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    Clinical Trial Results:
    A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of ALD518 in the Reduction of Oral Mucositis in Subjects With Head and Neck Cancer Receiving Concomitant Chemotherapy and Radiotherapy

    Summary
    EudraCT number
    		 2011-002669-40
    Trial protocol
    		 DE   AT   IT  
    Global end of trial date
    25 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2022
    First version publication date
    19 Oct 2022
    Other versions
    Summary report(s)
    		 ALD518-009 Clinical Trial Summary Report INS-717.547

    Trial information

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    Trial identification
    Sponsor protocol code
    ALD518-CLIN-009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01403064
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring
    Sponsor organisation address
    1020 First Avenue, King of Prussia, United States, 19406
    Public contact
    Study Director, CSL Behring, +1 610-878-4000 , clinicaltrials@cslbehring.com
    Scientific contact
    Study Director, CSL Behring, +1 610-878-4000 , clinicaltrials@cslbehring.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 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the clinical trial was to evaluate the safety and efficacy of ALD518 in modifying the course of oral mucositis (OM) in subjects with head and neck cancer (HNC) receiving concurrent chemotherapy and radiotherapy (CRT).
    Protection of trial subjects
    Standard of care procedures were employed in order to minimize harm to the patients. Study staff continuously interacted with the patients and were thoroughly trained on patient rights as well as medically trained to handle any adverse events. Study staff were well-informed on procedures to handle subjects from pre-screening through the completion of the study. All patients were explained the alternatives to being a part of the study. Procedures were also in place to ensure there was no undue coercion during the informed consent process.
    Background therapy
    		 Subjects were newly diagnosed with head and neck cancer and had not received previous treatment for oral mucositis. All enrolled subjects received a continuous course of conventional external beam irradiation delivered by intensity-modulated radiotherapy (IMRT) as single daily fractions of 2.0 to 2.2 Gy, with a cumulative radiation dose between 55 and 72 Gy at each site. Planned radiation treatment fields must include at least 2 oral sites (retromolar trigone, buccal mucosa, floor of mouth, tongue, or soft palate), with each site receiving ≥ 55 Gy. In addition to the experimental regimen (IMRT and ALD518 or IMRT and Placebo) randomized subjects also received a standard cisplatin or carboplatin CT regimen. Investigators were permitted to prescribe any concomitant medication or supportive therapy deemed necessary to provide adequate supportive care including antiemetics, systemic antibiotics, hydration to prevent renal damage, transfusions, topical fluoride, and saline rinses with the exceptions including Methotrexate, Nimesulide, Amifostine (Ethyol®), Antibiotic rinses and troches (antifungal rinses and troches are allowed for the treatment of candidiasis), Benzydamine hydrochloride, Caphosol, Cevimeline hydrochloride (Evoxac®), Glutamine as a prophylactic agent for mucositis, GM-CSF (e.g., Leukine®), IL-11 (Neumega®), ‘Magic mouthwash’, ‘Miracle mouthwash’ or other mouthwash solutions containing, Chlorhexidine, Hydrogen peroxide, or Diphenhydramine, Palifermin (Kepivance®) or other keratinocyte or fibroblast growth factor, Pilocarpine hydrochloride (Salagen®), Povidone-iodine rinses, Steroid rinses, Sucralfate in suspension form (use of sucralfate tablets is not proscribed), other biologic response modifiers – except hematopoietic growth factors for the management of anemia or myelosuppression and other investigational agents.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jul 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    76
    EEA total number of subjects
    34
    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)
    63
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 96 subjects were planned and 76 subjects were analyzed. 72 subjects entered long term follow up. The first subject, first visit occurred 29 August 2011 and the last subject, last visit occurred on 27 March 2014. This study was conducted at 20 study centers in Australia, Austria, Canada, Germany, Italy, and the USA.

