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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Weekly Doses of Palifermin (Recombinant Human Keratinocyte Growth Factor, rHuKGF) for the Reduction of Oral Mucositis in Subjects With Advanced Head and Neck Cancer Receiving Radiotherapy With Concurrent Chemotherapy (RT/CT)

    Summary
    EudraCT number
    2005-000213-35
    Trial protocol
    CZ   HU   AT   DE   IT  
    Global end of trial date
    11 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jun 2017
    First version publication date
    30 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20020402
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00101582
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Swedish Orphan Biovitrum AB
    Sponsor organisation address
    KISP, Stockholm, Sweden, 11276
    Public contact
    Medical Information, Swedish Orphan Biovitrum AB, 46 86972000, info@sobi.com
    Scientific contact
    Medical Information, Swedish Orphan Biovitrum AB, 46 86972000, info@sobi.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 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of palifermin administered at the dose of 180 μg/kg IV in 8 weekly doses relative to placebo in reducing the incidence of severe [World Health Organization Grade 3 or 4] oral mucositis (OM) in subjects with locally advanced HNC receiving RT/CT as definitive treatment for their disease.
    Protection of trial subjects
    This study was conducted in accordance with US Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Nov 2005
    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
    Canada: 2
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    United States: 56
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Czech Republic: 22
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    188
    EEA total number of subjects
    130
    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)
    162
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 46 sites globally; 5 in Austria, 2 in Canada, 4 in the Czech Republic, 4 in Germany, 5 in Hungary, 4 in Italy, 4 in Poland and 18 in the United States.

    Pre-assignment
    Screening details
    Subjects were screened and received a unique number from IVRS. Randomization to one of the two treatment groups occured 24 hours before first dose of IMP. Subjects were also stratified before randomization based on disease stage (3 or 4) and primary anatomical location of the tumor (oral cavity oropharynx, nasopharynx, or hypopharynx / larynx)

    Period 1
    Period 1 title
    Acute phase - Period A
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    A registration call was made into the IVRS within the 24 hours before the first dose of investigational product. At the completion of this call, a randomization number and drug box number(s) were assigned by the IVRS. From this point on, a subject was considered assigned to one of the two treatment groups.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received a single intravenous (IV) dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was given as intravenous bolus injections. Placebo was presented as lyophilized white powder in 6.25 mg single-dose vials to be reconstituted with 1.2 ml of sterile water for injection. The reconstituted solution contained 10 mM histidin (pH6.5), 4 % mannitol, 2 % sucrose, 0.010 % polysorbate 20 and no preservatives. A single dose of placebo was administered 3 days before the start of RT, then once weekly throughout the RT/CT period for a total of 8 doses.

    Arm title
    Palifermin
    Arm description
    Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/ chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.
    Arm type
    Experimental

    Investigational medicinal product name
    Palifermin
    Investigational medicinal product code
    Other name
    Kepivance
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Palifermin was given as intravenous bolus injections. Placebo was presented as lyophilized white powder in 6.25 mg single-dose vials to be reconstituted with 1.2 ml of sterile water for injection. The reconstituted solution contained 5 mg/mL (± 0.5 mg/mL) palifermin, 10 mM histidin (pH6.5), 4 % mannitol, 2 % sucrose, 0.010 % polysorbate 20 and no preservatives. A single dose of palifermin was administered 3 days before the start of RT, then once weekly throughout the RT/CT period for a total of 8 doses.

    Number of subjects in period 1
    Placebo Palifermin
    Started
    94
    94
    Completed
    83
    79
    Not completed
    11
    15
         Subjects who never received IMP
    3
    -
         Protocol deviation
    2
    1
         Other
    -
    2
         Noncompliance
    1
    2
         Adverse event, serious fatal
    -
    3
         Adverse event, non-fatal
    4
    5
         Consent withdrawn by subject
    1
    -
         Subject request
    -
    2
    Period 2
    Period 2 title
    Long-term follow up phase - Period B
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects who received placebo in Period A, acute phase.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Palifermin
    Arm description
    Subjects who received palifermin in Period A, acute phase.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Placebo Palifermin
    Started
    83
    79
    Completed
    40
    44
    Not completed
    51
    50
         Adverse event, serious fatal
    51
    50
    Joined
    8
    15
         Subjects not completed PeriodA counted in PeriodB
    -
    15
         Subjects not completed PeriodA counted in Period B
    8
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single intravenous (IV) dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.

    Reporting group title
    Palifermin
    Reporting group description
    Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/ chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.

    Reporting group values
    Placebo Palifermin Total
    Number of subjects
    94 94 188
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    83 79 162
        From 65-84 years
    11 15 26
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    14 15 29
        Male
    80 79 159
    Subject analysis sets

    Subject analysis set title
    Placebo - safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects receiving at least one dose of IMP (placebo) in the in the acute phase

    Subject analysis set title
    Palifermin - safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects receiving at least one dose of IMP (palifermin) in the in the acute phase

    Subject analysis set title
    Placebo - full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects randomized to the placebo treatment group in the study

    Subject analysis set title
    Palifermin - full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects randomized to the palifermin treatment group in the study

    Subject analysis set title
    Placebo - LTFU analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received placebo in the acute phase of the study - Period A

    Subject analysis set title
    Palifermin - LTFU analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received palifermin during the acute phase of the study, period A.

    Subject analysis sets values
    Placebo - safety analysis set Palifermin - safety analysis set Placebo - full analysis set Palifermin - full analysis set Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects
    91
    94
    94
    94
    91
    94
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    80
    79
    83
    79
    80
    79
        From 65-84 years
    11
    15
    11
    15
    11
    15
        85 years and over
    0
    0
    0
    0
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    13
    15
    14
    15
    13
    15
        Male
    78
    79
    80
    79
    78
    79

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single intravenous (IV) dose of placebo three days before the start of radiotherapy, and then 7 once weekly placebo doses during a 7-week radiotherapy/chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.

    Reporting group title
    Palifermin
    Reporting group description
    Participants received a single intravenous dose of palifermin at 180 μg/kg three days before the start of radiotherapy, and then 7 once weekly palifermin doses at the same dose level during a 7-week radiotherapy/ chemotherapy course. Chemotherapy consisted of 100 mg/m^2 cisplatin administered by IV infusion on Days 1, 22, and 43.
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received placebo in Period A, acute phase.

    Reporting group title
    Palifermin
    Reporting group description
    Subjects who received palifermin in Period A, acute phase.

    Subject analysis set title
    Placebo - safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects receiving at least one dose of IMP (placebo) in the in the acute phase

    Subject analysis set title
    Palifermin - safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects receiving at least one dose of IMP (palifermin) in the in the acute phase

    Subject analysis set title
    Placebo - full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects randomized to the placebo treatment group in the study

    Subject analysis set title
    Palifermin - full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects randomized to the palifermin treatment group in the study

    Subject analysis set title
    Placebo - LTFU analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received placebo in the acute phase of the study - Period A

    Subject analysis set title
    Palifermin - LTFU analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received palifermin during the acute phase of the study, period A.

    Primary: Incidence of Severe Oral Mucositis (WHO Grade 3 or 4)

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    End point title
    Incidence of Severe Oral Mucositis (WHO Grade 3 or 4)
    End point description
    Participants underwent evaluations of oral mucosal (OM) surfaces (mucositis assessments) 2 times weekly throughout radio/chemotherapy, and 2 times weekly thereafter until severe OM returned to grade ≤ 2 or until Week 15. During each evaluation, the following anatomical areas were assessed: upper lip; lower lip; right cheek; left cheek; right ventral & lateral tongue; left ventral & lateral tongue; floor of the mouth; hard palate; soft palate. A trained evaluator documented the findings using the World Health Organization (WHO) oral toxicity scale according to the following: Grade 0 = None; Grade 1 = Soreness, erythema; Grade 2 = Erythema, ulcers, ability to eat solids; Grade 3 = Ulcers, requires liquid diet; Grade 4 = Alimentation not possible.
    End point type
    Primary
    End point timeframe
    Up to week 15
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: subjects
        Yes
    62
    51
        No
    29
    43
        Unknown
    3
    0
    Statistical analysis title
    Incidence of Severe Oral Mucositis (WHO Grade 3 or
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.041
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.1417
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2779
         upper limit
    -0.0056

    Secondary: Duration of severe oral mucositis (WHO grade 3 or 4)

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    End point title
    Duration of severe oral mucositis (WHO grade 3 or 4)
    End point description
    The duration of severe oral mucositis (OM) was calculated as the number of days from the onset of severe OM (first time a WHO grade 3 or 4 was observed) to the day when severe OM was resolved (first time WHO grade 2 or less was observed after last WHO grade 3 or 4). Durations of 0 days were assigned to those participants who did not experience any WHO grade 3 or 4 during the study.
    End point type
    Secondary
    End point timeframe
    Up to 15 weeks
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: Days
        median (inter-quartile range (Q1-Q3))
    26 (0 to 50)
    5 (0 to 40)
    Statistical analysis title
    Duration of severe oral mucositis (grade 3 or 4)
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1122 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -8.865
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.6865
         upper limit
    -2.0435
    Notes
    [1] - The reported p-value is an adjusted p-value based on Hochberg procedure for the Type 1 error. Original p-value was 0.0160.

    Secondary: Time to onset of severe oral mucositis

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    End point title
    Time to onset of severe oral mucositis
    End point description
    Time to onset of severe (WHO Grade 3 or 4) oral mucositis (OM) was analyzed using the Kaplan-Meier procedure. Participants without an assessed event by the end of the acute OM evaluation phase were censored at the date of last assessment for severe OM.
    End point type
    Secondary
    End point timeframe
    Up to 15 weeks
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: Number of subjects
    62
    51
    Statistical analysis title
    Time to onset of severe oral mucositis
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1566 [2]
    Method
    Stratified Log-Rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.6603
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4546
         upper limit
    0.9592
    Notes
    [2] - Adjusted p-value was based on Hochberg procedure to control for the Type 1 error. Unadjustedl p-value was 0.0261.

    Secondary: Incidence of Xerostomia (grade 2 or higher CTCAE v3.0 dry mouth/xerostomia scale) at month 4 visit

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    End point title
    Incidence of Xerostomia (grade 2 or higher CTCAE v3.0 dry mouth/xerostomia scale) at month 4 visit
    End point description
    The number of participants with grade 2 or higher xerostomia (dryness of the oral mucosa) at the Month 4 visit, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Dry Mouth/Xerostomia scale.
    End point type
    Secondary
    End point timeframe
    Month 4
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: incidence
        Yes
    57
    37
        No
    19
    31
        Unknown
    18
    26
    Statistical analysis title
    Incidence of Xerostomia at month 4
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2314 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1291
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2542
         upper limit
    -0.0041
    Notes
    [3] - Adjusted p-value was based on Hochberg procedure to control for the Type 1 error. Original p-value was 0.0463.

    Secondary: Patient-reported mouth and soreness score

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    End point title
    Patient-reported mouth and soreness score
    End point description
    The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer [OMWQ-HN]): "How much mouth and throat soreness did you experience in the past 24 hours?" Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). For each participant, an average patient-reported mouth and throat soreness score was calculated by dividing the sum of the MTS scores at each assessment by the total number of assessments.
    End point type
    Secondary
    End point timeframe
    Assessed twice a week for up to 15 weeks.
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    88
    89
    Units: MTS score
        arithmetic mean (standard deviation)
    1.86 ± 0.65
    1.66 ± 0.73
    Statistical analysis title
    Patient-reported MTS score
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2849 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    -0.2006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4033
         upper limit
    0.0022
    Notes
    [4] - Adjusted p-value was based on Hochberg procedure to control for the Type 1 error. Original p-value was 0.0712.

    Secondary: Total dose of opioid analgesic used (mg of IV morphine equivalents)

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    End point title
    Total dose of opioid analgesic used (mg of IV morphine equivalents)
    End point description
    The total dose of opioid analgesics (mg of intravenous [IV] morphine equivalents) used by all participants. Participants with at least one reported administration of opioid analgesic (parenteral, peroral or transdermal) were considered to have received opioid analgesics. The total dose of opioid analgesics is the sum of all opioid analgesic administrations that have been converted to morphine equivalents.
    End point type
    Secondary
    End point timeframe
    Up to 15 weeks
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: mg of IV morphine equivalents
        arithmetic mean (standard deviation)
    1219.55 ± 1769.29
    1243.31 ± 2700.28
    Statistical analysis title
    Total dose of Opioid Analgesic used
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6835 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    26.4885
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -639.9243
         upper limit
    692.9012
    Notes
    [5] - Adjusted p-value was based on Hochberg procedure to control for the Type 1 error. Original p-value was 0.2384.

    Secondary: Incidence of unplanned delay of 5 or more days and discontinuation of chemotherapy

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    End point title
    Incidence of unplanned delay of 5 or more days and discontinuation of chemotherapy
    End point description
    Cisplatin was administered on Days 1, 22, and 43. An unplanned break in cisplatin refers to a delay of ≥ 5 days from the scheduled Day 22 or Day 43 cisplatin administration or a discontinuation of cisplatin for any reason.
    End point type
    Secondary
    End point timeframe
    During the 7 weeks of chemotherapy treatment
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: incidence
        Yes
    42
    49
        No
    52
    45
    Statistical analysis title
    Unplanned delay of 5 or more days of CT
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6835 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.0675
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0705
         upper limit
    0.2055
    Notes
    [6] - Adjusted p-value was based on Hochberg procedure to control for the Type 1 error. Unadjusted p-value was 0.3417.

    Secondary: Incidence of unplanned breaks in radiotherapy of >= 5 days Including discontinuation of radiotherapy

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    End point title
    Incidence of unplanned breaks in radiotherapy of >= 5 days Including discontinuation of radiotherapy
    End point description
    Participants with a duration of 5 days or more without an administration of radiotherapy or who discontinue radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy.
    End point type
    Secondary
    End point timeframe
    During the 7 weeks of radiotherapy
    End point values
    Placebo - full analysis set Palifermin - full analysis set
    Number of subjects analysed
    94
    94
    Units: incidence
        Yes
    11
    13
        No
    80
    80
        Did not receive RT
    3
    1
    Statistical analysis title
    Unplanned breaks or dicontinuation of RT
    Comparison groups
    Placebo - full analysis set v Palifermin - full analysis set
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9587 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.0027
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1063
         upper limit
    0.1009
    Notes
    [7] - Adjusted p-value was based on Hochberg procedure to control for the Type 1 error. Unadjusted p-value was also 0.9587.

    Secondary: Overall tumor response at week 12 visit

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    End point title
    Overall tumor response at week 12 visit
    End point description
    End point type
    Secondary
    End point timeframe
    From start of treatment until Week 12
    End point values
    Placebo - safety analysis set Palifermin - safety analysis set
    Number of subjects analysed
    91
    94
    Units: subjects
        Complete response
    39
    37
        Partial response
    40
    33
        Stable disease
    5
    6
        Disease progression
    0
    2
        Unknown
    7
    16
    No statistical analyses for this end point

    Secondary: Incidence of serum anti-palifermin neutralizing antibodies

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    End point title
    Incidence of serum anti-palifermin neutralizing antibodies
    End point description
    End point type
    Secondary
    End point timeframe
    Up to week 12
    End point values
    Placebo - safety analysis set Palifermin - safety analysis set
    Number of subjects analysed
    91 [8]
    94 [9]
    Units: incidence
        Baseline
    0
    0
        Week 4
    0
    0
        Week 8
    0
    0
        Week 12
    0
    0
        Overall
    0
    0
    Notes
    [8] - Number of subjects assessed at baseline was 88, and then 89, 84 and 82. Overall 90 subjects assessed
    [9] - Number of subjects assessed at baseline was 88, and then 85, 81 and 79. Overall 89 subjects assessed
    No statistical analyses for this end point

    Other pre-specified: Incidence of second primary tumors

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    End point title
    Incidence of second primary tumors
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dose of investigational product until end of trial
    End point values
    Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects analysed
    91
    94
    Units: Number of subjects
    11
    6
    No statistical analyses for this end point

    Other pre-specified: Incidence of other malignancies

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    End point title
    Incidence of other malignancies
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dose of investigational product until study end.
    End point values
    Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects analysed
    91
    94
    Units: Number of subjects
    3
    2
    No statistical analyses for this end point

    Other pre-specified: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dose of investigational product until study end.
    End point values
    Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects analysed
    91
    94
    Units: Number of subjects
    56
    56
    Statistical analysis title
    Progression free survival
    Comparison groups
    Placebo - LTFU analysis set v Palifermin - LTFU analysis set
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.78
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.726
         upper limit
    1.533

    Other pre-specified: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dose of investigational drug until study end.
    End point values
    Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects analysed
    91
    94
    Units: Number of subjects
    51
    50
    Statistical analysis title
    Overall survival
    Comparison groups
    Palifermin - LTFU analysis set v Placebo - LTFU analysis set
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.935
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.984
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.663
         upper limit
    1.459

    Other pre-specified: Incidence of leukoplakia

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    End point title
    Incidence of leukoplakia
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dose of investigational product until study end.
    End point values
    Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects analysed
    91
    94
    Units: Number of subjects
    3
    3
    No statistical analyses for this end point

    Other pre-specified: Time to local regional failure

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    End point title
    Time to local regional failure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dose of investigational product until end of trial.
    End point values
    Placebo - LTFU analysis set Palifermin - LTFU analysis set
    Number of subjects analysed
    91
    94
    Units: Number of subjects
    26
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 12 weeks (up to 15 weeks, maximum)
    Adverse event reporting additional description
    20020402 Primary Analysis
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Eight-week palifermin
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Eight-week palifermin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 94 (37.23%)
    26 / 91 (28.57%)
         number of deaths (all causes)
    7
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Laryngeal neoplasm
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal carcinoma
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder due to a general medical condition
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury asphyxiation
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Investigations
    Blood bilirubin abnormal
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine abnormal
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase abnormal
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood sodium abnormal
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase abnormal
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    5 / 94 (5.32%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Cryptogenic organizing pneumonia
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngolaryngeal pain
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         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
    Agranulocytosis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 94 (0.00%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobinaemia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (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
    2 / 94 (2.13%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope vasovagal
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    5 / 94 (5.32%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (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 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 94 (1.06%)
    4 / 91 (4.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 94 (4.26%)
    9 / 91 (9.89%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 94 (0.00%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis acute
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Candidiasis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis pseudomembranous
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected epidermal cyst
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 94 (2.13%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Eight-week palifermin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 94 (94.68%)
    81 / 91 (89.01%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    6 / 94 (6.38%)
    0 / 91 (0.00%)
         occurrences all number
    7
    0
    Hypertension
         subjects affected / exposed
    5 / 94 (5.32%)
    4 / 91 (4.40%)
         occurrences all number
    8
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 94 (4.26%)
    5 / 91 (5.49%)
         occurrences all number
    4
    6
    Fatigue
         subjects affected / exposed
    21 / 94 (22.34%)
    20 / 91 (21.98%)
         occurrences all number
    29
    30
    Malaise
         subjects affected / exposed
    5 / 94 (5.32%)
    1 / 91 (1.10%)
         occurrences all number
    6
    2
    Oedema peripheral
         subjects affected / exposed
    6 / 94 (6.38%)
    4 / 91 (4.40%)
         occurrences all number
    9
    5
    Pyrexia
         subjects affected / exposed
    16 / 94 (17.02%)
    19 / 91 (20.88%)
         occurrences all number
    20
    24
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 94 (9.57%)
    8 / 91 (8.79%)
         occurrences all number
    9
    8
    Depression
         subjects affected / exposed
    5 / 94 (5.32%)
    4 / 91 (4.40%)
         occurrences all number
    5
    4
    Insomnia
         subjects affected / exposed
    11 / 94 (11.70%)
    10 / 91 (10.99%)
         occurrences all number
    11
    10
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    25 / 94 (26.60%)
    13 / 91 (14.29%)
         occurrences all number
    41
    18
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    7 / 94 (7.45%)
    4 / 91 (4.40%)
         occurrences all number
    7
    4
    Weight decreased
         subjects affected / exposed
    25 / 94 (26.60%)
    26 / 91 (28.57%)
         occurrences all number
    43
    40
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 94 (22.34%)
    32 / 91 (35.16%)
         occurrences all number
    23
    46
    Leukopenia
         subjects affected / exposed
    21 / 94 (22.34%)
    11 / 91 (12.09%)
         occurrences all number
    28
    16
    Neutropenia
         subjects affected / exposed
    10 / 94 (10.64%)
    6 / 91 (6.59%)
         occurrences all number
    11
    9
    Thrombocytopenia
         subjects affected / exposed
    2 / 94 (2.13%)
    6 / 91 (6.59%)
         occurrences all number
    4
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 94 (17.02%)
    13 / 91 (14.29%)
         occurrences all number
    18
    15
    Dysphonia
         subjects affected / exposed
    11 / 94 (11.70%)
    8 / 91 (8.79%)
         occurrences all number
    17
    9
    Dyspnoea
         subjects affected / exposed
    6 / 94 (6.38%)
    5 / 91 (5.49%)
         occurrences all number
    9
    5
    Pharyngolaryngeal pain
         subjects affected / exposed
    20 / 94 (21.28%)
    22 / 91 (24.18%)
         occurrences all number
    21
    35
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 94 (3.19%)
    5 / 91 (5.49%)
         occurrences all number
    5
    6
    Dysgeusia
         subjects affected / exposed
    18 / 94 (19.15%)
    7 / 91 (7.69%)
         occurrences all number
    23
    8
    Headache
         subjects affected / exposed
    10 / 94 (10.64%)
    5 / 91 (5.49%)
         occurrences all number
    10
    6
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    11 / 94 (11.70%)
    7 / 91 (7.69%)
         occurrences all number
    14
    7
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    31 / 94 (32.98%)
    24 / 91 (26.37%)
         occurrences all number
    39
    29
    Diarrhoea
         subjects affected / exposed
    7 / 94 (7.45%)
    14 / 91 (15.38%)
         occurrences all number
    8
    16
    Dry mouth
         subjects affected / exposed
    9 / 94 (9.57%)
    5 / 91 (5.49%)
         occurrences all number
    12
    7
    Dyspepsia
         subjects affected / exposed
    5 / 94 (5.32%)
    4 / 91 (4.40%)
         occurrences all number
    7
    7
    Dysphagia
         subjects affected / exposed
    27 / 94 (28.72%)
    19 / 91 (20.88%)
         occurrences all number
    37
    35
    Nausea
         subjects affected / exposed
    47 / 94 (50.00%)
    42 / 91 (46.15%)
         occurrences all number
    76
    65
    Odynophagia
         subjects affected / exposed
    9 / 94 (9.57%)
    5 / 91 (5.49%)
         occurrences all number
    14
    6
    Oesophagitis
         subjects affected / exposed
    5 / 94 (5.32%)
    0 / 91 (0.00%)
         occurrences all number
    5
    0
    Oral pain
         subjects affected / exposed
    9 / 94 (9.57%)
    3 / 91 (3.30%)
         occurrences all number
    9
    3
    Vomiting
         subjects affected / exposed
    24 / 94 (25.53%)
    24 / 91 (26.37%)
         occurrences all number
    36
    41
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 94 (6.38%)
    1 / 91 (1.10%)
         occurrences all number
    6
    1
    Dermatitis
         subjects affected / exposed
    4 / 94 (4.26%)
    10 / 91 (10.99%)
         occurrences all number
    4
    11
    Rash
         subjects affected / exposed
    9 / 94 (9.57%)
    4 / 91 (4.40%)
         occurrences all number
    10
    4
    Skin hyperpigmentation
         subjects affected / exposed
    5 / 94 (5.32%)
    1 / 91 (1.10%)
         occurrences all number
    6
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    13 / 94 (13.83%)
    10 / 91 (10.99%)
         occurrences all number
    14
    13
    Dehydration
         subjects affected / exposed
    10 / 94 (10.64%)
    12 / 91 (13.19%)
         occurrences all number
    12
    18
    Hypokalaemia
         subjects affected / exposed
    19 / 94 (20.21%)
    8 / 91 (8.79%)
         occurrences all number
    19
    11
    Hypomagnesaemia
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 91 (3.30%)
         occurrences all number
    6
    3
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    11 / 94 (11.70%)
    14 / 91 (15.38%)
         occurrences all number
    15
    17
    Oral candidiasis
         subjects affected / exposed
    17 / 94 (18.09%)
    11 / 91 (12.09%)
         occurrences all number
    21
    12
    Oral fungal infection
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 91 (6.59%)
         occurrences all number
    5
    9

