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    Clinical Trial Results:
    LUX-Head & Neck 2 - A randomised, double-blind, placebo-controlled, phase III study to evaluate the efficacy and safety of afatinib (BIBW 2992) as adjuvant therapy after chemo-radiotherapy in primary unresected patients with stage III, IVa, or IVb loco-regionally advanced head and neck squamous cell carcinoma.

    Summary
    EudraCT number
    		 2011-000392-14
    Trial protocol
    		 GB   ES   BE   FR   NL   DE   FI   GR   AT   SE   IT   CZ   DK   PT   HU   PL  
    Global end of trial date
    12 Sep 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Dec 2021
    First version publication date
    20 Sep 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.131
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01345669
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    25 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective was to investigate the efficacy and safety of afatinib over placebo when given as adjuvant therapy after chemo-radiotherapy (CRT) in primary unresected patients with loco-regionally advanced squamous cell carcinomas (LA SCC) stage III or IVa/b of the oral cavity, oropharynx, or hypopharynx, or larynx stage IVa/b with high or intermediate risk of recurrence. The main objective of the trial was to test the superiority of afatinib as adjuvant therapy vs. placebo in terms of disease-free survival (DFS) for this trial patient population.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 14
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Brazil: 71
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Chile: 10
    Country: Number of subjects enrolled
    Czechia: 22
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Egypt: 2
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 65
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Greece: 21
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    India: 37
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Japan: 86
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Portugal: 43
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Spain: 91
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    United Kingdom: 60
    Country: Number of subjects enrolled
    United States: 50
    Worldwide total number of subjects
    799
    EEA total number of subjects
    375
    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)
    603
    From 65 to 84 years
    196
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomised, placebo-controlled, double-blind, parallel arms, multinational phase III trial in which patients were randomised 2:1 to Afatinib or Placebo.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist site which ensured that they met all strictly implemented inclusion/exclusion criteria. Subjects were not to be entered to trial treatment if any one of the specific entry criteria were violated.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Afatinib (BIBW 2992)
    Arm description
    		 Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib (BIBW 2992)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason (patients were discontinued after the trial was stopped prematurely by the DMC due to futility) necessitating withdrawal.

    Arm title
    		 Placebo
    Arm description
    		 Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason (patients were discontinued after the trial was stopped prematurely by the DMC due to futility) necessitating withdrawal.

    Number of subjects in period 1 [1]
    		Afatinib (BIBW 2992) Placebo
    Started
    411
    206
    Completed
    124
    87
    Not completed
    287
    119
         Consent withdrawn by subject
    52
    13
         Adverse event, non-fatal
    63
    9
         Other Reasons
    111
    60
         Second primary tumour
    4
    3
         Lost to follow-up
    1
    1
         Primary tumour recurrence
    53
    32
         Protocol deviation
    3
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.No Statistical analysis

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Afatinib (BIBW 2992)
    Reporting group description
    		 Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.

    Reporting group title
    Placebo
    Reporting group description
    		 Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.

    Reporting group values
    		 Afatinib (BIBW 2992) Placebo Total
    Number of subjects
    		 411 206 617
    Age categorical
    Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
    Units: Subjects
    Age Continuous
    Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
    Units: years
        arithmetic mean (standard deviation)
    		 58.3 ± 8.23 57.3 ± 8.64 -
    Gender, Male/Female
    Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
    Units: Subjects
        Female
    		 61 28 89
        Male
    		 350 178 528

    End points

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    End points reporting groups
    Reporting group title
    Afatinib (BIBW 2992)
    Reporting group description
    		 Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.

    Reporting group title
    Placebo
    Reporting group description
    		 Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.

    Primary: Disease Free Survival (DFS)

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    End point title
    		 Disease Free Survival (DFS)
    End point description
    Disease Free Survival defined as the time from randomisation until documented tumour recurrence/SPT or death from any cause, whichever occurred first. Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised). 99999: Non calculable because median or 75th percentile hasn't been reached. It is calculated when approximately 40% of the events had occurred.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    End point values
    		 Afatinib (BIBW 2992) Placebo
    Number of subjects analysed
    411 [1]
    206 [2]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    43.40 (16.82 to 99999)
    99999 (16.69 to 99999)
    Notes
    [1] - RS
    [2] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    DFS was analysed using a stratified log-rank test with nodal status (N0- N2a vs. N2b-N3) and ECOG performance status (0 vs. 1) being the stratification factors.
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.4806
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.126
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.809
         upper limit
    		 1.569
    Notes
    [3] - Hazard ratio (Afatinib vs. Placebo) from Cox proportional hazards model stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).

