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    Clinical Trial Results:
    A Phase 3, double-blind, multicenter, placebo-controlled study of PledOx used on top of modified FOLFOX6 (5 FU/FA and Oxaliplatin) to prevent chemotherapy induced peripheral neuropathy (CIPN) in patients with first-line metastatic colorectal cancer

    Summary
    EudraCT number
    		 2017-004754-42
    Trial protocol
    		 GB   BE   DE   FR   ES   HU   IT  
    Global end of trial date
    31 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2021
    First version publication date
    16 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PP06490
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03654729
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Egetis Therapeutics AB (formerly PledPharma AB)
    Sponsor organisation address
    Egetis Therapeutics AB Klara Norra Kyrkogata 26 , Stockholm , Sweden, SE 111 22 Stockholm
    Public contact
    Kristina Sjöblom Nygren, CMO, Head Clinical Development, Egetis Therapeutics, +46 732344698, kristina.sjoblom@egetis.com
    Scientific contact
    Kristina Sjöblom Nygren, CMO, Head Clinical Development, Egetis Therapeutics, +46 732344698, kristina.sjoblom@egetis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare each dose of PledOx (2 and 5 µmol/kg) vs placebo with respect to the proportion of subjects with moderate or severe chronic CIPN
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. An independent Data Monitoring Committee monitored accumulating safety, efficacy and other types of data throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Japan: 84
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    291
    EEA total number of subjects
    130
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    154
    From 65 to 84 years
    136
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited in the US, EU and Asia between 2018 and 1 March 2020.

    Pre-assignment
    Screening details
    		 386 subjects were screened in the 28 days before the start of treatment, 291 were randomised and 285 were were treated. The study was prematurely terminated and enrolled patients were followed until the data cut-off date of 31 August 2020; these patients have been assigned as "completed" in the disposition.

    Period 1
    Period 1 title
    Subjects randomised
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PledOx (2 µmol/kg)
    Arm description
    		 Calmangafodipir [PledOx] (2 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir (2 µmol/kg)
    Investigational medicinal product code
    Other name
    PledOx
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    PledOx 2 µmol/kg + mFOLFOX6 chemotherapy administered every 2 weeks (±2 days) for 12 cycles

    Arm title
    		 PledOx (5 µmol/kg)
    Arm description
    		 Calmangafodipir [PledOx] (5 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir (5 µmol/kg)
    Investigational medicinal product code
    Other name
    PledOx
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    PledOx 5 µmol/kg + mFOLFOX6 chemotherapy administered every 2 weeks (±2 days) for 12 cycles

    Arm title
    		 Placebo
    Arm description
    		 Placebo on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Placebo + mFOLFOX6 chemotherapy administered every 2 weeks (±2 days) for 12 cycles

    Number of subjects in period 1
    		PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Started
    97
    96
    98
    Completed
    96
    93
    96
    Not completed
    1
    3
    2
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    -
    1
    -
         Unknown
    -
    2
    2
    Period 2
    Period 2 title
    Subjects treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PledOx (2 µmol/kg)
    Arm description
    		 Calmangafodipir [PledOx] (2 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir (2 µmol/kg)
    Investigational medicinal product code
    Other name
    PledOx
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    PledOx 2 µmol/kg + mFOLFOX6 chemotherapy administered every 2 weeks (±2 days) for 12 cycles

    Arm title
    		 PledOx (5 µmol/kg)
    Arm description
    		 Calmangafodipir [PledOx] (5 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir (5 µmol/kg)
    Investigational medicinal product code
    Other name
    PledOx
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    PledOx 5 µmol/kg + mFOLFOX6 chemotherapy administered every 2 weeks (±2 days) for 12 cycles

    Arm title
    		 Placebo
    Arm description
    		 Placebo on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Placebo + mFOLFOX6 chemotherapy administered every 2 weeks (±2 days) for 12 cycles