    Pre-assignment
    Screening details
    		 Screening included adult subjects recently diagnosed with, pathologically confirmed, non-metastatic SCC of the oral cavity, oropharynx, hypopharynx or larynx and who had treatment plans for first-line CRT.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 0.9% saline administered as two intravenous infusions (IV) 3 weeks apart
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% saline administered as two intravenous infusions (IV) 3 weeks apart

    Arm title
    		 ALD518 (160 mg, OL)
    Arm description
    		 ALD518 160 mg IV every 4 weeks for a total of 2 doses in open-label (OL) treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALD518
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    ALD518 administered intravenously

    Arm title
    		 ALD518 (160 mg, R)
    Arm description
    		 ALD518 160 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.9% saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% saline administered as two intravenous infusions (IV) 3 weeks apart

    Arm title
    		 ALD518 (320 mg, R)
    Arm description
    		 ALD518 320 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALD518
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    ALD518 administered intravenously

    Number of subjects in period 1
    		Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Started
    24
    7
    23
    22
    Completed
    23
    7
    19
    19
    Not completed
    1
    0
    4
    3
         Adverse event, serious fatal
    -
    -
    1
    1
         Consent withdrawn by subject
    -
    -
    1
    1
         unknown
    1
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 0.9% saline administered as two intravenous infusions (IV) 3 weeks apart

    Reporting group title
    ALD518 (160 mg, OL)
    Reporting group description
    		 ALD518 160 mg IV every 4 weeks for a total of 2 doses in open-label (OL) treatment

    Reporting group title
    ALD518 (160 mg, R)
    Reporting group description
    		 ALD518 160 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment

    Reporting group title
    ALD518 (320 mg, R)
    Reporting group description
    		 ALD518 320 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment

    Reporting group values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R) Total
    Number of subjects
    		 24 7 23 22 76
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.8 ( 7.92 ) 56.3 ( 11.93 ) 58.6 ( 7.43 ) 55.1 ( 7.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 7 1 13
        Male
    		 20 6 16 21 63

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 0.9% saline administered as two intravenous infusions (IV) 3 weeks apart

    Reporting group title
    ALD518 (160 mg, OL)
    Reporting group description
    		 ALD518 160 mg IV every 4 weeks for a total of 2 doses in open-label (OL) treatment

    Reporting group title
    ALD518 (160 mg, R)
    Reporting group description
    		 ALD518 160 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment

    Reporting group title
    ALD518 (320 mg, R)
    Reporting group description
    		 ALD518 320 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment

    Primary: Number of Participants With All Grades of OM at a Radiation Dose of 55 Gy

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    End point title
    		 Number of Participants With All Grades of OM at a Radiation Dose of 55 Gy [1]
    End point description
    The 55 Gy ulcerative OM assessment is defined as the first ulcerative OM assessment that occurred on the day of or after the subject received the radiation therapy that first resulted in their cumulative dose of radiation being ≥ 55 Gy
    End point type
    Primary
    End point timeframe
    Up to 12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were used.
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24
    7
    23
    22
    Units: Participants
        number (not applicable)
    19
    5
    23
    17
    No statistical analyses for this end point

    Secondary: Number of Participants With Ulcerative OM at Varying Cumulative Radiation Doses (Gy)

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    End point title
    		 Number of Participants With Ulcerative OM at Varying Cumulative Radiation Doses (Gy)
    End point description
    The ulcerative OM assessment at a specific cumulative radiation dose (35 Gy, 45 Gy, 55 Gy or 65 Gy) is defined as the first ulcerative OM assessment that occurred on the day of or after the subject received the radiation therapy that first resulted in the specific cumulative dose of radiation being ≥35 Gy, ≥45 Gy, ≥55 Gy or≥ 65 Gy
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24 [2]
    7 [3]
    22 [4]
    20 [5]
    Units: Participants
    number (not applicable)
        35 Gy
    14
    6
    18
    13
        45 Gy
    21
    6
    20
    15
        55 Gy
    19
    5
    22
    15
        65 Gy
    15
    5
    19
    11
    Notes
    [2] - For 35, 45, 55, and 65 Gy, n = 24, 24, 24 and 18, respectively
    [3] - For 35, 45, 55, and 65 Gy, n = 7, 7, 7 and 6, respectively
    [4] - For 35, 45, 55, and 65 Gy, n = 22, 22, 22 and 19, respectively
    [5] - For 35, 45, 55, and 65 Gy, n = 20, 20, 20 and 16, respectively
    No statistical analyses for this end point