    Secondary: Disease Free Survival (DFS) rate at 2 years

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    End point title
    		 Disease Free Survival (DFS) rate at 2 years
    End point description
    Disease Free Survival (DFS) rate at 2 years. Probability of being disease free at 2 years in percentage is provided based on Kaplan-Meier method. Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised).
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Afatinib (BIBW 2992) Placebo
    Number of subjects analysed
    117 [4]
    76 [5]
    Units: Probability (%)
        number (confidence interval 95%)
    67.2 (61.2 to 72.5)
    73.5 (66.0 to 79.5)
    Notes
    [4] - RS
    [5] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Kaplan-Meier (KM) curves were calculated for each treatment group, separately, and the estimates of DFS probabilities from the curves and 95% CI (using the Greenwood standard error estimate) were tabulated
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.161
    Method
    		 Logrank
    Parameter type
    		 Difference in Kaplan-Meier estimates
    Point estimate
    -6.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.04
         upper limit
    		 2.5
    Notes
    [6] - Difference in Kaplan-Meier estimates of Afatinib vs. Placebo is provided.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS), defined as the time from randomisation until death (regardless of cause). Due to the small event rate in both treatment arms caused by the early termination of the trial, the hazard estimate is not interpretable. Hence presented the total randomized and the percentage of patients died. Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised).
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Afatinib (BIBW 2992) Placebo
    Number of subjects analysed
    411 [7]
    206 [8]
    Units: Percentage death events
        number (not applicable)
    15.1
    11.2
    Notes
    [7] - RS
    [8] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio from Cox proportional hazards model stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1301 [9]
    Method
    		 Logrank
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.444
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.895
         upper limit
    		 2.332
    Notes
    [9] - p−value (two−sided) from log−rank test stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).

    Secondary: Patients with improved Health Related Quality of Life (HRQOL)

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    End point title
    		 Patients with improved Health Related Quality of Life (HRQOL)
    End point description
    HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Improvement was defined as a score that improved from baseline by at least 10 points (on the 0-100 point scale) at any time during the study. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the study. Patients who had neither improved nor worsened were considered as stable. Percentages of patients with improvement in HRQoL are presented. Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Afatinib (BIBW 2992) Placebo
    Number of subjects analysed
    411 [10]
    206 [11]
    Units: Percentage of Patients
    number (not applicable)
        Swallowing (Q5−Q8 from QLQ−HN35)
    34.8
    27.2
        Pain HN35 (Q1−Q4 from QLQ−HN35)
    33.8
    26.2
        Global health status/QoL(Q29−Q30 from QLQ−C30)
    33.6
    38.3
    Notes
    [10] - RS
    [11] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Odds ratio and p−value from logistic regression analysis of ’improved vs. not improved’ stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3) for Swallowing (Q5−Q8 from QLQ−HN35).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0561
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.431
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.991
         upper limit
    		 2.068
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Odds ratio and p−value from logistic regression analysis of ’improved vs. not improved’ stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3) for Pain HN35 (Q1−Q4 from QLQ−HN35).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0523
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.446
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.996
         upper limit
    		 2.098
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Odds ratio and p−value from logistic regression analysis of ’improved vs. not improved’ stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3) for Global health status/QoL(Q29−Q30 from QLQ−C30).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.257
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.818
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.557
         upper limit
    		 1.158

    Secondary: Time to deterioration in Health Related Quality of Life (HRQOL)