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2004
    • The language regarding the administration of investigational product was changed to stress the need for not giving investigational product too close to CT administration. The rationale for giving the investigational product less than 24 hours before, during, or within 5 half-lives of the last chemotherapeutic agent, or 16 ours after completion of chemotherapy administration (whichever is longer), was that the impact of palifermin on the pharmacokinetics of 5-fluroruracil (5-FU) is unknown, nor is it known how 5-FU may impact the pharmacokinetics of palifermin. Thus, until any potential drug interactions are known, it was prudent to separate their administration from one another by an appropriate period of time based on the half-life of the drugs. • Opioid analgesic administration data were to be collected through the month 4 visit of phase B. The rationale for the collection of this data beyond week 12 was that some patients may still have been taking opioid analgesics for oral mouth pain, and the sponsor wanted to capture the end date of these medications. As the study was designed, the month 4 visit of phase B presented the next logical time to collect these data. • The rationale for the change in calculation of duration of OM (applied to all OM duration calculations, not just "severe") was to more appropriately capture data over the entire time frame from onset to resolution of an episode of OM.
    29 Mar 2005
    • The chemotherapy regimen has been changed from cisplatin and 5-fluorouracil (5-FU) administered during weeks 1 and 5 to cisplatin as a single agent administered during weeks 1, 4, and 7. Clinical sites expressed feasibility concerns about the cisplatin/5-FU combination regimen due to high toxicity and logistical requirements associated with the 5-FU continuous infusion; also, 5-FU was not considered standard of care in most clinical centers. This change was expected to make this study acceptable to more potential clinical study sites. No subjects had been enrolled at the time of this amendment. • The treatment arm of 4 weekly doses of palifermin was removed to make this a 2-arm study comparing 8 weekly doses of palifermin 180 μg/kg with 8 weekly doses of placebo; the number of subjects per treatment was to be 90, with same power as previously designed. The change in the study design from a 3-arm to a 2-arm study was based on the fact that clinical and preclinical data to date indicated that 8 weekly doses of palifermin was the schedule of primary interest. The efficacy of the 4 weekly doses palifermin treatment arm was to be evaluated in other studies of the palifermin clinical development program. • The PRO instrument was reduced from 8 to 5 questionnaires.
    17 Jan 2006
    The main reason for this amendment was guidance from the US FDA regarding one of the Early Stopping Guidelines for Safety (section 10.5.3 of the protocol). In amendment 2 dated 10 June 2005, language describing the first of 3 early stopping rules was changed and linked to the definition of PSLTs. Based on the FDA recommendations to include hematologic adverse events, the early stopping rule language was clarified accordingly. The following changes were also made: • A sentence was added to section 10.2.2.3 of the protocol (Patient-reported Outcome Evaluable Subset) addressing regulatory agency questions concerning analyses of PRO data of this study. • Language in section 10.5.2 of the protocol was removed to clarify and confirm that Amgen has no intention of performing an unplanned interim analysis.
    15 Dec 2008
    The sponsorship was transferred from Amgen Inc to Biovitrum AB.
    27 Jul 2015
    • For reducing the long-term safety follow-up (LTSF): At the time of the last analysis (10 April 2015), all subjects with locally advanced head and neck cancer in Study 20020402 who are still alive and stayed in the LTFU have had an opportunity to be followed for at least 9 years. Approximately 46% (86/185) of subjects who were treated with investigational product remain alive. The event rates in LTFU have been very low; therefore, relatively few events are expected to occur annually in future years. This rate of events is consistent with the type and stage of tumor treated in this study. Therefore, the endpoint for the duration of LTFU for the study was changed to limit LTFU to until death, loss to follow-up, or for up to 10 years from the last subject randomized. • Updates have been made to the sponsor contacts. • The informed consent form template has been removed from the appendices and references to that appendix in the body of the protocol have been removed.

    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.
    None reported
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