)
    Notes
    [1] - 99999 denotes that the value was not calculable (not reached)
    [2] - 99999 denotes that the value was not calculable (not reached)
    Statistical analysis title
    		 Durvalumab vs Placebo
    Statistical analysis description
    Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00251
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.87

    Primary: Progression Free Survival based on Blinded Independent Central Review (BICR) according to response evaluation criteria in solid tumors (RECIST 1.1)

    		 Close Top of page
    End point title
    		 Progression Free Survival based on Blinded Independent Central Review (BICR) according to response evaluation criteria in solid tumors (RECIST 1.1)
    End point description
    PFS was defined as the time from randomization until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression). Progression was defined using RECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. PFS was calculated using the Kaplan-Meier technique. The full analysis set (FAS) included all randomized patients, analyzed on an intent-to-treat (ITT) basis.
    End point type
    Primary
    End point timeframe
    Tumor scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed until 13 Feb 2017 DCO; up to a maximum of approximately 3 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Months
        median (confidence interval 95%)
    16.8 (13.0 to 18.1)
    5.6 (4.6 to 7.8)
    Statistical analysis title
    		 Durvalumab versus (vs) Placebo
    Statistical analysis description
    Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Comparison groups
    Placebo v Durvalumab (MEDI4736)
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.65

    Secondary: Proportion of patients alive and progression free at 12 months from (APF12) based on BICR assessments according to RECIST 1.1

    		 Close Top of page
    End point title
    		 Proportion of patients alive and progression free at 12 months from (APF12) based on BICR assessments according to RECIST 1.1
    End point description
    APF12 was defined as the percentage of patients who were alive and progression free per RECIST 1.1 at 12 months after randomization per Kaplan-Meier estimate of PFS at 12 months. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~ 12 weeks thereafter until confirmed disease progression. Assessed until 13 Feb 2017 DCO; up to a maximum of approximately 3 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Percentage of patients
        number (confidence interval 95%)
    55.9 (51.0 to 60.4)
    35.3 (29.0 to 41.7)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) based on BICR assesments according to RECIST 1.1

    		 Close Top of page
    End point title
    		 Objective Response Rate (ORR) based on BICR assesments according to RECIST 1.1
    End point description
    ORR was defined as the percentage of patients with at least one visit response of Complete Response (CR) or Partial Response (PR) per RECIST 1.1 for target lesions: CR: Disappearance of all target lesions; PR: >=30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~ 12 weeks thereafter until confirmed disease progression. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    443
    213
    Units: Percentage of patients
        number (confidence interval 95%)
    30.0 (25.79 to 34.53)
    17.8 (12.95 to 23.65)
    Statistical analysis title
    		 Durvalumab vs Placebo
    Statistical analysis description
    Analysis performed using Fisher's exact test with mid p-value modification by subtracting half of the probability of the observed table from Fisher's p-value.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Duration of Response (DoR) based on BICR assessments according to RECIST 1.1

    		 Close Top of page
    End point title
    		 Duration of Response (DoR) based on BICR assessments according to RECIST 1.1
    End point description
    DoR was defined as the time from date for first documented response of CR or PR until the first documented response of progression per RECIST 1.1 or death in the absence of progression. DoR was calculated using the Kaplan-Meier technique. The FAS included all randomized patients, analyzed on an ITT basis. Only patients with an objective response were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~ 12 weeks thereafter until confirmed disease progression. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    133 [3]
    38
    Units: Months
        median (confidence interval 95%)
    99999 (27.4 to 99999)
    18.4 (6.7 to 24.5)
    Notes
    [3] - 99999 denotes that the value was not calculable (not reached)
    No statistical analyses for this end point

    Secondary: Time to death or distant metastasis (TTDM) based on BICR assessments according to RECIST 1.1

    		 Close Top of page
    End point title
    		 Time to death or distant metastasis (TTDM) based on BICR assessments according to RECIST 1.1
    End point description
    TTDM was defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis was defined as any new lesion that was outside of the radiation field according to RECIST 1.1 or proven by biopsy. TTDM was calculated using the Kaplan-Meier technique. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~ 12 weeks thereafter until confirmed disease progression. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Months
        median (confidence interval 95%)
    28.3 (24.0 to 34.9)
    16.2 (12.5 to 21.1)
    Statistical analysis title
    		 Durvalumab vs Placebo
    Statistical analysis description
    Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.68