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    End point title
    		 Time to deterioration in Health Related Quality of Life (HRQOL)
    End point description
    HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Time to deterioration was defined as the time from randomisation to the first 10-point worsening on the 0-100 point scale. Patients with no deterioration (including those with disease recurrence/SPT) were censored at the last available HRQoL assessment date. Patients with no post-baseline assessments were censored on the day of randomisation. Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised). 99999: Non calculable because 75th percentile hasn't been reached.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Afatinib (BIBW 2992) Placebo
    Number of subjects analysed
    411 [12]
    206 [13]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        Swallowing (N=174, 74)
    18.43 (3.68 to 99999)
    31.44 (3.78 to 99999)
        Pain HN35 (N=185, 76)
    12.06 (1.91 to 99999)
    31.08 (3.78 to 99999)
        Global health status/QoL(N=205, 81)
    7.59 (1.87 to 99999)
    25.79 (6.21 to 99999)
    Notes
    [12] - RS
    [13] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    For swallowing scale; Hazard ratio from Cox proportional hazard model stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0591 [14]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.295
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.986
         upper limit
    		 1.7
    Notes
    [14] - P−value from log−rank test stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    For pain HN35 scale; Hazard ratio from Cox proportional hazard model stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0049 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.456
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.113
         upper limit
    		 1.905
    Notes
    [15] - P−value from log−rank test stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    For global health status/QoL scale; Hazard ratio from Cox proportional hazard model stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0002 [16]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.604
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.238
         upper limit
    		 2.079
    Notes
    [16] - P−value from log−rank test stratified by baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).

    Secondary: Health Related Quality of Life (HRQOL) scores over time

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    End point title
    		 Health Related Quality of Life (HRQOL) scores over time
    End point description
    HRQoL questionnaires focused on 3 scales: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Scoring of the symptom scales/items followed the European Organisation for Research and Treatment of Cancer (EORTC) scoring manual and a linear transformation of the scores to a 0-100 point scale. Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Afatinib (BIBW 2992) Placebo
    Number of subjects analysed
    411 [17]
    206 [18]
    Units: Unit on Scale
    least squares mean (standard error)
        Swallowing (N=397, 196)
    10.1 ± 1.00
    8.8 ± 1.12
        Pain HN35 (N=397, 195)
    13.1 ± 0.98
    9.9 ± 1.10
        Global health status/QoL(N=392, 194)
    29.6 ± 2.23
    33.0 ± 2.28
    Notes
    [17] - RS
    [18] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Scores (swallowing scale) over time were assessed using longitudinal mixed-effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG performance score and nodal status.
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.2232
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 3.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.08
    Notes
    [19] - Degrees of freedom calculated using the Kenward-Roger method. Afatinib minus Placebo mean adjusted for total with data for baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Scores (global health/QoL) over time were assessed using longitudinal mixed-effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG performance score and nodal status.
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.0005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.33
         upper limit
    		 -1.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.98
    Notes
    [20] - Degrees of freedom calculated using the Kenward-Roger method. Afatinib minus Placebo mean adjusted for total with data for baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Scores (pain scale) over time were assessed using longitudinal mixed-effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG performance score and nodal status.
    Comparison groups
    Afatinib (BIBW 2992) v Placebo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.0028
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 5.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.08
    Notes
    [21] - Degrees of freedom calculated using the Kenward-Roger method. Afatinib minus Placebo mean adjusted for total with data for baseline ECOG (0 or 1) and nodal status (N0−N2a or N2b−N3).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Afatinib
    Reporting group description
    		 Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.

    Reporting group title
    Placebo
    Reporting group description
    		 Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.

