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    Clinical Trial Results:
    A double blinded, randomized, multi centre, Three-armed phase II trial of PledOx in two different doses in combination with FOLFOX6 compared to placebo + FOLFOX6 in patients with metastatic colorectal cancer

    Summary
    EudraCT number
    		 2012-001367-76
    Trial protocol
    		 SE   PT   DE   BG   DK  
    Global end of trial date
    12 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Aug 2019
    First version publication date
    01 Aug 2019
    Other versions
    Summary report(s)
    		 Synopsis PLIANT CSR Part 1
    Synopsis PLIANT CSR Part 2
    Glimelius et al. Persistent prevention of oxaliplatin-induced. Acta Oncologica. 2018. DOI: 10.1080/0284186X.2017.1398836

    Trial information

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    Trial identification
    Sponsor protocol code
    PP095
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01619423
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PledPharma
    Sponsor organisation address
    Grev Turegatan 11C, Stockholm, Sweden,
    Public contact
    Nicklas Westerholm, PledPharma AB, +46 +46733542062, nicklas.westerholm@pledpharma.se
    Scientific contact
    Jacques Näsström, PledPharma AB, +46 737130979, jacques.nasstrom@pledpharma.se
    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
    12 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective Dose Escalation Phase: To characterize the prevalence, severity, drug-relatedness and seriousness of adverse events of PledOx in two doses Primary Objective Randomised Treatment Phase: Assess the efficacy of two different doses of PledOx when added to FOLFOX6 chemotherapy as measured by protection from FOLFOX6 toxicity on neutropenia grade 3 or 4 (NCI-CTCAE v4)
    Protection of trial subjects
    Safety Mn measurements in blood, measured at Screening, Day 13 or Day 14 of Cycle 4, End-of-Treatment and in the event of any Parkinson-like symptoms. Assessment of Mn-associated neurotoxicity (Parkinson-like symptoms) at every visit
    Background therapy
    		 The chemotherapy was modified FOLFOX6 [25] containing oxaliplatin 85 mg/m2 during 2 h followed by calcium-levofolinate (100 mg/m2) or calcium folinate (200 mg/m2) as a 2h infusion followed by 5-FU 400 mg/m2 i.v. bolus and 5-FU continuous infusion 2400 mg/m2 during 46 h. The chemotherapy was repeated every fortnight and planned for up to eight cycles after which a break was recommended. Tumour evaluations were performed after 4 and 8 cycles. Bevacizumab (5 mg/kg) was added at the discretion of the physician.
    Evidence for comparator
    		 Placebo. There are no effective preventive or therapeutic treatments for CIPN. Several agents have been tested, but they have so far failed. For therapy, the American Society of Clinical Oncology states that duloxetine may be used, whereas no recommendations can be given for other agents.
    Actual start date of recruitment
    06 Feb 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 20 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Bulgaria: 44
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Georgia: 33
    Country: Number of subjects enrolled
    Serbia: 53
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    173
    EEA total number of subjects
    79
    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)
    96
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 13 patients were randomised in part 1a (8 pts) and 1b (5 pts) and 173 patients were randomized in part 2a and 2b i.e., completed both steps of the randomization process. Thirty-nine patients were randomized in Part 2a and 134 patients were randomized in Part 2b.

    Pre-assignment
    Screening details
    		 21 pts were screened in part 1. 207 pts were screened for Part 2 (43 patients for Part 2a, 164 pts for Part 2b). 37 screening failures: 7 in part 1a+b ,4 in Part 2a and 26 in Part 2b. 4 additional pts in Part 2b completed the first step of randomization and received a randomization number, but were not allocated to treatment with IMP.