    Secondary: Proportion of patients alive and progression free at 18 months from (APF18) based on BICR assessments according to RECIST 1.1

    		 Close Top of page
    End point title
    		 Proportion of patients alive and progression free at 18 months from (APF18) based on BICR assessments according to RECIST 1.1
    End point description
    APF18 was defined as the percentage of patients who were alive and progression free per RECIST 1.1 at 18 months after randomization per the Kaplan-Meier estimate of PFS at 18 months. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~ 12 weeks thereafter until confirmed disease progression. Assessed until 13 Feb 2017 DCO; up to a maximum of approximately 3 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Percentage of patients
        number (confidence interval 95%)
    44.2 (37.7 to 50.5)
    27.0 (19.9 to 34.5)
    No statistical analyses for this end point

    Secondary: Percentage of Patients Alive at 24 Months (OS24)

    		 Close Top of page
    End point title
    		 Percentage of Patients Alive at 24 Months (OS24)
    End point description
    OS24 was defined as the percentage of patients who were alive at 24 months after randomization per the Kaplan-Meier estimate of OS at 24 months. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    From baseline until death due to any cause. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Percentage of patients
        number (confidence interval 95%)
    66.3 (61.7 to 70.4)
    55.6 (48.9 to 61.8)
    Statistical analysis title
    		 Durvalumab vs Placebo
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [4]
    Method
    		 z-test
    Confidence interval
    Notes
    [4] - P-value based on z-test where z-test statistic is the ratio of the log-transformed ratio of the cumulative hazards in the 2 treatment arms divided by square root of the variance. Variance was estimated using the delta method and Greenwood's formula.

    Secondary: Time to second progression or death (PFS2)

    		 Close Top of page
    End point title
    		 Time to second progression or death (PFS2)
    End point description
    PFS2 was defined as the time from randomization to the time of the second progression or death. The date of second progression was recorded by the investigator and defined according to local standard clinical practice, and could have involved any of the following: objective radiological, symptomatic progression, or death. RECIST assessments were not collected for assessment of PFS2. PFS2 was calculated using the Kaplan-Meier technique. The FAS included all randomized patients, analyzed on an ITT basis.
    End point type
    Secondary
    End point timeframe
    Following confirmed progression, patients were assessed every ~12 weeks until second disease progression. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Months
        median (confidence interval 95%)
    28.3 (25.1 to 34.7)
    17.1 (14.5 to 20.7)
    Statistical analysis title
    		 Durvalumab vs Placebo
    Statistical analysis description
    Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.73

    Secondary: Time to Deterioration of Global Health Status / Health-Related Quality of Life (HRQoL), Assessed Using European Organization for Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30)

    		 Close Top of page
    End point title
    		 Time to Deterioration of Global Health Status / Health-Related Quality of Life (HRQoL), Assessed Using European Organization for Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30)
    End point description
    Global health status/HRQoL was assessed using the EORTC QLQ-C30 global QoL scale which includes 2 items from the QLQ-C30: “How would you rate your overall health during the past week?" (Item 29) and “How would you rate your overall QoL during the past week?" (Item 30). Scores from 0 to 100 were derived for each item with higher scores indicating a better health status. Time to deterioration for global health status/HRQoL was defined as time from randomization until the date of first clinically meaningful deterioration (a decrease in global health status/HRQoL from baseline of ≥10) or death (by any cause) in the absence of a clinically meaningful deterioration. Time to deterioration was calculated using the Kaplan-Meier technique. The FAS included all randomized patients, analyzed on an ITT basis. Only patients with baseline scores ≥ 10 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At baseline, every 4 weeks for first 8 weeks, then every ~8 weeks until 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476
    237
    Units: Months
        median (confidence interval 95%)
    7.4 (5.5 to 9.3)
    5.7 (4.2 to 10.5)
    Statistical analysis title
    		 Durvalumab vs Placebo
    Statistical analysis description
    The hazard ratio and confidence interval (CI) were estimated from a stratified Cox proportional hazards model with the Breslow method to control for ties, the stratification factors age at randomization (<65 vs ≥65), sex (male vs female) and smoking history (smoker vs non-smoker) in the strata statement, and the CI calculated using a profile likelihood approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.664 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.18
    Notes
    [5] - Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.