    Secondary: Number of Participants With Severe OM at Varying Cumulative Radiation Doses (Gy)

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    End point title
    		 Number of Participants With Severe OM at Varying Cumulative Radiation Doses (Gy)
    End point description
    The severe OM assessment at a specific cumulative radiation dose (35 Gy, 45 Gy, 55 Gy or 65 Gy) is defined as the first severe OM assessment that occurred on the day of or after the subject received the radiation therapy that first resulted in the specific cumulative dose of radiation being ≥35 Gy, ≥45 Gy, ≥55 Gy or≥ 65 Gy
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24 [6]
    7 [7]
    22 [8]
    20 [9]
    Units: Participants
    number (not applicable)
        35 Gy
    6
    4
    6
    6
        45 Gy
    10
    5
    8
    9
        55 Gy
    12
    5
    9
    11
        65 Gy
    10
    3
    12
    7
    Notes
    [6] - For 35, 45, 55, and 65 Gy, n = 24, 24, 24 and 18, respectively
    [7] - For 35, 45, 55, and 65 Gy, n = 7, 7, 7 and 6, respectively
    [8] - For 35, 45, 55, and 65 Gy, n = 22, 22, 22 and 19, respectively
    [9] - For 35, 45, 55, and 65 Gy, n = 20, 20, 20 and 16, respectively
    No statistical analyses for this end point

    Secondary: Duration of Ulcerative and Severe OM

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    End point title
    		 Duration of Ulcerative and Severe OM
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24
    7
    23
    22
    Units: Days
    arithmetic mean (standard deviation)
        Ulcerative
    42.0 ( 23.17 )
    55.1 ( 26.57 )
    48.3 ( 16.71 )
    38.0 ( 29.53 )
        Severe
    22.4 ( 23.28 )
    35.1 ( 28.02 )
    22.7 ( 18.95 )
    21.5 ( 25.01 )
    No statistical analyses for this end point

    Secondary: Time to Onset of Ulcerative and Severe OM

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    End point title
    		 Time to Onset of Ulcerative and Severe OM
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24 [10]
    7 [11]
    23 [12]
    22 [13]
    Units: Days
    arithmetic mean (standard deviation)
        Ulcerative
    23.7 ( 7.05 )
    18.7 ( 5.32 )
    22.9 ( 5.97 )
    24.3 ( 13.37 )
        Severe
    37.0 ( 11.81 )
    26.1 ( 5.72 )
    43.1 ( 17.55 )
    38.0 ( 15.64 )
    Notes
    [10] - For ulcerative and severe OM, n = 22 and 15, respectively
    [11] - For ulcerative and severe OM, n = 6 and 5, respectively
    [12] - For ulcerative and severe OM, n = 22 and 20, respectively
    [13] - For ulcerative and severe OM, n = 18 and 14, respectively
    No statistical analyses for this end point

    Secondary: Oral Mucositis Daily Questionnaire (OMDQ) Overall Health Score at Varying Cumulative Radiation Doses (Gy)

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    End point title
    		 Oral Mucositis Daily Questionnaire (OMDQ) Overall Health Score at Varying Cumulative Radiation Doses (Gy)
    End point description
    Scored on a scale from 0 (worst possible overall health) to 10 (perfect overall health). Higher scores represent better overall health.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24 [14]
    7 [15]
    23 [16]
    22 [17]
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    6.5 ( 1.95 )
    8.4 ( 1.40 )
    7.2 ( 1.66 )
    6.7 ( 2.35 )
        35 Gy (up to 12 weeks)
    5.2 ( 2.08 )
    6.6 ( 2.07 )
    5.2 ( 2.05 )
    5.5 ( 1.91 )
        45 Gy (up to 12 weeks)
    5.6 ( 1.89 )
    5.7 ( 2.14 )
    5.4 ( 1.86 )
    5.4 ( 2.40 )
        55 Gy (up to 12 weeks)
    5.1 ( 1.96 )
    5.9 ( 2.54 )
    5.3 ( 2.22 )
    5.1 ( 2.27 )
        65 Gy (up to 12 weeks)
    5.6 ( 1.79 )
    5.7 ( 3.08 )
    5.3 ( 2.11 )
    5.6 ( 2.37 )
    Notes
    [14] - For baseline, 35, 45, 55, and 65 Gy, n = 22, 24, 24, 22, and 18, respectively
    [15] - For baseline, 35, 45, 55, and 65 Gy, n = 7, 7, 7, 7, and 6, respectively
    [16] - For baseline, 35, 45, 55, and 65 Gy, n = 20, 22, 21, 21, and 16, respectively
    [17] - For baseline, 35, 45, 55, and 65 Gy, n = 18, 20, 17, 18, and 14, respectively
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) Questionnaire Overall Assessment Score at Varying Cumulative Radiation Doses (Gy)