    Period 1
    Period 1 title
    Part 2a + 2b treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Treatment in Parts 2a and 2b was blinded for the patient and investigator. To ensure blinding, the IMP was prepared by an unblinded nurse/pharmacist not otherwise involved in the study. The unblinded nurse/pharmacist prepared the IMP in a yellow-colored syringe, masking the color of the IMP. The syringe was connected to orange tubing which continued to mask the IMP also during administration. The prepared IMP, i.e. the syringe and tubing was provided to the blinded nurse who performed the admin

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 2 Group A (Pledox 2 μmol/kg)
    Arm description
    		 PledOx 2 μmol/kg + mFOLFOX6
    Arm type
    		 Experimental

    Investigational medicinal product name
    PledOx 2 μmol/kg
    Investigational medicinal product code
    Other name
    Calmangafodipir
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMP (PledOx or placebo) was given as a single pre-treatment infusion over approximately 5 minutes, 10 minutes prior to oxaliplatin administration in the mFOLFOX6 regimen. The pre-treatment IMP was given before each chemotherapy cycle for up to 8 treatment cycles, every 2 weeks.

    Arm title
    		 Part 2 Group B (Pledox 5 μmol/kg)
    Arm description
    		 Pledox 5 μmol/kg + mFOLGOX6
    Arm type
    		 Experimental

    Investigational medicinal product name
    PledOx 5 μmol/kg
    Investigational medicinal product code
    Other name
    Calmangafodipir
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    IMP (PledOx or placebo) was given as a single pre-treatment infusion over approximately 5 minutes, 10 minutes prior to oxaliplatin administration in the mFOLFOX6 regimen. The pre-treatment IMP was given before each chemotherapy cycle for up to 8 treatment cycles, every 2 weeks.

    Arm title
    		 Part 2 Group B (Pledox 10 μmol/kg)
    Arm description
    		 Pledox 10 μmol/kg + mFOLGOX6
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pledox 10 μmol/kg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    PledOx 10 μmol/kg + mFOLFOX6 in 8 cycles Name of Active ingredient: Calmangafodipir

    Arm title
    		 Part 2 Group C (Placebo)
    Arm description
    		 Placebo + mFOLFOX6
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo + mFOLFOX6 in 8 cycles Name of Active ingredient: None

    Number of subjects in period 1
    		Part 2 Group A (Pledox 2 μmol/kg) Part 2 Group B (Pledox 5 μmol/kg) Part 2 Group B (Pledox 10 μmol/kg) Part 2 Group C (Placebo)
    Started
    57
    45
    11
    60
    Completed
    44
    30
    6
    48
    Not completed
    13
    15
    5
    12
         Consent withdrawn by subject
    1
    4
    -
    1
         Physician decision
    -
    -
    -
    1
         Adverse event, non-fatal
    1
    1
    2
    1
         Death
    1
    1
    1
    -
         Other reason
    1
    1
    -
    -
         Lost to follow-up
    2
    2
    -
    -
         Progressive disease
    7
    6
    2
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 2 Group A (Pledox 2 μmol/kg)
    Reporting group description
    		 PledOx 2 μmol/kg + mFOLFOX6

    Reporting group title
    Part 2 Group B (Pledox 5 μmol/kg)
    Reporting group description
    		 Pledox 5 μmol/kg + mFOLGOX6

    Reporting group title
    Part 2 Group B (Pledox 10 μmol/kg)
    Reporting group description
    		 Pledox 10 μmol/kg + mFOLGOX6

    Reporting group title
    Part 2 Group C (Placebo)
    Reporting group description
    		 Placebo + mFOLFOX6

    Reporting group values
    		 Part 2 Group A (Pledox 2 μmol/kg) Part 2 Group B (Pledox 5 μmol/kg) Part 2 Group B (Pledox 10 μmol/kg) Part 2 Group C (Placebo) Total
    Number of subjects
    		 57 45 11 60 173
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 28 27 5 36 96
        From 65-84 years
    		 29 18 6 24 77
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Age distribution by randomised group
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ± 8.9 62.6 ± 10.4 64.8 ± 9.4 62.0 ± 9.4 -
    Gender categorical
    Units: Subjects
        Female
    		 16 21 6 14 57
        Male
    		 41 24 5 46 116
    Race
    Frequency of subjects by race category
    Units: Subjects
        Caucasian
    		 57 44 11 58 170
        Asian or Pacific Islander
    		 1 0 1
        African descent
    		 1 1
        Mixed/Multi-racial
    		 0 0
        Other
    		 1 1
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients who had received at least one dose of the IMP