    Secondary: Time to Deterioration of Primary Patient-Reported Outcome (PRO) Symptoms, Assessed Using European Organization for Research and Treatment of Cancer QoL lung cancer module (EORTC QLQ-LC13)

    		 Close Top of page
    End point title
    		 Time to Deterioration of Primary Patient-Reported Outcome (PRO) Symptoms, Assessed Using European Organization for Research and Treatment of Cancer QoL lung cancer module (EORTC QLQ-LC13)
    End point description
    The EORTC QLQ-LC13 is a lung cancer specific module from the EORTC comprising 13 questions to assess lung cancer symptoms, treatment related side-effects and pain medication. Scores from 0 to 100 were derived for each symptom item with higher scores representing greater symptom severity. Time to symptom deterioration was defined as time from randomization until date of first clinically meaningful symptom deterioration (an increase in the score from baseline of ≥10) or death (by any cause) in the absence of a clinically meaningful symptom deterioration. Results are presented for time to deterioration in the following PRO endpoints identified as primary for EORTC QLQ-LC13: dyspnea, cough, hemoptysis and chest pain. Time to deterioration was calculated using the Kaplan-Meier technique. The FAS included all randomized patients, analyzed on an ITT basis. Only patients with baseline scores ≤ 90 were included in the analysis. 'n' denotes number of patients analyzed for each category.
    End point type
    Secondary
    End point timeframe
    At baseline, every 4 weeks for first 8 weeks, then every ~8 weeks until 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed until 22 Mar 2018 DCO; up to a maximum of approximately 4 years.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    476 [6]
    237 [7]
    Units: Months
    median (confidence interval 95%)
        Dyspnea (n=467, 230)
    2.8 (1.9 to 3.7)
    3.7 (2.3 to 4.1)
        Cough (n=442, 216)
    5.6 (4.5 to 7.3)
    5.6 (3.7 to 6.0)
        Hemoptysis (n=472, 232)
    99999 (99999 to 99999)
    29.6 (21.2 to 99999)
        Chest pain (n=463, 229)
    11.1 (7.4 to 18.6)
    8.3 (5.6 to 13.8)
    Notes
    [6] - 99999 denotes that the value was not calculable (not reached)
    [7] - 99999 denotes that the value was not calculable (not reached)
    Statistical analysis title
    		 Dyspnea: Durvalumab vs Placebo
    Statistical analysis description
    The hazard ratio and CI were estimated from a stratified Cox proportional hazards model with the Breslow method to control for ties, the stratification factors age at randomization (<65 vs ≥65), sex (male vs female) and smoking history (smoker vs non-smoker) in the strata statement, and the CI calculated using a profile likelihood approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.522 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.29
    Notes
    [8] - Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Statistical analysis title
    		 Chest Pain: Durvalumab vs Placebo
    Statistical analysis description
    The hazard ratio and CI were estimated from a stratified Cox proportional hazards model with the Breslow method to control for ties, the stratification factors age at randomization (<65 vs ≥65), sex (male vs female) and smoking history (smoker vs non-smoker) in the strata statement, and the CI calculated using a profile likelihood approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.626 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.19
    Notes
    [9] - Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Statistical analysis title
    		 Hemoptysis: Durvalumab vs Placebo
    Statistical analysis description
    Treatment comparison for hemoptysis. The hazard ratio and CI were estimated from a stratified Cox proportional hazards model with the Breslow method to control for ties, the stratification factors age at randomization (<65 vs ≥65), sex (male vs female) and smoking history (smoker vs non-smoker) in the strata statement, and the CI calculated using a profile likelihood approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048 [10]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1
    Notes
    [10] - Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.
    Statistical analysis title
    		 Cough: Durvalumab vs Placebo
    Statistical analysis description
    The hazard ratio and CI were estimated from a stratified Cox proportional hazards model with the Breslow method to control for ties, the stratification factors age at randomization (<65 vs ≥65), sex (male vs female) and smoking history (smoker vs non-smoker) in the strata statement, and the CI calculated using a profile likelihood approach.
    Comparison groups
    Durvalumab (MEDI4736) v Placebo
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.12
    Notes
    [11] - Analysis performed using a stratified log rank test adjusting for age at randomization (<65 vs ≥65), sex (male vs female), and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach.