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    End point title
    		 Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) Questionnaire Overall Assessment Score at Varying Cumulative Radiation Doses (Gy)
    End point description
    The FACT-HN consists of 28 general + 11 head and neck specific items, each rated on a 0 (not at all) to 4 (very much) Likert type scale. The total score ranges from 0 to 148. Higher scores represent better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24 [18]
    7 [19]
    23 [20]
    22 [21]
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    116.5 ( 15.86 )
    129.4 ( 12.63 )
    113.8 ( 19.53 )
    111.3 ( 20.94 )
        35 Gy (up to 12 weeks)
    92.9 ( 20.14 )
    100.3 ( 24.14 )
    96.2 ( 21.18 )
    92.2 ( 19.96 )
        45 Gy (up to 12 weeks)
    90.6 ( 18.18 )
    94.7 ( 30.14 )
    89.7 ( 23.49 )
    86.6 ( 21.34 )
        55 Gy (up to 12 weeks)
    89.6 ( 19.36 )
    82.3 ( 17.79 )
    84.4 ( 25.67 )
    81.1 ( 22.13 )
        65 Gy (up to 12 weeks)
    85.2 ( 18.13 )
    93.6 ( 27.50 )
    86.5 ( 18.00 )
    86.5 ( 23.95 )
    Notes
    [18] - For baseline, 35, 45, 55, and 65 Gy, n = 22, 23, 24, 24, and 18, respectively
    [19] - For baseline, 35, 45, 55, and 65 Gy, n = 7, 7, 7, 6, and 6, respectively
    [20] - For baseline, 35, 45, 55, and 65 Gy, n = 22, 22, 20, 19, and 19, respectively
    [21] - For baseline, 35, 45, 55, and 65 Gy, n = 20, 20, 19, 19, and 16, respectively
    No statistical analyses for this end point

    Secondary: Functional Assessment of Chronic Illness Therapy - Fatigue Questionnaire (FACIT-F) Score at Varying Cumulative Radiation Doses (Gy)

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    End point title
    		 Functional Assessment of Chronic Illness Therapy - Fatigue Questionnaire (FACIT-F) Score at Varying Cumulative Radiation Doses (Gy)
    End point description
    The responses to the 13 items on the FACIT-F questionnaire are each measured on a 5-point Likert scale from 0 (not at all fatigued) to 4 (very much fatigued). The total score ranges from 0 to 52. Higher scores represent more fatigue.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 12 weeks
    End point values
    		 Placebo ALD518 (160 mg, OL) ALD518 (160 mg, R) ALD518 (320 mg, R)
    Number of subjects analysed
    24 [22]
    7 [23]
    23 [24]
    22 [25]
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    42.5 ( 7.26 )
    47.6 ( 3.26 )
    42.6 ( 8.61 )
    39.7 ( 10.94 )
        35 Gy (up to 12 weeks)
    31.1 ( 12.56 )
    30.1 ( 16.63 )
    34.0 ( 9.59 )
    31.2 ( 13.56 )
        45 Gy (up to 12 weeks)
    30.3 ( 11.42 )
    28.9 ( 15.61 )
    31.2 ( 12.33 )
    30.4 ( 11.65 )
        55 Gy (up to 12 weeks)
    29.9 ( 12.95 )
    20.8 ( 14.70 )
    28.0 ( 12.95 )
    26.8 ( 13.71 )
        65 Gy (up to 12 weeks)
    29.6 ( 10.81 )
    26.8 ( 18.71 )
    27.3 ( 9.65 )
    29.5 ( 12.40 )
    Notes
    [22] - For baseline, 35, 45, 55, and 65 Gy, n = 24, 22, 24, 24, and 18, respectively
    [23] - For baseline, 35, 45, 55, and 65 Gy, n = 7, 7, 7, 6, and 6, respectively
    [24] - For baseline, 35, 45, 55, and 65 Gy, n = 23, 22, 20, 20, and 19, respectively
    [25] - For baseline, 35, 45, 55, and 65 Gy, n = 21, 20, 19, 19, and 16, respectively
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 15 months for each participant
    Adverse event reporting additional description
    Safety Population defined as any subject who received at least 1 dose of ALD518 or placebo. Subjects were analyzed based on the treatment they received. As pre-specified, the two treatment groups that received 160 mg were combined into one 160 mg group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 0.9% saline administered as two intravenous infusions (IV) 3 weeks apart