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All FAS patients who had also fulfilled the following: o Had sufficiently complied with the CSP (i.e., had no major protocol deviations) o Had available data for the assessment of the primary variable (i.e., at least 1 post-baseline assessment of oxaliplatin-induced neuropathy) during the treatment phase

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of the IMP

    Subject analysis sets values
    		 Full Analysis Set Per Protocol Analysis Set Safety Analysis Set
    Number of subjects
    173
    169
    173
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    96
    94
    96
        From 65-84 years
    77
    75
    77
        85 years and over
    0
    0
    0
    Age continuous
    Age distribution by randomised group
    Units: years
        arithmetic mean (standard deviation)
    62.7 ± 9.6
    62.7 ± 9.6
    62.7 ± 9.6
    Gender categorical
    Units: Subjects
        Female
    57
    57
        Male
    116
    116
    Race
    Frequency of subjects by race category
    Units: Subjects
        Caucasian
    170
    170
        Asian or Pacific Islander
    1
    1
        African descent
    1
    1
        Mixed/Multi-racial
    0
    0
        Other
    1
    1

    End points

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    End points reporting groups
    Reporting group title
    Part 2 Group A (Pledox 2 μmol/kg)
    Reporting group description
    		 PledOx 2 μmol/kg + mFOLFOX6

    Reporting group title
    Part 2 Group B (Pledox 5 μmol/kg)
    Reporting group description
    		 Pledox 5 μmol/kg + mFOLGOX6

    Reporting group title
    Part 2 Group B (Pledox 10 μmol/kg)
    Reporting group description
    		 Pledox 10 μmol/kg + mFOLGOX6

    Reporting group title
    Part 2 Group C (Placebo)
    Reporting group description
    		 Placebo + mFOLFOX6

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients who had received at least one dose of the IMP

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All FAS patients who had also fulfilled the following: o Had sufficiently complied with the CSP (i.e., had no major protocol deviations) o Had available data for the assessment of the primary variable (i.e., at least 1 post-baseline assessment of oxaliplatin-induced neuropathy) during the treatment phase

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of the IMP

    Primary: Presence of neuropathy Grade 2 or higher (according to the OSSS criteria for oxaliplatin-related paresthesia/dysesthesia)

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    End point title
    		 Presence of neuropathy Grade 2 or higher (according to the OSSS criteria for oxaliplatin-related paresthesia/dysesthesia)
    End point description
    Presence of neuropathy Grade 2 or higher (according to the OSSS criteria for oxaliplatin-related paresthesia/dysesthesia). Assessment of oxaliplatin-related neuropathy symptoms (neurosensory neurotoxicity) was performed prior to infusion on Day 1 of Cycle 1 and ≤36 h prior to the next cycle of each cycle in association with assessments of chemotherapy-induced AEs and DLTs and whenever any sign of neuropathy was observed. Grading was performed according to OSSS criteria for oxaliplatin-related paresthesia/dysesthesia: Grade 0=no symptoms; Grade 1= Paresthesias/dysesthesias of short duration that resolve and do not interfere with function; Grade2=Paresthesias/dysesthesias, interfering with function, but not activities of daily living. Paraesthesia, dysaesthesia persisting between cycles; Grade 3= Paresthesias/dysesthesias with pain or with functional impairment that also interfere with daily living. Paraesthesia, dysaesthesia causing functional impairment; Grade 4= Persistent parest.
    End point type
    Primary
    End point timeframe
    This was assessed during chemotherapy treatment up to EOT.
    End point values
    		 Part 2 Group A (Pledox 2 μmol/kg) Part 2 Group B (Pledox 5 μmol/kg) Part 2 Group B (Pledox 10 μmol/kg) Part 2 Group C (Placebo) Full Analysis Set
    Number of subjects analysed
    56
    45
    11
    60
    172
    Units: Grade 0 to 4
        CIPN
    56
    45
    11
    60
    172
    Statistical analysis title
    		 Logistic Regression Analysis for Repeated Mea
    Statistical analysis description
    As originally planned in the SAP, presence of oxaliplatin-induced neuropathy of Grade 2 or higher (according to the OSSS criteria) was analyzed using a logistic regression model for repeat measures, and the GEE method was used to estimate the parameters of the model. The analysis was based on neuropathy assessments associated with the end of each of the 8 treatment cycles, and the model was adjusted for treatment group and addition of bevacizumab treatment to mFOLFOX6.
    Comparison groups
    Part 2 Group A (Pledox 2 μmol/kg) v Part 2 Group B (Pledox 5 μmol/kg) v Part 2 Group B (Pledox 10 μmol/kg) v Part 2 Group C (Placebo)
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.1749 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.666
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.163
    Notes
    [1] - The type-I error rate was set to 0.10 using one-sided tests and controlled using a hierarchical structure of analyses and a closed testing procedure in the following order 1. Superiority of PledOx 2 μmol/kg and PledOx 5 μmol/kg over placebo 2. Superiority of PledOx 2 μmol/kg over placebo 3. Superiority of PledOx 5 μmol/kg over placebo 4. Superiority of PledOx 2 μmol/kg over PledOx 5 μmol/kg 5. Superiority of PledOx 2 μmol/kg, PledOx 5 μmol/kg and PledOx 10 μmol/kg over placebo.
    [2] - 1. First order of the hierchical test procedure is given above 2. 0.3148 3. 0.1392 4. 0.7183 5. 0.1579

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were assessed and recorded at each hospital visit from first IMP administration to the EOT visit, 14 days after the final IMP administration. Any AEs that were ongoing at the End-of-Treatment visit were followed up until resolution or end of FU
    Adverse event reporting additional description
    For each AE, site staff recorded start and stop dates, outcome, actions taken with treatment, if any other medication or treatment was given, seriousness, intensity, severity and causality.. Intensity was rated as mild, moderate, or severe. Severity was graded according to NCI-CTCAE v4 criteria as mild, moderate, severe, lifethreatening or death.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Part 2 Group A (Pledox 2 μmol/kg)
    Reporting group description
    		 PledOx 2 μmol/kg + mFOLFOX6

    Reporting group title
    Part 2 Group B (Pledox 5 μmol/kg)
    Reporting group description
    		 Pledox 5 μmol/kg + mFOLGOX6

    Reporting group title
    Part 2 Group B (Pledox 10 μmol/kg)
    Reporting group description
    		 Pledox 10 μmol/kg + mFOLGOX6

    Reporting group title
    Part 2 Group C (Placebo)
    Reporting group description
    		 Placebo + mFOLFOX6

    Reporting group title
    Part 1a Pledox 2 μmol/kg
    Reporting group description
    		 -

    Reporting group title
    Part 1a Pledox 10 μmol/kg
    Reporting group description
    		 -

    Reporting group title
    Part 1b Pledox 2+10 μmol/kg
    Reporting group description
    		 -

    Reporting group title
    Part 1b Pledox 1+5 μmol/kg
    Reporting group description
    		 -