    Secondary: Number of Patients with Anti-Drug Antibody (ADA) Response to Durvalumab

    		 Close Top of page
    End point title
    		 Number of Patients with Anti-Drug Antibody (ADA) Response to Durvalumab
    End point description
    ADA positive post-baseline only was also referred to as treatment-induced ADA positive. Treatment-boosted ADA was defined as baseline positive ADA titer that was boosted by ≥4-fold following drug administration. Persistently positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Confirmed ADA positive samples were subsequently tested in a neutralizing antibody assay. The ADA evaluable population included patients who had non-missing baseline ADA and at least 1 non-missing post-baseline ADA results.
    End point type
    Secondary
    End point timeframe
    Samples were collected pre-dose on Day 1 (Week 0), Week 8, Week 24 and Week 48. Analysis performed at 22 Mar 2018 DCO.
    End point values
    		 Durvalumab (MEDI4736) Placebo
    Number of subjects analysed
    416
    204
    Units: Patients
        ADA positive at any visit
    19
    10
        ADA positive post-baseline only
    8
    5
        Treatment-boosted ADA positive
    0
    0
        ADA positive at baseline and post-baseline
    2
    2
        ADA positive at baseline only
    9
    3
        ADA persistently positive
    5
    5
        ADA transient positive
    5
    2
        Neutralizing antibodies positive at any visit
    3
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum concentrations

    		 Close Top of page
    End point title
    		 Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum concentrations [12]
    End point description
    To evaluate PK, blood samples were collected pre-dose and post-dose and trough and peak serum concentrations of durvalumab, respectively, were determined. Pre-dose samples were taken within 60 minutes before infusion and post-dose samples were taken within 10 minutes after the end of infusion. The PK analysis set included all patients who received at least 1 dose of durvalumab per the protocol, for whom any post-dose data were available, and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses. 'n' denotes number of patients analyzed for each category.
    End point type
    Secondary
    End point timeframe
    Samples were collected pre-dose on Day 1 (Week 0), Week 8, Week 24 and Week 48, and post-dose on Day 1 (Week 0) and Week 24. Analysis performed at 22 Mar 2018 DCO.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is reporting PK data for durvalumab and therefore reporting results for the placebo arm is not applicable.
    End point values
    		 Durvalumab (MEDI4736)
    Number of subjects analysed
    473
    Units: Micrograms per milliliter
    geometric mean (geometric coefficient of variation)
        Week 0: peak concentration (n=385)
    191.00 ± 72.4
        Week 8: trough concentration (n=289)
    120.00 ± 62.2
        Week 24: trough concentration (n=225)
    177.00 ± 47.9
        Week 24: peak concentration (n=207)
    373.00 ± 43.6
        Week 48: trough concentration (n=213)
    186.00 ± 67.4
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Serious and non-serious treatment-emergent adverse event (TEAE) data collected during the 12-month treatment period. Deaths (all causes) collected for entire duration of the study. Assessed until 11 Jan 2021 DCO for study completion.
    Adverse event reporting additional description
    TEAEs include events from first dose of study drug until earlier of 90 days after last dose or date of first subsequent therapy. 473 and 236 patients in durvalumab and placebo groups, respectively, received treatment but 2 patients randomized to placebo received 1 dose of durvalumab in error and are included in the durvalumab safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients in the placebo group were to receive matching placebo for intravenous infusion Q2W for up to 12 months.

    Reporting group title
    Durvalumab (MEDI4736)
    Reporting group description
    		 Patients in the durvalumab (MEDI4736) monotherapy group were to receive durvalumab 10 mg/kg Q2W via intravenous infusion for up to 12 months.