    Reporting group title
    ALD518 (160 mg)
    Reporting group description
    		 ALD518 160 mg IV every 4 weeks for a total of 2 doses in open-label (OL) treatment or ALD518 160 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment.

    Reporting group title
    ALD518 (320 mg)
    Reporting group description
    		 ALD518 320 mg IV every 3 weeks for a total of 2 doses in randomized (R) treatment

    Serious adverse events
    		 Placebo ALD518 (160 mg) ALD518 (320 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 23 (30.43%)
    15 / 32 (46.88%)
    8 / 21 (38.10%)
         number of deaths (all causes)
    0
    4
    2
         number of deaths resulting from adverse events
    0
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 32 (9.38%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive airway disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal fistula
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood phosphorous decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 32 (9.38%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo ALD518 (160 mg) ALD518 (320 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 23 (95.65%)
    32 / 32 (100.00%)
    21 / 21 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Tumour ulceration
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Aortic dilatation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Hypotension
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    2
    Lymphoedema
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 32 (12.50%)
    4 / 21 (19.05%)
         occurrences all number
    3
    4
    4
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Catheter site inflammation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Catheter site pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    Drug intolerance
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Face oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Fatigue
         subjects affected / exposed
    8 / 23 (34.78%)
    7 / 32 (21.88%)
    5 / 21 (23.81%)
         occurrences all number
    8
    7
    5
    Hyperthermia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion site erythema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Local swelling
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Localized oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Malaise
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    1
    Pyrexia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 32 (9.38%)
    7 / 21 (33.33%)
         occurrences all number
    2
    3
    7
    Dysphonia
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 32 (9.38%)
    3 / 21 (14.29%)
         occurrences all number
    3
    3
    3
    Dyspnoea
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Epiglottic oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 32 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    4
    1
    Hiccups
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Hypoxia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Increased upper airway secretion
         subjects affected / exposed
    4 / 23 (17.39%)
    4 / 32 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    4
    4
    1
    Laryngeal oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 23 (17.39%)
    8 / 32 (25.00%)
    6 / 21 (28.57%)
         occurrences all number
    4
    8
    6
    Pleuritic pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum discolored
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Sputum increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Anxiety
         subjects affected / exposed
    1 / 23 (4.35%)
    4 / 32 (12.50%)
    4 / 21 (19.05%)
         occurrences all number
    1
    4
    4
    Confusional state
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Depressed mood
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    4 / 32 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    1
    4
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    3 / 21 (14.29%)
         occurrences all number
    2
    2
    3
    Blood alkaline phosphotase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Blood chloride decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 32 (9.38%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 32 (15.63%)
    1 / 21 (4.76%)
         occurrences all number
    1
    5
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Blood urea increased
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram change
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Globulins decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Haematocrit decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 32 (3.13%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    2
    Haemoglobin decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 32 (9.38%)
    2 / 21 (9.52%)
         occurrences all number
    2
    3
    2
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    0
    2
    Mean cell haemoglobin concentration decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Mean cell haemoglobin decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Mean cell volume decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    6 / 21 (28.57%)
         occurrences all number
    2
    2
    6
    Platelet count decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    7 / 32 (21.88%)
    8 / 21 (38.10%)
         occurrences all number
    2
    7
    8
    Prealbumin decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Renal function test abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Reticulocyte count decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Weight decreased
         subjects affected / exposed
    7 / 23 (30.43%)
    11 / 32 (34.38%)