    Serious adverse events
    		 Afatinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 411 (19.46%)
    51 / 206 (24.76%)
         number of deaths (all causes)
    62
    23
         number of deaths resulting from adverse events
    9
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    3 / 411 (0.73%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm recurrence
         subjects affected / exposed
    5 / 411 (1.22%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal squamous cell carcinoma
         subjects affected / exposed
    2 / 411 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recurrent cancer
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Disease recurrence
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 411 (0.49%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 411 (0.73%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal dyspnoea
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    8 / 411 (1.95%)
    8 / 206 (3.88%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract oedema
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoradionecrosis
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation fibrosis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 411 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Carotid artery thrombosis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (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
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 411 (0.97%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal tear
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         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 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 411 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glossitis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (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
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 411 (0.00%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    2 / 411 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin infection
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 411 (0.24%)
    5 / 206 (2.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 411 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 411 (0.73%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 411 (0.24%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    1 / 411 (0.24%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 411 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    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
    		 Afatinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    407 / 411 (99.03%)
    169 / 206 (82.04%)
    Investigations
    Weight decreased
         subjects affected / exposed
    67 / 411 (16.30%)
    19 / 206 (9.22%)
         occurrences all number
    73
    21
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 411 (4.38%)
    12 / 206 (5.83%)
         occurrences all number
    21
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 411 (2.68%)
    13 / 206 (6.31%)
         occurrences all number
    13
    16
    Dysgeusia
         subjects affected / exposed
    34 / 411 (8.27%)
    10 / 206 (4.85%)
         occurrences all number
    38
    10
    Headache
         subjects affected / exposed
    18 / 411 (4.38%)
    12 / 206 (5.83%)
         occurrences all number
    19
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 411 (5.60%)
    7 / 206 (3.40%)
         occurrences all number
    26
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 411 (10.46%)
    23 / 206 (11.17%)
         occurrences all number
    58
    29
    Fatigue
         subjects affected / exposed
    61 / 411 (14.84%)
    21 / 206 (10.19%)
         occurrences all number
    72
    21
    Mucosal inflammation
         subjects affected / exposed
    126 / 411 (30.66%)
    17 / 206 (8.25%)
         occurrences all number
    178
    21
    Pyrexia
         subjects affected / exposed
    29 / 411 (7.06%)
    7 / 206 (3.40%)
         occurrences all number
    36
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    21 / 411 (5.11%)
    6 / 206 (2.91%)
         occurrences all number
    23
    8
    Cheilitis
         subjects affected / exposed
    22 / 411 (5.35%)
    1 / 206 (0.49%)
         occurrences all number
    25
    1
    Constipation
         subjects affected / exposed
    33 / 411 (8.03%)
    20 / 206 (9.71%)
         occurrences all number
    35
    22
    Diarrhoea
         subjects affected / exposed
    335 / 411 (81.51%)
    41 / 206 (19.90%)
         occurrences all number
    826
    61
    Dyspepsia
         subjects affected / exposed
    42 / 411 (10.22%)
    10 / 206 (4.85%)
         occurrences all number
    48
    11
    Dry mouth
         subjects affected / exposed
    55 / 411 (13.38%)
    25 / 206 (12.14%)
         occurrences all number
    67
    28
    Dysphagia
         subjects affected / exposed
    48 / 411 (11.68%)
    21 / 206 (10.19%)
         occurrences all number
    51
    22
    Gastrooesophageal reflux disease
         subjects affected / exposed
    23 / 411 (5.60%)
    2 / 206 (0.97%)
         occurrences all number
    23
    2
    Nausea
         subjects affected / exposed
    43 / 411 (10.46%)
    24 / 206 (11.65%)
         occurrences all number
    56
    31
    Oral pain
         subjects affected / exposed
    23 / 411 (5.60%)
    6 / 206 (2.91%)
         occurrences all number
    27
    6
    Stomatitis
         subjects affected / exposed
    107 / 411 (26.03%)
    12 / 206 (5.83%)
         occurrences all number
    149
    16
    Vomiting
         subjects affected / exposed
    40 / 411 (9.73%)
    20 / 206 (9.71%)
         occurrences all number
    49
    25
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    35 / 411 (8.52%)
    30 / 206 (14.56%)
         occurrences all number
    41
    36
    Dysphonia
         subjects affected / exposed
    22 / 411 (5.35%)
    17 / 206 (8.25%)
         occurrences all number
    24
    18
    Epistaxis
         subjects affected / exposed
    54 / 411 (13.14%)
    3 / 206 (1.46%)
         occurrences all number
    74
    3
    Oropharyngeal pain
         subjects affected / exposed
    27 / 411 (6.57%)
    14 / 206 (6.80%)
         occurrences all number
    28
    14
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    112 / 411 (27.25%)
    6 / 206 (2.91%)
         occurrences all number
    154
    6
    Acne
         subjects affected / exposed
    22 / 411 (5.35%)
    2 / 206 (0.97%)
         occurrences all number
    28
    6
    Erythema
         subjects affected / exposed
    28 / 411 (6.81%)
    5 / 206 (2.43%)
         occurrences all number
    35
    5
    Dry skin
         subjects affected / exposed
    76 / 411 (18.49%)
    16 / 206 (7.77%)
         occurrences all number
    85
    18
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    30 / 411 (7.30%)
    0 / 206 (0.00%)
         occurrences all number
    32
    0
    Pruritus
         subjects affected / exposed
    58 / 411 (14.11%)
    13 / 206 (6.31%)
         occurrences all number
    77
    15
    Rash
         subjects affected / exposed
    188 / 411 (45.74%)
    34 / 206 (16.50%)
         occurrences all number
    310
    45
    Skin fissures
         subjects affected / exposed
    40 / 411 (9.73%)
    1 / 206 (0.49%)
         occurrences all number
    56
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 411 (2.43%)
    12 / 206 (5.83%)
         occurrences all number
    11
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 411 (3.16%)
    17 / 206 (8.25%)
         occurrences all number
    14
    20
    Muscle spasms
         subjects affected / exposed
    26 / 411 (6.33%)
    9 / 206 (4.37%)
         occurrences all number
    37
    9
    Neck pain
         subjects affected / exposed
    11 / 411 (2.68%)
    11 / 206 (5.34%)
         occurrences all number
    12
    13
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    21 / 411 (5.11%)
    2 / 206 (0.97%)
         occurrences all number
    27
    4
    Nasopharyngitis
         subjects affected / exposed
    22 / 411 (5.35%)
    18 / 206 (8.74%)
         occurrences all number
    25
    20
    Paronychia
         subjects affected / exposed
    85 / 411 (20.68%)
    4 / 206 (1.94%)
         occurrences all number
    105
    4
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 411 (4.62%)
    15 / 206 (7.28%)
         occurrences all number
    23
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    74 / 411 (18.00%)
    23 / 206 (11.17%)
         occurrences all number
    87
    28

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2011
    With the introduction of this amendment, in addition to some clarifications and minor changes in study definitions, or revisions for consistency or to avoid repetitions, the following changes were made. The start of treatment was amended to start as soon as possible after randomisation and preferably on the day of randomisation. Also, tumour recurrence was changed to tumour recurrence/SPT to take into consideration that not all new tumours would be recurrence of previous tumours. Definitions for the evaluation of DILI were added. The central review procedure for imaging data for tumour assessments was clarified.
    28 Jun 2012
    With the introduction of this amendment, in addition to some clarifications and minor changes in study definitions, or revisions for consistency or to avoid repetitions, the following changes were made. Patients were eligible if CRT had been completed no longer than 24 weeks before randomisation to allow potential patients to recover from side effects induced by prior CRT, and to allow more time to perform neck dissection after CRT. The definition of NED was further clarified to provide recommendations for the assessment of lymph nodes. The first exclusion criteria (simultaneous HNSCC primaries) was removed. In the primary analysis of DFS, it was clarified that the 2 stratification factors would be included in the Cox model as strata and not as covariates. Sensitivity analyses of the primary endpoint were defined.
    11 Feb 2014
    With the introduction of this amendment, in addition to some clarifications and minor changes in study definitions, revisions for consistency or to avoid repetitions, or updates in the afatinib drug profile, the following changes were made. The best response to subsequent anticancer therapy was to be collected. Following a change in sponsor guidelines, after the first FUV (FUV1), SAEs and AESIs were to be reported if considered relevant by the investigator (signs and symptoms of recurrence/SPT were reported until recurrence/SPT had been radiologically confirmed). It was clarified that that neck dissection was allowed prior to CRT as neck dissection is not regarded as tumour resection and thus the overall patient population (primary unresected HNSCC) remained the same. Also, recognising that a patient may need longer time to recover before resuming treatment, patients who had not recovered within 21 days did not have to be discontinued. Instead, it was recommended that study medication be restarted as soon as clinically possible and within 21 days. The reporting period for AEs was clarified due to new guidelines for AE reporting. Due to extended recruitment, the text was revised to show that the first patients in the study would be followed for approximately 6 years rather than 4 years. The planned number of centres was increased from approximately 100 to approximately 200.
    17 Jul 2015
    With the introduction of this amendment, in addition to some clarifications and minor changes in study definitions, revisions for consistency or to avoid repetitions, or updating the drug profile for afatinib, the following changes were made. Further endpoints were added (time to loco-regional failure; time to distant failure; occurrence of SPTs). Some details of the primary analysis were revised, and it was to be conducted when approximately 309 patients had tumour recurrence/SPT or died (rather than when 408 patients had tumour recurrence/SPTs or died). The sample size calculation was revised to account for recently published data. It was clarified that since patients were considered having NED at randomisation, samples for biomarker analyses were typically those collected at diagnosis. The definition of DILI was revised following introduction of a new guideline.

    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.
    The trial was stopped prematurely due to futility. At that point, 27.7% of patients in the study discontinued study medication prematurely due to study stop.
    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.

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