    Serious adverse events
    		 Placebo Durvalumab (MEDI4736)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 234 (23.08%)
    138 / 475 (29.05%)
         number of deaths (all causes)
    154
    262
         number of deaths resulting from adverse events
    15
    21
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giant cell tumour of tendon sheath
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral ischaemia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Calculus prostatic
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 234 (0.43%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute interstitial pneumonitis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopleural fistula
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 234 (0.43%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    7 / 234 (2.99%)
    17 / 475 (3.58%)
         occurrences causally related to treatment / all
    5 / 8
    18 / 18
         deaths causally related to treatment / all
    2 / 3
    4 / 4
    Pneumonia aspiration
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 234 (0.00%)
    5 / 475 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed anxiety and depressed mood
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain natriuretic peptide increased
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation oesophagitis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    4 / 234 (1.71%)
    17 / 475 (3.58%)
         occurrences causally related to treatment / all
    0 / 5
    4 / 17
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Post procedural fistula
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 234 (0.00%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 234 (0.43%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Atrioventricular block complete
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 234 (0.00%)
    5 / 475 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eosinophilic myocarditis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 234 (0.00%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular hole
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 234 (0.85%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis membranous
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular acidosis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 234 (0.00%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 234 (0.85%)
    4 / 475 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia necrotising
         subjects affected / exposed
    2 / 234 (0.85%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia adenoviral
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 234 (5.98%)
    33 / 475 (6.95%)
         occurrences causally related to treatment / all
    1 / 16
    5 / 39
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endotoxaemia
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    West Nile viral infection
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 234 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 234 (0.00%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peritonitis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 234 (0.43%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Iron overload
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 234 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 234 (0.43%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Durvalumab (MEDI4736)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    212 / 234 (90.60%)
    436 / 475 (91.79%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 234 (3.42%)
    26 / 475 (5.47%)
         occurrences all number
    8
    29
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    22 / 234 (9.40%)
    70 / 475 (14.74%)
         occurrences all number
    23
    92
    Oedema peripheral
         subjects affected / exposed
    9 / 234 (3.85%)
    37 / 475 (7.79%)
         occurrences all number
    10
    41
    Non-cardiac chest pain
         subjects affected / exposed
    21 / 234 (8.97%)
    35 / 475 (7.37%)
         occurrences all number
    22
    39
    Fatigue
         subjects affected / exposed
    47 / 234 (20.09%)
    114 / 475 (24.00%)
         occurrences all number
    52
    130
    Asthenia
         subjects affected / exposed
    31 / 234 (13.25%)
    51 / 475 (10.74%)
         occurrences all number
    50
    73
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    59 / 234 (25.21%)
    169 / 475 (35.58%)
         occurrences all number
    75
    220
    Dyspnoea
         subjects affected / exposed
    57 / 234 (24.36%)
    106 / 475 (22.32%)
         occurrences all number
    67
    133
    Productive cough
         subjects affected / exposed
    19 / 234 (8.12%)
    46 / 475 (9.68%)
         occurrences all number
    26
    53
    Pneumonitis
         subjects affected / exposed
    11 / 234 (4.70%)
    44 / 475 (9.26%)
         occurrences all number
    11
    46
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 234 (7.26%)
    45 / 475 (9.47%)
         occurrences all number
    18
    47
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    33 / 234 (14.10%)
    80 / 475 (16.84%)
         occurrences all number
    33
    84
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 234 (9.40%)
    33 / 475 (6.95%)
         occurrences all number
    25
    36
    Headache
         subjects affected / exposed
    21 / 234 (8.97%)
    52 / 475 (10.95%)
         occurrences all number
    23
    58
    Paraesthesia
         subjects affected / exposed
    12 / 234 (5.13%)
    22 / 475 (4.63%)
         occurrences all number
    13
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 234 (11.11%)
    35 / 475 (7.37%)
         occurrences all number
    32
    39
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    20 / 234 (8.55%)
    57 / 475 (12.00%)
         occurrences all number
    27
    59
    Diarrhoea
         subjects affected / exposed
    46 / 234 (19.66%)
    87 / 475 (18.32%)
         occurrences all number
    56
    136
    Vomiting
         subjects affected / exposed
    19 / 234 (8.12%)
    36 / 475 (7.58%)
         occurrences all number
    25
    45
    Nausea
         subjects affected / exposed
    31 / 234 (13.25%)
    68 / 475 (14.32%)
         occurrences all number
    43
    88
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    12 / 234 (5.13%)
    37 / 475 (7.79%)
         occurrences all number
    12
    38
    Pruritus
         subjects affected / exposed
    14 / 234 (5.98%)
    60 / 475 (12.63%)
         occurrences all number
    17
    70
    Rash
         subjects affected / exposed
    18 / 234 (7.69%)
    61 / 475 (12.84%)
         occurrences all number
    23
    72
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    4 / 234 (1.71%)
    54 / 475 (11.37%)
         occurrences all number
    4
    62
    Hyperthyroidism
         subjects affected / exposed
    4 / 234 (1.71%)
    35 / 475 (7.37%)
         occurrences all number
    4
    39
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    44 / 234 (18.80%)
    83 / 475 (17.47%)
         occurrences all number
    49
    110
    Myalgia
         subjects affected / exposed
    10 / 234 (4.27%)
    38 / 475 (8.00%)
         occurrences all number
    13
    41
    Musculoskeletal chest pain
         subjects affected / exposed
    18 / 234 (7.69%)
    25 / 475 (5.26%)
         occurrences all number
    21
    27
    Back pain
         subjects affected / exposed
    27 / 234 (11.54%)
    50 / 475 (10.53%)
         occurrences all number
    31
    55
    Pain in extremity
         subjects affected / exposed
    14 / 234 (5.98%)
    31 / 475 (6.53%)
         occurrences all number
    14
    35
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 234 (10.26%)
    57 / 475 (12.00%)
         occurrences all number
    30
    69
    Bronchitis
         subjects affected / exposed
    19 / 234 (8.12%)
    33 / 475 (6.95%)
         occurrences all number
    22
    44
    Urinary tract infection
         subjects affected / exposed
    13 / 234 (5.56%)
    28 / 475 (5.89%)
         occurrences all number
    13
    42
    Pneumonia
         subjects affected / exposed
    12 / 234 (5.13%)
    48 / 475 (10.11%)
         occurrences all number
    14
    54
    Nasopharyngitis
         subjects affected / exposed
    14 / 234 (5.98%)
    42 / 475 (8.84%)
         occurrences all number
    18
    51
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    12 / 234 (5.13%)
    24 / 475 (5.05%)
         occurrences all number
    18
    33
    Decreased appetite
         subjects affected / exposed
    29 / 234 (12.39%)
    69 / 475 (14.53%)
         occurrences all number
    32
    84