    11 / 21 (52.38%)
         occurrences all number
    7
    11
    11
    White blood cell count decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 32 (9.38%)
    9 / 21 (42.86%)
         occurrences all number
    2
    3
    9
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Post procedural haematoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Post procedural oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Radiation fibrosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Radiation skin injury
         subjects affected / exposed
    7 / 23 (30.43%)
    8 / 32 (25.00%)
    5 / 21 (23.81%)
         occurrences all number
    7
    8
    5
    Suture related complication
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Tracheal obstruction
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Bundle branch block left
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 32 (9.38%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    2
    Aphasia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Aphonia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 23 (4.35%)
    7 / 32 (21.88%)
    1 / 21 (4.76%)
         occurrences all number
    1
    7
    1
    Drooling
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Dysgeusia
         subjects affected / exposed
    12 / 23 (52.17%)
    11 / 32 (34.38%)
    5 / 21 (23.81%)
         occurrences all number
    12
    11
    5
    Headache
         subjects affected / exposed
    8 / 23 (34.78%)
    6 / 32 (18.75%)
    3 / 21 (14.29%)
         occurrences all number
    8
    6
    3
    Hypogeusia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Myoclonus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Polyneuropathy
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue biting
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Tongue paralysis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Drug dependence
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    4 / 23 (17.39%)
    6 / 32 (18.75%)
    1 / 21 (4.76%)
         occurrences all number
    4
    6
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 23 (17.39%)
    10 / 32 (31.25%)
    4 / 21 (19.05%)
         occurrences all number
    4
    10
    4
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Erythropenia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Leukopenia
         subjects affected / exposed
    7 / 23 (30.43%)
    13 / 32 (40.63%)
    6 / 21 (28.57%)
         occurrences all number
    7
    13
    6
    Lymphadenopathy
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphatic obstruction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Lymphopenia
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 32 (9.38%)
    2 / 21 (9.52%)
         occurrences all number
    2
    3
    2
    Neutropenia
         subjects affected / exposed
    3 / 23 (13.04%)
    10 / 32 (31.25%)
    5 / 21 (23.81%)
         occurrences all number
    3
    10
    5
    Pancytopenia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 23 (8.70%)
    9 / 32 (28.13%)
    7 / 21 (33.33%)
         occurrences all number
    2
    9
    7
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Ear discomfort
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Ear pain
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 32 (15.63%)
    3 / 21 (14.29%)
         occurrences all number
    1
    5
    3
    Hyperacusis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoacusis
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    Tinnitis
         subjects affected / exposed
    4 / 23 (17.39%)
    2 / 32 (6.25%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    2
    Vertigo
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 32 (9.38%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    Aphagia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Breath odor
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    Constipation
         subjects affected / exposed
    13 / 23 (56.52%)
    22 / 32 (68.75%)
    9 / 21 (42.86%)
         occurrences all number
    13
    22
    9
    Diarrhoea
         subjects affected / exposed
    10 / 23 (43.48%)
    7 / 32 (21.88%)
    3 / 21 (14.29%)
         occurrences all number
    10
    7
    3
    Dry mouth
         subjects affected / exposed
    10 / 23 (43.48%)
    11 / 32 (34.38%)
    5 / 21 (23.81%)
         occurrences all number
    10
    11
    5
    Dyspepsia
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 32 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    3
    4
    1
    Dysphagia
         subjects affected / exposed
    6 / 23 (26.09%)
    12 / 32 (37.50%)
    2 / 21 (9.52%)
         occurrences all number
    6
    12
    2
    Epigastric discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 32 (15.63%)
    2 / 21 (9.52%)
         occurrences all number
    1
    5
    2
    Glossitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    3
    Haemorrhoids
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Mouth ulceration
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    14 / 23 (60.87%)
    20 / 32 (62.50%)
    14 / 21 (66.67%)
         occurrences all number
    14
    20
    14
    Odynophagia
         subjects affected / exposed
    5 / 23 (21.74%)
    5 / 32 (15.63%)
    4 / 21 (19.05%)
         occurrences all number
    5
    5
    4
    Oral mucosal erythema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
         subjects affected / exposed
    9 / 23 (39.13%)
    3 / 32 (9.38%)
    7 / 21 (33.33%)
         occurrences all number
    9
    3
    7
    Regurgitation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Saliva altered
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    2
    Salivary hypersecretion
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    Stomatitis