    Serious adverse events
    		 Part 2 Group A (Pledox 2 μmol/kg) Part 2 Group B (Pledox 5 μmol/kg) Part 2 Group B (Pledox 10 μmol/kg) Part 2 Group C (Placebo) Part 1a Pledox 2 μmol/kg Part 1a Pledox 10 μmol/kg Part 1b Pledox 2+10 μmol/kg Part 1b Pledox 1+5 μmol/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 57 (14.04%)
    4 / 45 (8.89%)
    2 / 11 (18.18%)
    6 / 60 (10.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    1
    1
    1
    2
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Brain contusion
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central ven
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stoma closure
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 45 (2.22%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 45 (2.22%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 45 (2.22%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    1 / 11 (9.09%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 45 (2.22%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    1 / 60 (1.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 45 (0.00%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 45 (2.22%)
    0 / 11 (0.00%)
    0 / 60 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Part 2 Group A (Pledox 2 μmol/kg) Part 2 Group B (Pledox 5 μmol/kg) Part 2 Group B (Pledox 10 μmol/kg) Part 2 Group C (Placebo) Part 1a Pledox 2 μmol/kg Part 1a Pledox 10 μmol/kg Part 1b Pledox 2+10 μmol/kg Part 1b Pledox 1+5 μmol/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 57 (96.49%)
    45 / 45 (100.00%)
    11 / 11 (100.00%)
    60 / 60 (100.00%)
    4 / 5 (80.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Neutropenia
         subjects affected / exposed
    15 / 57 (26.32%)
    17 / 45 (37.78%)
    2 / 11 (18.18%)
    29 / 60 (48.33%)
    2 / 5 (40.00%)
    3 / 3 (100.00%)
    1 / 2 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    28
    44
    2
    72
    4
    17
    8
    12
    Nervous system disorders
    Neurotoxicity
         subjects affected / exposed
    29 / 57 (50.88%)
    15 / 45 (33.33%)
    5 / 11 (45.45%)
    26 / 60 (43.33%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    87
    33
    11
    81
    0
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    15 / 57 (26.32%)
    12 / 45 (26.67%)
    6 / 11 (54.55%)
    18 / 60 (30.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    41
    27
    13
    59
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    11 / 57 (19.30%)
    13 / 45 (28.89%)
    1 / 11 (9.09%)
    12 / 60 (20.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    18
    27
    1
    21
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    7 / 57 (12.28%)
    11 / 45 (24.44%)
    2 / 11 (18.18%)
    9 / 60 (15.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    7
    17
    4
    19
    0
    0
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 45 (8.89%)
    0 / 11 (0.00%)
    6 / 60 (10.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    8
    0
    8
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    39 / 57 (68.42%)
    26 / 45 (57.78%)
    5 / 11 (45.45%)
    38 / 60 (63.33%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    71
    47
    5
    75
    0
    0
    0
    0
    Anaemia
         subjects affected / exposed
    13 / 57 (22.81%)
    13 / 45 (28.89%)
    2 / 11 (18.18%)
    16 / 60 (26.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    17
    27
    4
    24
    0
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    11 / 57 (19.30%)
    12 / 45 (26.67%)
    3 / 11 (27.27%)
    22 / 60 (36.67%)
    2 / 5 (40.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    2 / 3 (66.67%)
         occurrences all number
    16
    27
    3
    51
    7
    19
    15
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 57 (36.84%)
    18 / 45 (40.00%)
    0 / 11 (0.00%)
    31 / 60 (51.67%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
    3 / 3 (100.00%)
         occurrences all number
    47
    49
    0
    91
    2
    2
    1
    3
    Pyrexia
         subjects affected / exposed
    2 / 57 (3.51%)
    8 / 45 (17.78%)
    0 / 11 (0.00%)
    9 / 60 (15.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    11
    0
    13
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 57 (35.09%)
    16 / 45 (35.56%)
    4 / 11 (36.36%)
    28 / 60 (46.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    31
    29
    11
    76
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    17 / 57 (29.82%)
    21 / 45 (46.67%)
    5 / 11 (45.45%)
    20 / 60 (33.33%)
    1 / 5 (20.00%)
    3 / 3 (100.00%)
    1 / 2 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    33
    39
    5
    46
    1
    5
    1
    2
    Vomiting
         subjects affected / exposed
    10 / 57 (17.54%)
    6 / 45 (13.33%)
    1 / 11 (9.09%)
    9 / 60 (15.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    13
    6
    2
    18
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 57 (31.58%)
    11 / 45 (24.44%)
    2 / 11 (18.18%)
    16 / 60 (26.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    31
    12
    3
    35
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2013
    Changed dose from 10 to 5 μmol/kg for the highest dose group.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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