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: There were six subjects randomised who were not treated. The baseline period represents subjects who were treated and the baseline data are presented for the subjects treated.
    Number of subjects in period 2 [2]
    		PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Started
    96
    93
    96
    Completed
    66
    70
    69
    Not completed
    30
    23
    27
         Consent withdrawn by subject
    8
    5
    4
         Physician decision
    1
    -
    -
         Study terminated by Sponsor
    3
    5
    4
         Death
    9
    9
    16
         Unknown
    2
    2
    3
         Non-compliance with study drug
    -
    1
    -
         Lost to follow-up
    2
    -
    -
         Progressive disease
    3
    -
    -
         Site terminated by Sponsor
    1
    -
    -
         Protocol deviation
    1
    1
    -
    Notes
    [2] - 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: There were six subjects randomised who were not treated. The baseline period represents subjects who were treated and the baseline data are presented for the subjects treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PledOx (2 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (2 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    PledOx (5 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (5 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group values
    		 PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo Total
    Number of subjects
    		 96 93 96 285
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 48 52 51 151
        From 65-84 years
    		 47 41 45 133
        85 years and over
    		 1 0 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.5 ( 10.5 ) 62.9 ( 9.6 ) 61.6 ( 12.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 36 43 40 119
        Male
    		 60 50 56 166
    Race
    Units: Subjects
        Asian
    		 41 40 39 120
        Black or African American
    		 0 1 1 2
        Unknown
    		 6 7 5 18
        White
    		 49 45 51 145
    ECOG baseline status
    Units: Subjects
        Score 0
    		 65 62 53 180
        Score 1
    		 31 31 41 103
        Unknown
    		 0 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    PledOx (2 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (2 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    PledOx (5 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (5 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.
    Reporting group title
    PledOx (2 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (2 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    PledOx (5 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (5 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Primary: Moderate or severe chronic chemotherapy induced peripheral neuropathy (CIPN)

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    End point title
    		 Moderate or severe chronic chemotherapy induced peripheral neuropathy (CIPN)
    End point description
    Proportion of subjects (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy).
    End point type
    Primary
    End point timeframe
    9 months
    End point values
    		 PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Number of subjects analysed
    54
    55
    57
    Units: Number of patients
    31
    27
    25
    Statistical analysis title
    		 PledOx (2 µmol/kg) versus Placebo
    Comparison groups
    PledOx (2 µmol/kg) v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2266
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.3842
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8172
         upper limit
    		 2.3446
    Statistical analysis title
    		 PledOx (5 µmol/kg) versus Placebo
    Statistical analysis description
    Cochran-Mantel-Haenszel estimate of the common relative risk of moderate to severe CIPN.
    Comparison groups
    PledOx (5 µmol/kg) v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7434
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0951
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6356
         upper limit
    		 1.887

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival defined as time from randomisation until progressive disease (according to Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) or death from any cause.
    End point type
    Secondary
    End point timeframe
    12 and 24 months; analysis performed based on available data at cut-off 31 August 2020
    End point values
    		 PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Number of subjects analysed
    95
    93
    95
    Units: Number of events
    40
    36
    36
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival defined as time from randomisation to death from any cause. If the subject was alive at the end of the follow-up period (or was lost to follow-up), the subject was censored on the last date the subject was known to be alive.
    End point type
    Secondary
    End point timeframe
    36 months; analysis performed based on available data at cut-off 31 August 2020
    End point values
    		 PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Number of subjects analysed
    95
    93
    95
    Units: Number of events
    9
    9
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening until 30 days after the end of treatment visit which occurred after up to 6 months of treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    PledOx (2 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (2 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    PledOx (5 µmol/kg)
    Reporting group description
    		 Calmangafodipir [PledOx] (5 µmol/kg) on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo on day 1 every 2 weeks to subjects as an intravenous infusion, combined with mFOLFOX6 chemotherapy.

    Serious adverse events
    		 PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 96 (28.13%)
    21 / 93 (22.58%)
    24 / 96 (25.00%)
         number of deaths (all causes)
    9
    9
    16
         number of deaths resulting from adverse events
    2
    3
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to spine
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour perforation
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Hypotension
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Thrombosis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Euthanasia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Fatigue
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Generalised oedema
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Pyrexia
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Drug hypersensitivity
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Hypersensitivity
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Infusion related reaction
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Urticaria
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian vein thrombosis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 93 (3.23%)
    0 / 96 (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
    Respiratory distress
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Blood bilirubin increased
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Wound dehiscence
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Wound haemorrhage
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Cardiac disorders
    Cardiogenic shock
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Cerebral infarction
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Presyncope
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Syncope
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 93 (2.15%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 93 (2.15%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 93 (0.00%)
    0 / 96 (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
    Colitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 93 (1.08%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 93 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 96 (2.08%)
    1 / 93 (1.08%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Pancreatitis acute
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Parotitis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 96 (3.13%)
    1 / 93 (1.08%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 93 (1.08%)
    0 / 96 (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
    Corona virus infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Device related infection
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 93 (0.00%)
    0 / 96 (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
    Diverticulitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 93 (1.08%)
    0 / 96 (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
    Necrotising fasciitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Peritonitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneunonia
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 93 (1.08%)
    0 / 96 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Sepsis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 93 (0.00%)
    0 / 96 (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
    Wound infection
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Cachexia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 93 (1.08%)
    0 / 96 (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
    Dehydration
         subjects affected / exposed
    1 / 96 (1.04%)
    1 / 93 (1.08%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 93 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 96 (0.00%)
    3 / 93 (3.23%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         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
    		 PledOx (2 µmol/kg) PledOx (5 µmol/kg) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 96 (96.88%)
    91 / 93 (97.85%)
    95 / 96 (98.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 96 (12.50%)
    11 / 93 (11.83%)
    12 / 96 (12.50%)
         occurrences all number
    12
    16
    16
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 96 (14.58%)
    17 / 93 (18.28%)
    21 / 96 (21.88%)
         occurrences all number
    23
    47
    41
    Fatigue
         subjects affected / exposed
    25 / 96 (26.04%)
    23 / 93 (24.73%)
    23 / 96 (23.96%)
         occurrences all number
    38
    33
    35
    Malaise
         subjects affected / exposed
    6 / 96 (6.25%)
    4 / 93 (4.30%)
    9 / 96 (9.38%)
         occurrences all number
    6
    5
    10
    Oedema peripheral
         subjects affected / exposed
    6 / 96 (6.25%)
    3 / 93 (3.23%)
    4 / 96 (4.17%)
         occurrences all number
    8
    3
    5
    Pyrexia
         subjects affected / exposed
    12 / 96 (12.50%)
    8 / 93 (8.60%)
    9 / 96 (9.38%)
         occurrences all number
    15
    11
    10
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    5 / 96 (5.21%)
    2 / 93 (2.15%)
    5 / 96 (5.21%)
         occurrences all number
    6
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 96 (4.17%)
    6 / 93 (6.45%)
    6 / 96 (6.25%)
         occurrences all number
    4
    7
    6
    Dyspnoea
         subjects affected / exposed
    3 / 96 (3.13%)
    4 / 93 (4.30%)
    5 / 96 (5.21%)
         occurrences all number
    3
    4
    6
    Epistaxis
         subjects affected / exposed
    13 / 96 (13.54%)
    14 / 93 (15.05%)
    9 / 96 (9.38%)
         occurrences all number
    18
    15
    13
    Hiccups
         subjects affected / exposed
    4 / 96 (4.17%)
    3 / 93 (3.23%)
    5 / 96 (5.21%)
         occurrences all number
    10
    6
    6
    Oropharyngeal pain
         subjects affected / exposed
    2 / 96 (2.08%)
    5 / 93 (5.38%)
    2 / 96 (2.08%)
         occurrences all number
    3
    5
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 96 (5.21%)
    3 / 93 (3.23%)
    5 / 96 (5.21%)
         occurrences all number
    5
    3
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 96 (5.21%)
    7 / 93 (7.53%)
    8 / 96 (8.33%)
         occurrences all number
    5
    8
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 96 (6.25%)
    7 / 93 (7.53%)
    7 / 96 (7.29%)
         occurrences all number
    7
    8
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 96 (0.00%)
    5 / 93 (5.38%)
    6 / 96 (6.25%)
         occurrences all number
    0
    5
    8
    Dysgeusia
         subjects affected / exposed
    16 / 96 (16.67%)
    20 / 93 (21.51%)
    21 / 96 (21.88%)
         occurrences all number
    18
    23
    24
    Headache
         subjects affected / exposed
    7 / 96 (7.29%)
    7 / 93 (7.53%)
    5 / 96 (5.21%)
         occurrences all number
    10
    7
    6
    Neuropathy peripheral
         subjects affected / exposed
    32 / 96 (33.33%)
    33 / 93 (35.48%)
    36 / 96 (37.50%)
         occurrences all number
    89
    84
    74
    Paraesthesia
         subjects affected / exposed
    17 / 96 (17.71%)
    15 / 93 (16.13%)
    18 / 96 (18.75%)
         occurrences all number
    26
    25
    35
    Peripheral sensory neuropathy
         subjects affected / exposed
    42 / 96 (43.75%)
    40 / 93 (43.01%)
    42 / 96 (43.75%)
         occurrences all number
    86
    79
    97
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 96 (11.46%)
    8 / 93 (8.60%)
    14 / 96 (14.58%)
         occurrences all number
    17
    15
    23
    Leukopenia
         subjects affected / exposed
    12 / 96 (12.50%)
    10 / 93 (10.75%)
    14 / 96 (14.58%)
         occurrences all number
    29
    22
    26
    Neutropenia
         subjects affected / exposed
    40 / 96 (41.67%)
    48 / 93 (51.61%)
    37 / 96 (38.54%)
         occurrences all number
    91
    97
    90
    Thrombocytopenia
         subjects affected / exposed
    12 / 96 (12.50%)
    16 / 93 (17.20%)
    16 / 96 (16.67%)
         occurrences all number
    26
    28
    36
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 96 (16.67%)
    14 / 93 (15.05%)
    16 / 96 (16.67%)
         occurrences all number
    21
    21
    18
    Abdominal pain upper
         subjects affected / exposed
    5 / 96 (5.21%)
    4 / 93 (4.30%)
    5 / 96 (5.21%)
         occurrences all number
    5
    5
    6
    Constipation
         subjects affected / exposed
    24 / 96 (25.00%)
    15 / 93 (16.13%)
    14 / 96 (14.58%)
         occurrences all number
    26
    17
    19
    Diarrhoea
         subjects affected / exposed
    32 / 96 (33.33%)
    27 / 93 (29.03%)
    41 / 96 (42.71%)
         occurrences all number
    56
    37
    68
    Dyspepsia
         subjects affected / exposed
    8 / 96 (8.33%)
    6 / 93 (6.45%)
    4 / 96 (4.17%)
         occurrences all number
    10
    7
    4
    Nausea
         subjects affected / exposed
    34 / 96 (35.42%)
    42 / 93 (45.16%)
    47 / 96 (48.96%)
         occurrences all number
    67
    69
    82
    Stomatitis
         subjects affected / exposed
    29 / 96 (30.21%)
    24 / 93 (25.81%)
    29 / 96 (30.21%)
         occurrences all number
    39
    41
    43
    Vomiting
         subjects affected / exposed
    11 / 96 (11.46%)
    16 / 93 (17.20%)
    20 / 96 (20.83%)
         occurrences all number
    24
    32
    30
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    9 / 96 (9.38%)
    11 / 93 (11.83%)
    13 / 96 (13.54%)
         occurrences all number
    9
    14
    13
    Dermatitis acneiform
         subjects affected / exposed
    9 / 96 (9.38%)
    7 / 93 (7.53%)
    10 / 96 (10.42%)
         occurrences all number
    15
    8
    18
    Dry skin
         subjects affected / exposed
    9 / 96 (9.38%)
    11 / 93 (11.83%)
    4 / 96 (4.17%)
         occurrences all number
    9
    11
    7
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 96 (7.29%)
    4 / 93 (4.30%)
    6 / 96 (6.25%)
         occurrences all number
    10
    6
    6
    Rash
         subjects affected / exposed
    6 / 96 (6.25%)
    19 / 93 (20.43%)
    14 / 96 (14.58%)
         occurrences all number
    13
    30
    18
    Skin fissures
         subjects affected / exposed
    1 / 96 (1.04%)
    5 / 93 (5.38%)
    1 / 96 (1.04%)
         occurrences all number
    2
    7
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    5 / 96 (5.21%)
    1 / 93 (1.08%)
    2 / 96 (2.08%)
         occurrences all number
    6
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 96 (5.21%)
    4 / 93 (4.30%)
    6 / 96 (6.25%)
         occurrences all number
    5
    5
    8
    Muscle spasms
         subjects affected / exposed
    1 / 96 (1.04%)
    6 / 93 (6.45%)
    4 / 96 (4.17%)
         occurrences all number
    1
    9
    4
    Myalgia
         subjects affected / exposed
    3 / 96 (3.13%)
    2 / 93 (2.15%)
    10 / 96 (10.42%)
         occurrences all number
    3
    2
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 96 (4.17%)
    4 / 93 (4.30%)
    5 / 96 (5.21%)
         occurrences all number
    5
    5
    5
    Paronychia
         subjects affected / exposed
    2 / 96 (2.08%)
    7 / 93 (7.53%)
    8 / 96 (8.33%)
         occurrences all number
    3
    8
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    30 / 96 (31.25%)
    26 / 93 (27.96%)
    27 / 96 (28.13%)
         occurrences all number
    47
    33
    42
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 96 (5.21%)
    1 / 93 (1.08%)
    2 / 96 (2.08%)
         occurrences all number
    6
    3
    3
    Hypokalaemia
         subjects affected / exposed
    3 / 96 (3.13%)
    7 / 93 (7.53%)
    9 / 96 (9.38%)
         occurrences all number
    5
    11
    17
    Hypomagnesaemia
         subjects affected / exposed
    5 / 96 (5.21%)
    7 / 93 (7.53%)
    5 / 96 (5.21%)
         occurrences all number
    5
    8
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2018
    • Added more rationale for the 2 μmol/kg dose • Amended contraceptive measures • Pregnancy added as a criterion for Investigational Medicinal Product (IMP) discontinuation • Amended the schedule for the Month 3 and Month 6 Assessment Visits • Added time points for assessing health economic impact • Added clarity over when computed tomography (CT)/magnetic resonance imaging (MRI) scans should be performed. Removed CT/MRI assessment at Treatment Visit 12. • Clarified that “graduated tuning fork” referred to the vibration sensitivity test.
    20 Feb 2018
    • Increased the duration of contraception after the completion of study therapy • Removed ‘Australia’ from the protocol, as the study was not to be conducted there • Amended the volume of blood collected for manganese evaluations
    20 Jun 2018
    • Updated text to include Asian centres in the study • Included input regarding pregnancy from Competent Authorities into the protocol text • Updated information on the use of background therapy
    12 Sep 2018
    • Adjusted the number of subjects included in the pharmacokinetic (PK) and electrocardiogram (ECG) examinations. • Included input from the US Food and Drug Administration (FDA) to the protocol text • Updated background information.
    09 Jul 2019
    • Added conversion and maintenance strategy during the Treatment Phase • Added region and PK sub-study as stratification factors to randomization • Updated exclusion criteria to exclude subjects with resectable metastatic disease and to add an exception for hepatitis B virus (HBV) infection • Clarified study procedures and timing in relation to assessments during Screening, Treatment, and Follow-up Phases • Clarified blinding procedures, IMP storage requirements, and IMP destruction guide • Removed the 8-hour time point from PK assessment • Specified that adverse events will be collected after signing the informed consent form
    09 Jan 2020
    • Updated exclusion criteria to exclude subjects with any history of seizures • Updated infusion duration for PledOx/placebo • Updated potential risks according to recently reported serious adverse events (SAEs) • Clarified DSMB review requirement for adverse events/SAEs of seizures, anaphylactoid reactions, and allergic infusion reactions • Clarified stopping criteria for subjects with seizures • Added details for premedications before PledOx/placebo infusion • Clarified procedures to be followed in case a death is an outcome of an event • Clarified PledOx-related adverse events • Specified the situations that trigger a brain MRI investigation and a neurological examination • Updated the flow chart of monitoring increased manganese level and/or Parkinson-like symptoms
    15 May 2020
    The rationale for this amendment was to update the protocol regarding the decision to prematurely terminate the study and to include changes resulting from the COVID-19 pandemic and associated site/country restrictions. • Updated study duration with implementation of an estimated data cut-off date by 30 Sep 2020 • Discontinuation of IMP, screening and randomization of patients, PK assessments, ECG measurements, and serum β-HCG pregnancy tests • Discontinuation of blood manganese samples with the exception of patients with Parkinson-like symptoms • Continuation of study visits as originally planned but without dosing of IMP • Collection of adverse events and concomitant medications up to 30 days after the end of treatment visit and until resolution • Collection of overall survival data until the estimated data cut-off date by 30 Sep 2020 • Added an option for remote data collection during the COVID-19 pandemic for some assessments, according to local requirements • Amended statistical section, making reference to the updated statistical analysis plan

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Mar 2020
    On 23 January 2020, the Sponsor announced that the United States (US) Food and Drug Administration (FDA) had issued a clinical hold in the US of the POLAR program. The implication was that recruitment and dosing of patients in the POLAR-M study was halted in the US. On 01 March 2020, the Sponsor decided to place recruitment and dosing of patients in the POLAR program on hold. The decision followed interactions with the French regulatory authority, ANSM and the US clinical hold. As of 02 March 2020, no investigational medicinal product (IMP) was administered and no more patients were enrolled. Enrolled patients continued to be followed until the data cut-off date of 31 August 2020.
    -

    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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