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Swollen tongue
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Tongue oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Vomiting
         subjects affected / exposed
    9 / 23 (39.13%)
    12 / 32 (37.50%)
    10 / 21 (47.62%)
         occurrences all number
    9
    12
    10
    Hepatobiliary disorders
    Hyperbilirubinemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    1
    Ecchymosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Photodermatosis
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Pruritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Psoriasis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Rash macular
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Rash pruritic
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Skin discoloration
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Skin exfoliation
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nocturia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Oliguria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Polyuria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle twitching
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Neck pain
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 32 (6.25%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    1
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Pain in jaw
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Febrile infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Infective glossitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 32 (3.13%)
    3 / 21 (14.29%)
         occurrences all number
    4
    1
    3
    Oral candidiasis
         subjects affected / exposed
    11 / 23 (47.83%)
    18 / 32 (56.25%)
    8 / 21 (38.10%)
         occurrences all number
    11
    18
    8
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Pharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pseudomonas infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Staphylococcal pharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea cruris
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheostomy infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Viral infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 23 (21.74%)
    4 / 32 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    5
    4
    1
    Dehydration
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 32 (15.63%)
    1 / 21 (4.76%)
         occurrences all number
    1
    5
    1
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Electrolyte imbalance
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Gout
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 32 (3.13%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    4 / 21 (19.05%)
         occurrences all number
    1
    2
    4
    Hypokalaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 32 (15.63%)
    4 / 21 (19.05%)
         occurrences all number
    0
    5
    4
    Hypomagnesaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 32 (6.25%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 32 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Hypophagia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 32 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2012
    •Updated to indicate that the DMC approved the addition of 4 subjects in the open-label phase of the study and changed dosing schedule from every 4 weeks to every 3 weeks. •For inclusion criteria (IC) #3, clarified regions of radiation treatment and added “retromolar trigone”. •In IC #4, removed details for chemo regimens; sites instructed to use their standard of care. •Changed day of first dose of ALD518 to Day 0 from Day 1. •Removed RECIST criteria and replaced with standard TNM criteria. •Added Canada to list of countries participating. •Added Cockcroft-Gault calculation for renal function in IC #7. •Revised IC #8 to state that subjects cannot be currently breastfeeding. •Revised exclusion criteria (EC) #10 to include previous exposure to active TB or histoplasmosis infection, in addition to previous history. •Deleted EC #12 and EC #18 •Added EC #19 - to exclude subjects who have a history of diverticulosis, diverticulitis, perforated diverticular diseases, or small bowel and/or upper GI perforation •Updated likely duration of clinical trial participation to 16 months from 15 months. •Added death to primary safety endpoints. •Clarified the upper transaminase level criteria in the Criteria for Discontinuation of Investigational Product. •Lab safety tests changed from collection every 3-4 weeks during RT to collection every week during RT. •Plasma IL-6 changed to Serum IL-6 •2 additional PK and immunogenicity timepoints added –Visits 8 and 14 – due to dosing schedule change. •Clarification added to continue OM assessments of subjects who have OM at week 4 post-RT •Clarification stating that Visit 18 should always be the last day of radiation therapy. •Added new figures to show the PK modeling for 3 week dosing and to compare 3 week to 4 week dosing. •Updated vital sign schedule new ALD518 infusion schedule. •Added updates regarding SAE reporting contact info. •Clarified that screen-failed population will not be statistically analysed.
    27 Nov 2012
    •Revised exclusion criteria #1 to exclude subjects who have tumor invasion of major vessels. •Germany and Canada were the only countries to request this amendment. The Nov 2012 administrative letter (below) was acceptable in all other countries. Administrative Letter 09 Nov 2012 •Revised exclusion criteria #1 to exclude subjects who have tumor invasion of major vessels.

    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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