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    Clinical Trial Results:
    Phase 3b Study for Management of Ocular Side Effects in Subjects with EGFR-amplified Glioblastoma Receiving Depatuxizumab Mafodotin (ABT-414)

    Summary
    EudraCT number
    		 2017-003171-64
    Trial protocol
    		 GB   NL   DE  
    Global end of trial date
    03 Mar 2020

    Results information
    Results version number
    		 v1
    This version publication date
    04 Mar 2021
    First version publication date
    04 Mar 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    M16-534
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03419403
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    AbbVie, Global Medical Services, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    AbbVie, Global Medical Services, 001 8006339110, abbvieclinicaltrials@abbvie.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
    03 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this Phase 3b open-label, randomized, exploratory study was to evaluate the effect of several ophthalmologic prophylactic treatment strategies for the management of ocular side effects (OSEs) in subjects with epidermal growth factor receptor (EGFR)-amplified glioblastoma (GBM) treated with depatuxizumab mafodotin (ABT-414). All subjects received ABT-414 during both phases of the treatment period plus 1 of 3 prophylactic ophthalmologic treatments (standard steroids; standard steroids with vasoconstrictors and cold compress; and enhanced steroids with vasoconstrictors and cold compress. The study had a screening period of up to 7 weeks after surgery, a 6-week concomitant Chemoradiation Phase (radiation plus temozolomide [RT/TMZ]), an Adjuvant Phase (TMZ) beginning approximately 4 weeks after completion of chemoradiation, and a Follow-Up Phase. The study was terminated because clinical development of ABT-414 in glioblastoma was stopped due to lack of survival benefit.
    Protection of trial subjects
    Subjects must have voluntarily signed and dated an informed consent form, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 30
    Worldwide total number of subjects
    40
    EEA total number of subjects
    1
    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)
    33
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All randomized subjects; two subjects were randomized to the study but received no doses of depatuxizumab mafodotin or prophylactic eye treatments.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Steroids
    Arm description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Steroid eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Intraocular use
    Dosage and administration details
    1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days;

    Investigational medicinal product name
    Depatuxizumab mafodotin
    Investigational medicinal product code
    Other name
    ABT-414
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 – 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 – 40 minute infusion for 12 cycles.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 – 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.

    Arm title
    		 Standard Steroids + Vasoconstrictor + Cold Compress
    Arm description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. The cold compress should be applied in increments no longer than 30 min (could be shorter if the participant was uncomfortable).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Steroid eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Intraocular use
    Dosage and administration details
    1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days;

    Investigational medicinal product name
    Vasoconstrictor eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Intraocular use
    Dosage and administration details
    1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion;

    Investigational medicinal product name
    Depatuxizumab mafodotin
    Investigational medicinal product code
    Other name
    ABT-414
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 – 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 – 40 minute infusion for 12 cycles.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 – 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.

    Arm title
    		 Enhanced Steroids + Vasoconstrictor + Cold Compress
    Arm description
    		 Enhanced steroid eye drops: 1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Ophthalmic Steroid Ointment; applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. Cold compress was to be applied in increments no longer than 30 min (could be shorter if the patient is uncomfortable).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Steroid eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Intraocular use
    Dosage and administration details
    1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days;

    Investigational medicinal product name
    Vasoconstrictor eye drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Intraocular use
    Dosage and administration details
    1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion;

    Investigational medicinal product name
    Ophthalmic steroid ointment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Ocular use
    Dosage and administration details
    Applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days;

    Investigational medicinal product name
    Depatuxizumab mafodotin
    Investigational medicinal product code
    Other name
    ABT-414
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 – 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 – 40 minute infusion for 12 cycles.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 – 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.

    Number of subjects in period 1 [1]
    		Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Started
    14
    12
    12
    Completed
    2
    3
    0
    Not completed
    12
    9
    12
         Left study due to COVID-19 restrictions
    1
    1
    -
         Progressive disease (per protocol)
    -
    2
    2
         Other, not specified
    6
    4
    5
         Withdrawal by subject
    5
    2
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two subjects were randomized to the study but received no doses of depatuxizumab mafodotin or prophylactic eye treatments and are not included in any treatment group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Steroids
    Reporting group description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days

    Reporting group title
    Standard Steroids + Vasoconstrictor + Cold Compress
    Reporting group description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. The cold compress should be applied in increments no longer than 30 min (could be shorter if the participant was uncomfortable).

    Reporting group title
    Enhanced Steroids + Vasoconstrictor + Cold Compress
    Reporting group description
    		 Enhanced steroid eye drops: 1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Ophthalmic Steroid Ointment; applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. Cold compress was to be applied in increments no longer than 30 min (could be shorter if the patient is uncomfortable).

    Reporting group values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress Total
    Number of subjects
    		 14 12 12 38
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.6 ( 9.85 ) 55.2 ( 10.53 ) 57.3 ( 8.69 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 1 8
        Male
    		 11 8 11 30

    End points

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    End points reporting groups
    Reporting group title
    Standard Steroids
    Reporting group description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days

    Reporting group title
    Standard Steroids + Vasoconstrictor + Cold Compress
    Reporting group description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. The cold compress should be applied in increments no longer than 30 min (could be shorter if the participant was uncomfortable).

    Reporting group title
    Enhanced Steroids + Vasoconstrictor + Cold Compress
    Reporting group description
    		 Enhanced steroid eye drops: 1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Ophthalmic Steroid Ointment; applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. Cold compress was to be applied in increments no longer than 30 min (could be shorter if the patient is uncomfortable).

    Primary: Percentage of Participants Who Required a Change in Ocular Side Effect (OSE) Management

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    End point title
    		 Percentage of Participants Who Required a Change in Ocular Side Effect (OSE) Management [1]
    End point description
    Inadequate control of ocular side effects (OSE) was defined as either a ≥ 3-line decline from baseline (≥ +0.3 on LogMAR scale) in visual acuity (with baseline correction determined at the screening ophthalmology visit)) or ≥ Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) scale.
    End point type
    Primary
    End point timeframe
    Within 8 weeks after the initial dose of depatuxizumab mafodotin
    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: Treatment differences were not evaluated due to small sample size.
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [2]
    12 [3]
    12 [4]
    Units: percentage of participants
    number (not applicable)
        Bilateral vision
    50.0
    27.3
    41.7
        Vision in worst eye
    64.3
    72.7
    50.0
    Notes
    [2] - Subjects rcvd ≥1 ABT-414 dose + ≥1 post-baseline value w/in 8 wks after 1st dose for LogMAR or CEAE
    [3] - Subjects rcvd ≥1 ABT-414 dose + ≥1 post-baseline value w/in 8 wks after 1st dose for LogMAR or CEAE
    [4] - Subjects rcvd ≥1 ABT-414 dose + ≥1 post-baseline value w/in 8 wks after 1st dose for LogMAR or CEAE
    No statistical analyses for this end point

    Secondary: Change From Baseline In Logarithm of the Minimum Angle of Resolution (LogMAR) Scale After Bandage Contact Lens (BCL) Intervention

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    End point title
    		 Change From Baseline In Logarithm of the Minimum Angle of Resolution (LogMAR) Scale After Bandage Contact Lens (BCL) Intervention
    End point description
    The change on the LogMAR Scale from last assessment prior to BCL intervention to 2 weeks after BCL intervention was calculated. The LogMAR scale measures visual acuity on a continuous scale, with a LogMAR value of 0 equivalent to 20/20 visual acuity. Normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment. In the table below, a value of 999 indicates not calculable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 18 weeks after initial dose of depatuxizumab mafodotin
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [5]
    12 [6]
    12 [7]
    Units: units on a scale
    arithmetic mean (standard deviation)
        W/in 8 wks of 1st dose:Bilateral vision (n= 4,2,3)
    0.325 ( 0.1248 )
    0.13 ( 0.099 )
    0.54 ( 0.1442 )
        W/in 8 wks of 1st dose:Worst eye (n= 4,2,3)
    0.435 ( 0.0574 )
    0.52 ( 0.3111 )
    0.867 ( 0.2914 )
        W/in 8 wks of 1st adj dose:Bil vision (n= 1,2,0)
    -0.1 ( 999 )
    0.41 ( 0.2404 )
    999 ( 999 )
        W/in 8 wks of 1st adj dose:Worst eye (n= 1,2,0)
    -0.1 ( 999 )
    0.33 ( 0.0141 )
    999 ( 999 )
    Notes
    [5] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [6] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [7] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Cumulative Dose of Depatuxizumab Mafodotin Received During Chemoradiation and During Adjuvant Treatment

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    End point title
    		 Cumulative Dose of Depatuxizumab Mafodotin Received During Chemoradiation and During Adjuvant Treatment
    End point description
    The cumulative dose of depatuxizumab mafodotin administered was tabulated.
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [8]
    12 [9]
    12 [10]
    Units: mg/kg
        arithmetic mean (standard deviation)
    8.5 ( 5.86 )
    10.5 ( 7.35 )
    7.0 ( 3.67 )
    Notes
    [8] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [9] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [10] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Time to Bandage Contact Lens (BCL) Intervention

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    End point title
    		 Time to Bandage Contact Lens (BCL) Intervention
    End point description
    The time to initiation of bandage contact lenses for those participants who required intervention due to inadequate control of ocular side effects (OSE) was calculated. In the table below, a value of 999 indicates not calculable due to insufficient number of participants with events
    End point type
    Secondary
    End point timeframe
    Up to 9 months after the first dose of depatuxizumab mafodotin
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [11]
    12 [12]
    12 [13]
    Units: months
        median (confidence interval 95%)
    999 (1.1 to 999)
    3.6 (1.1 to 999)
    2.1 (1.1 to 999)
    Notes
    [11] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [12] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [13] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Time to Ocular Side Effect (OSE) Symptom Resolution After Drug Discontinuation (Reversibility)

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    End point title
    		 Time to Ocular Side Effect (OSE) Symptom Resolution After Drug Discontinuation (Reversibility)
    End point description
    The time from discontinuation of depatuxizumab mafodotin to OSE symptom resolution (reversibility) was to be recorded.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until 49 days after last depatuxizumab mafodotin administration, up to 47 weeks
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: weeks
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [14] - Data were not collected for this outcome (due to early termination of the study)
    [15] - Data were not collected for this outcome (due to early termination of the study)
    [16] - Data were not collected for this outcome (due to early termination of the study)
    No statistical analyses for this end point

    Secondary: Time to Restart Depatuxizumab Mafodotin if Interrupted Due to Ocular Side Effects After Bandage Contact Lens (BCL) Intervention

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    End point title
    		 Time to Restart Depatuxizumab Mafodotin if Interrupted Due to Ocular Side Effects After Bandage Contact Lens (BCL) Intervention
    End point description
    The time to restart depatuxizumab mafodotin treatment if it was interrupted due to ocular side effects after BCL Intervention was tabulated.
    End point type
    Secondary
    End point timeframe
    From the last assessment prior to BCL intervention to the end of BCL intervention
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: weeks
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [17] - Data were not collected for this outcome (due to early termination of the study)
    [18] - Data were not collected for this outcome (due to early termination of the study)
    [19] - Data were not collected for this outcome (due to early termination of the study)
    No statistical analyses for this end point

    Secondary: Treatment-Emergent Corneal Epithelial Adverse Event (CEAE) Grade at Each Visit

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    End point title
    		 Treatment-Emergent Corneal Epithelial Adverse Event (CEAE) Grade at Each Visit
    End point description
    The corneal epithelial adverse event (CEAE) rating scale is designed to record symptoms associated with corneal epitheliopathy caused by antibody-drug conjugates and to grade the severity of findings. The overall CEAE grade is measured on a scale of 0 to 5, with higher values being more severe, reflecting the impact of corneal abnormalities on visual activities of daily living (ADLs). Additional detailed information is collected for specific domains that are commonly affected, with the following ranges (each in order of increasing severity): ocular discomfort (0 - 4), photophobia (0 - 3), and reading (1 - 3).
    End point type
    Secondary
    End point timeframe
    Up to 63 weeks
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [20]
    12 [21]
    12 [22]
    Units: participants
        Week 1: Grade 0
    10
    8
    5
        Week 1: Grade 1
    1
    3
    1
        Week 3: Grade 0
    4
    5
    7
        Week 3: Grade 1
    10
    6
    3
        Week 3: Grade 2
    0
    0
    1
        Week 5: Grade 0
    1
    0
    2
        Week 5: Grade 1
    7
    5
    6
        Week 5: Grade 2
    1
    3
    2
        Week 5: Grade 3
    4
    2
    2
        Week 7: Grade 0
    0
    0
    2
        Week 7: Grade 1
    3
    4
    0
        Week 7: Grade 2
    4
    6
    5
        Week 7: Grade 3
    2
    0
    2
        Week 9: Grade 0
    1
    0
    1
        Week 9: Grade 1
    1
    2
    0
        Week 9: Grade 2
    3
    5
    4
        Week 9: Grade 3
    2
    0
    1
        Week 11: Grade 0
    0
    0
    1
        Week 11: Grade 1
    2
    1
    0
        Week 11: Grade 2
    2
    0
    3
        Week 11: Grade 3
    1
    0
    1
        Week 11: Grade 4
    1
    0
    0
        Week 13: Grade 1
    1
    0
    1
        Adj Week 1: Grade 0
    0
    1
    0
        Adj Week 1: Grade 1
    1
    3
    2
        Adj Week 1: Grade 2
    3
    2
    2
        Adj Week 1: Grade 3
    1
    0
    0
        Adj Week 5: Grade 0
    0
    2
    2
        Adj Week 5: Grade 1
    1
    3
    0
        Adj Week 5: Grade 2
    4
    0
    1
        Adj Week 5: Grade 3
    1
    1
    0
        Adj Week 9: Grade 0
    0
    1
    0
        Adj Week 9: Grade 1
    0
    2
    1
        Adj Week 9: Grade 2
    2
    2
    2
        Adj Week 9: Grade 3
    1
    1
    0
        Adj Week 13: Grade 0
    0
    1
    0
        Adj Week 13: Grade 1
    0
    2
    0
        Adj Week 13: Grade 2
    2
    2
    2
        Adj Week 13: Grade 3
    1
    0
    0
        Adj Week 17: Grade 0
    0
    0
    1
        Adj Week 17: Grade 1
    0
    1
    0
        Adj Week 17: Grade 2
    2
    3
    0
        Adj Week 21: Grade 1
    0
    0
    1
        Adj Week 21: Grade 2
    2
    3
    0
        Adj Week 25: Grade 1
    0
    2
    0
        Adj Week 25: Grade 2
    1
    1
    0
        Adj Week 29: Grade 2
    1
    0
    0
        Adj Week 29: Grade 4
    0
    1
    0
    Notes
    [20] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [21] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [22] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Percentage of Participants That Recovered to <3-line Decline From Baseline (≤ +0.3 LogMAR) in Visual Acuity After Bandage Contact Lens (BCL) Intervention

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    End point title
    		 Percentage of Participants That Recovered to <3-line Decline From Baseline (≤ +0.3 LogMAR) in Visual Acuity After Bandage Contact Lens (BCL) Intervention
    End point description
    Recovery was defined as return to <3-line decline from baseline (≤ +0.3 LogMAR) in visual acuity after BCL intervention.
    End point type
    Secondary
    End point timeframe
    From the last assessment prior to BCL intervention to the end of BCL intervention
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    0 [23]
    0 [24]
    0 [25]
    Units: percentage of participants
        number (not applicable)
    Notes
    [23] - Data were not collected for this outcome (due to early termination of the study)
    [24] - Data were not collected for this outcome (due to early termination of the study)
    [25] - Data were not collected for this outcome (due to early termination of the study)
    No statistical analyses for this end point

    Secondary: Number of Participants With Depatuxizumab Mafodotin Dose Modifications Due to Ocular Side Effects (OSE)

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    End point title
    		 Number of Participants With Depatuxizumab Mafodotin Dose Modifications Due to Ocular Side Effects (OSE)
    End point description
    Dose modifications included depatuxizumab mafodotin withdrawal, interruption, and reductions in dose initiated due to OSEs.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until 49 days after last depatuxizumab mafodotin administration, up to 47 weeks
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [26]
    12 [27]
    12 [28]
    Units: participants
    2
    3
    2
    Notes
    [26] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [27] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [28] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Number of Participants With Depatuxizumab Mafodotin Dose Modifications to Ocular Side Effects After Bandage Contact Lens (BCL) Intervention

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    End point title
    		 Number of Participants With Depatuxizumab Mafodotin Dose Modifications to Ocular Side Effects After Bandage Contact Lens (BCL) Intervention
    End point description
    Dose modifications included depatuxizumab mafodotin withdrawal, interruption, and reductions in dose initiated due to OSEs after BCL intervention.
    End point type
    Secondary
    End point timeframe
    From the last assessment prior to BCL intervention to the end of BCL intervention, up to 38 weeks
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    14 [29]
    12 [30]
    12 [31]
    Units: participants
    2
    1
    0
    Notes
    [29] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [30] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [31] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Maximum Change From Baseline on the Logarithm of the Minimum Angle of Resolution (LogMAR) Scale

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    End point title
    		 Maximum Change From Baseline on the Logarithm of the Minimum Angle of Resolution (LogMAR) Scale
    End point description
    The LogMAR scale measures visual acuity on a continuous scale, with a LogMAR value of 0 equivalent to 20/20 visual acuity. Normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment. The baseline observation is defined as the last non-missing measurement collected prior to the first dose of depatuxizumab mafodotin.
    End point type
    Secondary
    End point timeframe
    Within 8 weeks after the initial dose of depatuxizumab mafodotin
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    12 [32]
    10 [33]
    9 [34]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Bilateral vision
    0.353 ( 0.1888 )
    0.402 ( 0.1985 )
    0.272 ( 0.3888 )
        Vision in worst eye
    0.482 ( 0.2028 )
    0.528 ( 0.3073 )
    0.430 ( 0.5120 )
    Notes
    [32] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [33] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [34] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Treatment Emergent Corneal Epithelial Adverse Event (CEAE) Grade at Each Visit After Bandage Contact Lens (BCL) Intervention

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    End point title
    		 Treatment Emergent Corneal Epithelial Adverse Event (CEAE) Grade at Each Visit After Bandage Contact Lens (BCL) Intervention
    End point description
    The corneal epithelial adverse event (CEAE) rating scale is designed to record symptoms associated with corneal epitheliopathy caused by antibody-drug conjugates and to grade the severity of findings. The overall CEAE grade is measured on a scale of 0 to 5, with higher values being more severe, reflecting the impact of corneal abnormalities on visual activities of daily living (ADLs). Additional detailed information is collected for specific domains that are commonly affected, with the following ranges (each in order of increasing severity): ocular discomfort (0 - 4), photophobia (0 - 3), and reading (1 - 3).
    End point type
    Secondary
    End point timeframe
    From the last assessment prior to BCL intervention to the end of BCL intervention, up to 38 weeks
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    7 [35]
    4 [36]
    4 [37]
    Units: participants
        Week 5: Grade 1
    2
    0
    0
        Week 7: Grade 2
    1
    1
    0
        Week 9: Grade 2
    1
    1
    1
        Week 11: Grade 2
    0
    0
    2
        Week 11: Grade 3
    1
    0
    0
        Week 13: Grade 1
    1
    0
    0
        Adj Week 1: Grade 1
    0
    0
    1
        Adj Week 1: Grade 2
    0
    0
    1
        Adj Week 5: Grade 0
    0
    1
    1
        Adj Week 5: Grade 1
    0
    1
    0
        Adj Week 5: Grade 2
    1
    0
    1
        Adj Week 5: Grade 3
    1
    0
    0
        Adj Week 9: Grade 0
    0
    1
    0
        Adj Week 9: Grade 1
    0
    0
    1
        Adj Week 9: Grade 2
    0
    0
    1
        Adj Week 9: Grade 3
    1
    0
    0
        Adj Week 13: Grade 0
    0
    2
    0
        Adj Week 13: Grade 1
    0
    1
    0
        Adj Week 13: Grade 2
    1
    0
    1
        Adj Week 13: Grade 3
    1
    0
    0
        Adj Week 17: Grade 1
    0
    1
    0
        Adj Week 17: Grade 2
    1
    1
    0
        Adj Week 21: Grade 2
    2
    1
    0
        Adj Week 25: Grade 1
    0
    1
    0
        Adj Week 25: Grade 2
    1
    0
    0
        Adj Week 29: Grade 2
    1
    0
    0
    Notes
    [35] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [36] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    [37] - Safety population: randomized subjects who rcvd ≥1 dose of ABT-414 with available data
    No statistical analyses for this end point

    Secondary: Time to Re-initiation of Depatuxizumab Mafodotin After Dose Interruption

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    End point title
    		 Time to Re-initiation of Depatuxizumab Mafodotin After Dose Interruption
    End point description
    The time from dose interruption until re-initiation or permanent discontinuation of depatuxizumab mafodotin was to be recorded.
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    End point values
    		 Standard Steroids Standard Steroids + Vasoconstrictor + Cold Compress Enhanced Steroids + Vasoconstrictor + Cold Compress
    Number of subjects analysed
    0 [38]
    0 [39]
    0 [40]
    Units: weeks
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    Notes
    [38] - Data were not collected for this outcome (due to early termination of the study)
    [39] - Data were not collected for this outcome (due to early termination of the study)
    [40] - Data were not collected for this outcome (due to early termination of the study)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) collected from 1st dose of ABT-414 until 49 d after last dose, up to 47 wks. SAEs and protocol-related nonserious AEs were collected from the time the subject signed consent.
    Adverse event reporting additional description
    TEAEs and SAEs are defined as any AE or SAE with onset or worsening reported by a participant from the time that the first dose of depatuxizumab mafodotin is administered until 49 days have elapsed following discontinuation of study drug. TEAEs were collected whether elicited or spontaneously reported by the participant.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Standard Steroids
    Reporting group description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days

    Reporting group title
    Enhanced Steroids + Vasoconstrictor + Cold Compress
    Reporting group description
    		 Enhanced steroid eye drops: 1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Ophthalmic Steroid Ointment; applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. Cold compress was to be applied in increments no longer than 30 min (could be shorter if the patient is uncomfortable).

    Reporting group title
    Standard Steroids + Vasoconstrictor + Cold Compress
    Reporting group description
    		 Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4– 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of infusion; and 2 – 4 times during the remainder of the infusion day). Continuing 4 – 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion. The cold compress was to be applied in increments no longer than 30 min (could be shorter if the participant was uncomfortable).

    Serious adverse events
    		 Standard Steroids Enhanced Steroids + Vasoconstrictor + Cold Compress Standard Steroids + Vasoconstrictor + Cold Compress
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 14 (42.86%)
    4 / 12 (33.33%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    1
    1
    1
         number of deaths resulting from adverse events
    1
    0
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MALIGNANT NEOPLASM PROGRESSION
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    TUMOUR PSEUDOPROGRESSION
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (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
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (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
    HEMIPARESIS
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STATUS EPILEPTICUS
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (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 and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    0 / 12 (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
    Eye disorders
    ULCERATIVE KERATITIS
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    VOMITING
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EYE INFECTION
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard Steroids Enhanced Steroids + Vasoconstrictor + Cold Compress Standard Steroids + Vasoconstrictor + Cold Compress
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    12 / 12 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    HYPOTENSION
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    CHEST PAIN
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    FATIGUE
         subjects affected / exposed
    6 / 14 (42.86%)
    7 / 12 (58.33%)
    9 / 12 (75.00%)
         occurrences all number
    10
    8
    10
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    PYREXIA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    MENSTRUATION IRREGULAR
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    PROSTATIC OBSTRUCTION
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    4
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    EPISTAXIS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    PLEURITIC PAIN
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    RHINITIS ALLERGIC
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    AGITATION
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    ANXIETY
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    3
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    DEPRESSION
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    INSOMNIA
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 14 (14.29%)
    3 / 12 (25.00%)
    5 / 12 (41.67%)
         occurrences all number
    2
    4
    7
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    4 / 14 (28.57%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    4
    3
    2
    BLOOD BILIRUBIN ABNORMAL
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    BLOOD CALCIUM INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    BLOOD PHOSPHORUS DECREASED
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    CARDIAC MURMUR
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    INTRAOCULAR PRESSURE INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    7
    0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    NEUTROPHIL COUNT INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    Injury, poisoning and procedural complications
    ARTHROPOD BITE
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    CORNEAL ABRASION
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    FALL
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0
    INCISION SITE PAIN
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    INFUSION RELATED REACTION
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    RADIATION NECROSIS
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    RADIATION SKIN INJURY
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    SKIN ABRASION
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    CARDIOMEGALY
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    TACHYCARDIA
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    APRAXIA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    BALANCE DISORDER
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    BRAIN OEDEMA
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    DIZZINESS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    2
    DYSGEUSIA
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    3
    HEADACHE
         subjects affected / exposed
    5 / 14 (35.71%)
    4 / 12 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    5
    5
    3
    HEMIPARESIS
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    SEIZURE
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    1
    SYNCOPE
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    TREMOR
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    VASOGENIC CEREBRAL OEDEMA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    LEUKOPENIA
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    LYMPHOPENIA
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    NEUTROPENIA
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    2
    THROMBOCYTOPENIA
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 12 (25.00%)
    5 / 12 (41.67%)
         occurrences all number
    4
    7
    7
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    HYPOACUSIS
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Eye disorders
    ACQUIRED EPIBLEPHARON
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    CONJUNCTIVITIS ALLERGIC
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    DIPLOPIA
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    DRY EYE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    EYELID PTOSIS
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    FOREIGN BODY SENSATION IN EYES
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    VISION BLURRED
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    ANAL INCONTINENCE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    CONSTIPATION
         subjects affected / exposed
    5 / 14 (35.71%)
    2 / 12 (16.67%)
    4 / 12 (33.33%)
         occurrences all number
    5
    2
    4
    DIARRHOEA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    DRY MOUTH
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    DUODENAL ULCER
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    DYSPHAGIA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    GASTRITIS EROSIVE
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    HAEMORRHOIDS
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    MOUTH ULCERATION
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    NAUSEA
         subjects affected / exposed
    6 / 14 (42.86%)
    3 / 12 (25.00%)
    6 / 12 (50.00%)
         occurrences all number
    7
    3
    7
    STOMATITIS
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    VOMITING
         subjects affected / exposed
    5 / 14 (35.71%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    5
    1
    1
    Hepatobiliary disorders
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    3
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 12 (41.67%)
    2 / 12 (16.67%)
         occurrences all number
    2
    7
    2
    DERMATITIS
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    DRY SKIN
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    ERYTHEMA
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    PETECHIAE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    RASH
         subjects affected / exposed
    3 / 14 (21.43%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    0
    1
    RASH MACULO-PAPULAR
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    RASH PRURITIC
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    SCAR PAIN
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    NOCTURIA
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    URINARY INCONTINENCE
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    BACK PAIN
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    MUSCULAR WEAKNESS
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    5
    0
    0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    NECK PAIN
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    BALANITIS CANDIDA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    ORAL CANDIDIASIS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    ORAL HERPES
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    SINUSITIS
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 12 (25.00%)
    3 / 12 (25.00%)
         occurrences all number
    4
    3
    5
    DEHYDRATION
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    MALNUTRITION
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2018
    Version 2.0 •Implemented safety measures for subjects with hepatic laboratory abnormalities due to a Grade 5 acute liver injury in a patient receiving depatuxizumab mafodotin in an ongoing study •Provided guidelines for depatuxizumab mafodotin dose modifications due to hepatic laboratory abnormalities •Provided guidelines for management and evaluation of severe hepatic laboratory abnormalities and for data collection •Provided clarification on measurements of visual acuity (VA) •Primary measure of interest, used for assessing the VA component of primary endpoint and other changes from baseline in VA, defined as VA with baseline correction, to be determined at the initial ophthalmology examination and used throughout the study •Provided additional flexibility in OSE management once endpoints for study objectives were assessed •Allowed subjects to transition to the Investigator Discretion Phase once key period of interest for OSE observation has ended (after 8 wks of adjuvant therapy) regardless of CEAE grade or prior intervention with BCLs •Increased frequency of vasoconstrictor eye drop administration, as consistent with labeling information •Clarified sequence of steroid eye drop substitution: initial eye drop is Prednisolone acetate 1% suspension and substitution with 0.1% dexamethasone phosphate is allowed after emergency of ocular side effects, if deemed necessary •Provided clarification on supportive care measures allowed or prohibited during Initial Prophylaxis and BCL Intervention phases of OSE management •Clarified language describing optional biomarker study •Clarified purpose of optional cornea collection: histopathologic evaluation of the post-mortem corneal tissue will be assessed to further characterize histopathologic features of OSEs •Specified that non-corrective (plano) bandage contact lenses are to be used in the study •Provided clarification on adverse event reporting by following current template language
    14 Dec 2018
    Version 3.0 •Updated Benefits and Risks to patients to reflect clinical study data reported in current Investigator Brochure and updated Reference for IB •Added active infection with hepatitis B virus, hepatitis C virus, or HIV as exclusion criteria •Provided updated contraception language to be consistent with AbbVie protocol template •Prohibited use of live attenuated vaccines during study and for 49 days after end of study drug administration •Clarified instructions for withdrawal of subjects and discontinuation of study •Clarified use of vasoconstrictor eye drops 4 - 6 times in total on day of infusion, including 2-4 times during remainder of infusion day, and 4 - 6 times/day in total on Day 1 - Day 2 after infusion •Clarified that all adverse events reported will be collected from the time of study drug administration until 49 days after last depatuxizumab mafodotin administration; clarified that administration of depatuxizumab mafodotin must be discontinued immediately in the event that a subject becomes pregnant during the study •Included instructions for Toxicity Management in Protocol; moved from Operations Manual. •Updated CTCAE to version 5.0 for grading of clinical toxicity in order to use most recent version. •Specified that study drug should be permanently discontinued if subject develops corneal ulceration with impending perforation (CU) or corneal perforation (CP) •Clarified end of study as the date of subject's last visit •Added time points for collection of visual quality of life questionnaire and visual symptoms questionnaire; added time points for collection of perception of treatment value question; provided clarification on timing and type of pregnancy tests; added randomization visit with prophylactic treatment for OSE; clarified timing of central lab tests during Follow Up 35 Day visit and not at Follow Up 49 Day visit; added Post-Treatment Follow Up visit at 49 Day
    28 May 2019
    Version 4.0 •Added brief summary of results for the protocol-specified interim efficacy analysis for INTELLANCE-1 in the Introduction •Provided modified study procedures and instructions for depatuxizumab mafodotin dosing in for those subjects who were currently receiving depatuxizumab mafodotin and who choose to continue depatuxizumab mafodotin. No additional efficacy data was to be collected, and procedures were minimized to include those necessary for study drug dosing, safety monitoring and collection of safety data related to adverse events.

    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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