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jun 2014
    The protocol was updated to add text to indicate study treatment should be discontinued if there is confirmed progression of disease following a previous response to study treatment.
    08 Aug 2014
    The protocol was updated to: • Add an interim analysis for PFS. • Reduce the frequency of specified study procedures and assessments following a review of the existing maturing Phase I safety database. • Increase the frequency of hematology and serum chemistry assessments and biomarkers; add the option of a 24-hour urine collection; and add assessments of temperature, respiratory rate and oxygen saturation for consistency with concurrent durvalumab studies. • Add justification for retreatment with durvalumab. • Update the criteria for Hy’s Law. • Add secondary objectives and outcome measures for time to relapse and time to death or distant metastasis. • Remove text for duration of response evaluation.
    18 Feb 2015
    The protocol was updated to: • Allow patients a longer time period for resolution of toxicities from concurrent chemoradiation. • Clarify requirements regarding the chemoradiation therapy schedule and radiotherapy dose given. • Update an exclusion criterion, allowing patients with Grade 1 asymptomatic pneumonitis to participate in the study. • Update an inclusion criterion for adequate organ and marrow function to align with available clinical data and recommendations for the program.
    11 Feb 2016
    The protocol was updated to: • Remove time to relapse from study assessments. • Revise “Investigator site” assessments to “BICR” assessments. • Add an additional OS interim analysis. • Change the alpha level between PFS and OS for statistical testing of the co-primary endpoints. Additional adjustments were made with respect to the multiple testing procedures for controlling the Type I error rate. • Change the timing of the PFS interim analysis to a later time point. • Include additional laboratory parameters to table of assessments (amylase and lipase). • Clarify how a patient’s weight is to be indicated for dosing calculations. • Update the list of potential adverse events of special interest (AESIs). • Update the clinically meaningful change in baseline score for EORTC QLQ-LC13. • Revise the PRO endpoints identified as primary for EORTC QLQ-LC13.
    09 Oct 2017
    The protocol was updated to: • Clarify requirements for independent data monitoring committee reviews. • Update retreatment criteria to allow patients to receive maximum benefit from treatment, and update guidance to Investigators for treatment and data collection for these patients. • Revise an Appendix to match updated toxicity management guidelines from August 2016.
    07 Dec 2017
    The protocol was updated to: • Revise an Appendix to match updated toxicity management guidelines from November 2017. • Update the list of potential AESIs. • Updated the study timetable and end-of-study procedures to clarify the circumstances under which the study may continue.
    04 Sep 2019
    The protocol was updated to: • Extend the estimated study completion date from Q3 2019 to Q2 2021 for the purposes of long-term follow-up. • Clarify that both primary analyses have been performed. • Amend the table of assessments, including removal of quality of life scales, removal of specified sampling and reducing frequency of scans. • Add mandatory biopsy requirement for entering retreatment. • Clarify availability of retreatment following the final DCO. • Clarify that survival follow-up will be completed upon completion of this protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Results of interim PFS analysis are considered as final PFS analysis; results of interim OS analysis are considered as final OS analysis. Patients were followed up for long-term survival until approximately 5 years after last patient enrolled.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sun Apr 28 21:58:54 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA