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    Clinical Trial Results:
    A Randomised Open Label Exploratory, Safety and Tolerability Study with PP100-01 in Patients Treated with the 12-hour Regimen of N-Acetylcysteine for Paracetamol/Acetaminophen Overdose

    Summary
    EudraCT number
    		 2017-000246-21
    Trial protocol
    		 GB  
    Global end of trial date
    08 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Sep 2019
    First version publication date
    06 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PP100-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03177395
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PledPharma
    Sponsor organisation address
    Grev Turegatan 10C, Stockholm, Sweden, 11446
    Public contact
    Malin Nittve, PledPharma AB, +46 (0)708368702, malin.nittve@pledpharma.se
    Scientific contact
    Malin Nittve, PledPharma AB, +46 (0)708368702, malin.nittve@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
    03 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Paracetamol can be harmful to the liver when an excessive dose has been taken. To help prevent liver damage, an antidote known as acetylcysteine is given. However a few patients can develop liver damage even if they get acetylcysteine. This study will give a new drug (calmangafodipir - PP100-01) in combination with a new 12-hour regimen for giving acetylcysteine. The principal research question is does the combination of calmangafodipir and acetylcysteine produce any unexpected side-effects?
    Protection of trial subjects
    The participants were given an oral explanation and a written Patient Information Sheet (PIS) explaining the aims of the study and the potential risks and benefits of the study treatments. The participant was given enough time to consider the study and ask questions regarding their participation in the study. Both the participant and the person delegated to take consent, signed and personally dated the ICF. Only patients with capacity were invited to participate in the study. Potential entry into the study depended on the patient's blood results confirming need for NAC and an assessment of capacity by a doctor in the Emergency Department. . All patients requiring NAC treatment were given this regardless of entry into the study.
    Background therapy
    		 To address the high incidence of ADRs and prolonged duration of the standard NAC regimen, a shorter 12 h intravenous regimen has been developed (the ‘SNAP’ regimen). The NAC regimen was 300 mg/kg NAC IV (200 mg/ml) in 5% glucose (dextrose) or 0.9% sodium chloride over 12 hours. This was divided as follows: • 100mg/kg of NAC in 200 mL over 2 hours ("loading dose"), then • 200 mg/kg of NAC in 1000 ml over l0 hours. Dose of NAC was adjusted according to participant weight
    Evidence for comparator
    		 Acetylcysteine (NAC) is effective at preventing liver injury if administered promptly, but it is substantially less effective if started later than around 8 h after overdose.
    Actual start date of recruitment
    05 Jun 2017
    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
    United Kingdom: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    23
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 To meet the target of 24 participants randomised, a total of 304 patients were screened and assessed for eligibility. Patients screened had toxicology presentations that included but were not exclusively paracetamol overdose. The main reasons for not being included was failure to meet inclusion criteria (n=216) or due to exclusion criteria (n=39).

    Pre-assignment
    Screening details
    		 Decision to treat with NAC is based on a nomogram to identify patients who require NAC treatment following a paracetamol overdose . This is based on paracetamol concentration and time from ingestion. In patients presenting later than 8h as well as staggered POD, NAC treatment is initiated if the patient had ingested more than 150 mg/kg APAP

    Pre-assignment period milestones
    Number of subjects started
    		 24
    Number of subjects completed
    		 24

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Allocation sequence for each dosing cohort was created by an Edinburgh Clinical Trials Unit (ECTU) programmer using computer-generated randomnumbers, using blocking to ensure the required 6:2 ratio. The randomisation list was held centrally at ECTU in order to conceal treatment allocations until these were implemented via the secureweb-based randomisation system. No blinding of participants or emergency department staff. Statistical analysis plan was written blinded to treatment allocations

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NAC alone
    Arm description
    		 NAC infusion 100mg/kg in 200ml 'loading dose' at timepoint '0'. 12 hour NAC regime will be continued with the second dose: 200mg/kg NAC in 1000ml i.v. over 10hr as per standard care protocol in NHS Lothian. At the end of the 12-hour NAC regimen the decision to continue NAC was made by assessment of the clinical blood sample taken at the 10-hour time-point. NAC was continued at 200 mg/kg in 1000 ml i.v administered over a further 10 hours if any of the following criteria were reached: • the ALT has more than doubled since the admission measurement, OR • the ALT is two times the upper limit of normal or more (≥100 IU/L), OR • the INR is greater than 1.3, OR • paracetamol concentration > 20 mg/mL
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC
    Arm description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: Group A: PP100-01 (2 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir
    Investigational medicinal product code
    PP100-01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Treatment started with the first NAC bag of 100 mg/kg in 200 ml (“loading dose”) at time point ‘0’. PP100-01 treatment (2 μmol/kg, 5 μmol/kg or 10 μmol/kg) was administered intravenously as a bolus infusion over 5 minutes at the dose specified by the dosing cohort following the loading dose of NAC. The 12-hour NAC regimen was continued with the second dose: 200 mg/kg NAC in 1000 mL i.v over 10 hours. At the end of the 12-hour NAC regimen the decision to continue NAC was made by assessment of the clinical blood sample taken at the 10-hour time-point. NAC was continued at 200 mg/kg in 1000 ml i.v administered over a further 10 hours if any of the following criteria were reached: • the ALT has more than doubled since the admission measurement, OR • the ALT is two times the upper limit of normal or more (≥100 IU/L), OR • the INR is greater than 1.3, OR • paracetamol concentration > 20 mg/mL

    Arm title
    		 Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC
    Arm description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (5 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir
    Investigational medicinal product code
    PP100-01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Treatment started with the first NAC bag of 100 mg/kg in 200 ml (“loading dose”) at time point ‘0’. PP100-01 treatment (2 μmol/kg, 5 μmol/kg or 10 μmol/kg) was administered intravenously as a bolus infusion over 5 minutes at the dose specified by the dosing cohort following the loading dose of NAC. The 12-hour NAC regimen was continued with the second dose: 200 mg/kg NAC in 1000 mL i.v over 10 hours. At the end of the 12-hour NAC regimen the decision to continue NAC was made by assessment of the clinical blood sample taken at the 10-hour time-point. NAC was continued at 200 mg/kg in 1000 ml i.v administered over a further 10 hours if any of the following criteria were reached: • the ALT has more than doubled since the admission measurement, OR • the ALT is two times the upper limit of normal or more (≥100 IU/L), OR • the INR is greater than 1.3, OR • paracetamol concentration > 20 mg/mL

    Arm title
    		 Group C: PP001-01 (Calmangafodipir) + NAC
    Arm description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (10 umol/kg calmangafodipir) after the "loading" dose of NAC PP100-01 treatment is administered intravenously over 5 minutes.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Calmangafodipir
    Investigational medicinal product code
    PP100-01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Treatment started with the first NAC bag of 100 mg/kg in 200 ml (“loading dose”) at time point ‘0’. PP100-01 treatment (2 μmol/kg, 5 μmol/kg or 10 μmol/kg) was administered intravenously as a bolus infusion over 5 minutes at the dose specified by the dosing cohort following the loading dose of NAC. The 12-hour NAC regimen was continued with the second dose: 200 mg/kg NAC in 1000 mL i.v over 10 hours. At the end of the 12-hour NAC regimen the decision to continue NAC was made by assessment of the clinical blood sample taken at the 10-hour time-point. NAC was continued at 200 mg/kg in 1000 ml i.v administered over a further 10 hours if any of the following criteria were reached: • the ALT has more than doubled since the admission measurement, OR • the ALT is two times the upper limit of normal or more (≥100 IU/L), OR • the INR is greater than 1.3, OR • paracetamol concentration > 20 mg/mL

    Number of subjects in period 1
    		NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC
    Started
    6
    6
    6
    6
    Completed
    6
    6
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NAC alone
    Reporting group description
    		 NAC infusion 100mg/kg in 200ml 'loading dose' at timepoint '0'. 12 hour NAC regime will be continued with the second dose: 200mg/kg NAC in 1000ml i.v. over 10hr as per standard care protocol in NHS Lothian. At the end of the 12-hour NAC regimen the decision to continue NAC was made by assessment of the clinical blood sample taken at the 10-hour time-point. NAC was continued at 200 mg/kg in 1000 ml i.v administered over a further 10 hours if any of the following criteria were reached: • the ALT has more than doubled since the admission measurement, OR • the ALT is two times the upper limit of normal or more (≥100 IU/L), OR • the INR is greater than 1.3, OR • paracetamol concentration > 20 mg/mL

    Reporting group title
    Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: Group A: PP100-01 (2 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group title
    Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (5 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group title
    Group C: PP001-01 (Calmangafodipir) + NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (10 umol/kg calmangafodipir) after the "loading" dose of NAC PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Total
    Number of subjects
    		 6 6 6 6 24
    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)
    		 6 5 6 6 23
        From 65-84 years
    		 0 1 0 0 1
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    All treatment groups included both male and female patients with an overall balance of 13 female versus 11 male patients
    Units: Subjects
        Female
    		 2 4 4 3 13
        Male
    		 4 2 2 3 11
    Type of overdose
    Type of overdose
    Units: Subjects
        Acute, ≤8 h to NAC
    		 2 4 4 4 14
        Acute, over 8 h to NAC
    		 3 2 2 1 8
        Staggered intentional
    		 0 0 0 1 1
        Supra-therapeutic
    		 1 0 0 0 1
    Any other drugs ingested
    Any other drugs ingested
    Units: Subjects
        yes
    		 5 4 5 5 19
        No
    		 1 2 1 1 5
    Time from ingestion of paracetamol to hospital presentation (hours)
    Time from ingestion of paracetamol to hospital presentation (hours)
    Units: hours
        arithmetic mean (standard deviation)
    		 8.8 ( 6.2 ) 6.0 ( 2.6 ) 5.8 ( 2.1 ) 4.9 ( 2.1 ) -
    Presentation paracetamol concentration (mg/L)
    Presentation paracetamol concentration (mg/L)
    Units: mg/mL
        arithmetic mean (standard deviation)
    		 76 ( 81 ) 127 ( 90 ) 74 ( 44 ) 127 ( 47 ) -
    Total paracetamol ingested (mg/kg)
    Total paracetamol ingested (mg/kg)
    Units: mg/kg
        arithmetic mean (standard deviation)
    		 185 ( 156 ) 235 ( 77 ) 229 ( 72 ) 397 ( 476 ) -
    Time from ingestion of paracetamol to start of NAC treatment (hours)
    Time from ingestion of paracetamol to start of NAC treatment (hours)
    Units: hours
        arithmetic mean (standard deviation)
    		 12.1 ( 5.2 ) 9.8 ( 6.5 ) 10.2 ( 6.9 ) 8.6 ( 4.1 ) -
    Time from ingestion of paracetamol to start of calmangafodipir (hours)
    Time from ingestion of paracetamol to start of calmangafodipir (hours)
    Units: hours
        arithmetic mean (standard deviation)
    		 NA ( NA ) 12.6 ( 6.8 ) 10.8 ( 4.1 ) 11.8 ( 5.4 ) -
    Serum creatinine (μmol/L)
    Serum creatinine (μmol/L)
    Units: μmol/L
        arithmetic mean (standard deviation)
    		 74.7 ( 11.0 ) 67.5 ( 13.3 ) 67.3 ( 17.2 ) 69.5 ( 13.1 ) -
    Subject analysis sets

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients will be included in the full analysis population, the primary population for analysis of efficacy, if they have received any PP100–01 or NAC. Data will be analysed according to the randomised treatment group. The stringent per-protocol population includes patients from the full analysis population for whom the study protocol has been followed without any major violations. The population for safety analysis will be patients who have received any PP100–01 or NAC. Data will be analysed according to the treatment received (NAC plus PP100– 01, or NAC alone)

    Subject analysis sets values
    		 Full analysis
    Number of subjects
    24
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    23
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    All treatment groups included both male and female patients with an overall balance of 13 female versus 11 male patients
    Units: Subjects
        Female
    13
        Male
    11
    Type of overdose
    Type of overdose
    Units: Subjects
        Acute, ≤8 h to NAC
    14
        Acute, over 8 h to NAC
    8
        Staggered intentional
    1
        Supra-therapeutic
    1
    Any other drugs ingested
    Any other drugs ingested
    Units: Subjects
        yes
    19
        No
    5
    Time from ingestion of paracetamol to hospital presentation (hours)
    Time from ingestion of paracetamol to hospital presentation (hours)
    Units: hours
        arithmetic mean (standard deviation)
    6.4 ( 6.2 )
    Presentation paracetamol concentration (mg/L)
    Presentation paracetamol concentration (mg/L)
    Units: mg/mL
        arithmetic mean (standard deviation)
    101 ( 66 )
    Total paracetamol ingested (mg/kg)
    Total paracetamol ingested (mg/kg)
    Units: mg/kg
        arithmetic mean (standard deviation)
    262 ( 195 )
    Time from ingestion of paracetamol to start of NAC treatment (hours)
    Time from ingestion of paracetamol to start of NAC treatment (hours)
    Units: hours
        arithmetic mean (standard deviation)
    10.2 ( 5.7 )
    Time from ingestion of paracetamol to start of calmangafodipir (hours)
    Time from ingestion of paracetamol to start of calmangafodipir (hours)
    Units: hours
        arithmetic mean (standard deviation)
    11.7 ( 5.4 )
    Serum creatinine (μmol/L)
    Serum creatinine (μmol/L)
    Units: μmol/L
        arithmetic mean (standard deviation)
    69.8 ( 13.6 )

    End points

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    End points reporting groups
    Reporting group title
    NAC alone
    Reporting group description
    		 NAC infusion 100mg/kg in 200ml 'loading dose' at timepoint '0'. 12 hour NAC regime will be continued with the second dose: 200mg/kg NAC in 1000ml i.v. over 10hr as per standard care protocol in NHS Lothian. At the end of the 12-hour NAC regimen the decision to continue NAC was made by assessment of the clinical blood sample taken at the 10-hour time-point. NAC was continued at 200 mg/kg in 1000 ml i.v administered over a further 10 hours if any of the following criteria were reached: • the ALT has more than doubled since the admission measurement, OR • the ALT is two times the upper limit of normal or more (≥100 IU/L), OR • the INR is greater than 1.3, OR • paracetamol concentration > 20 mg/mL

    Reporting group title
    Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: Group A: PP100-01 (2 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group title
    Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (5 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group title
    Group C: PP001-01 (Calmangafodipir) + NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (10 umol/kg calmangafodipir) after the "loading" dose of NAC PP100-01 treatment is administered intravenously over 5 minutes.

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients will be included in the full analysis population, the primary population for analysis of efficacy, if they have received any PP100–01 or NAC. Data will be analysed according to the randomised treatment group. The stringent per-protocol population includes patients from the full analysis population for whom the study protocol has been followed without any major violations. The population for safety analysis will be patients who have received any PP100–01 or NAC. Data will be analysed according to the treatment received (NAC plus PP100– 01, or NAC alone)

    Primary: Safety Events

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    End point title
    		 Safety Events [1]
    End point description
    All randomised patientswere analysed for the safety and tolerability primary outcomes. During the 7 days after randomisation 23 out of 24 patients had at least one AE. Eleven patients had at least one SAE within the 90 day follow up period; 5 patients had at least one SAE within 7 days of randomisation. These SAEs were spread across the 4 treatment groups. The primary objective of this phase 1 trial was to assess the adverse events (AEs) and serious adverse events (SAEs) associated with calmangafodipir co-treatment with the SNAP NAC treatment regime in patients with paracetamol overdose. The data generated were descriptive; there was no hypothesis tested. Therefore, we did not perform any analysis which would generate a P value
    End point type
    Primary
    End point timeframe
    90 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary objective of this phase 1 trial was to assess the adverse events (AEs) and serious adverse events (SAEs) associated with calmangafodipir co-treatment with the SNAP NAC treatment regime in patients with paracetamol overdose. The data generated were descriptive; there was no hypothesis tested. Therefore, we did not perform any analysis which would generate a P value
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: subjects
        Any AE
    6
    6
    6
    6
    24
        Any SAE
    2
    4
    2
    3
    11
        AE after commencement of NAC treatment
    6
    5
    6
    6
    23
        SAE after commencement of NAC treatment
    1
    1
    1
    2
    5
        AE where outcome was death
    0
    0
    1
    0
    1
        AE unrelated to NAC
    3
    5
    3
    5
    16
        AE possibly related to NAC
    2
    2
    2
    2
    8
        AE probably related to NAC
    3
    2
    3
    2
    10
        AE definitely related to NAC
    2
    3
    1
    1
    7
        AE unrelated to PP100-01
    6
    6
    5
    6
    23
        AE possibly related to PP001-01
    0
    4
    2
    2
    8
        Ae probably related to PP100-01
    0
    0
    0
    0
    0
        AE definitely related to PP100-01
    0
    0
    0
    0
    0
        Any SUSAR
    0
    0
    0
    1
    1
        Any SUSAR related to NAC
    0
    0
    0
    0
    0
        SUSAR to PP100-01
    0
    0
    0
    1
    1
        SUSAR to NAC and PP100-01
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: ALT

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    End point title
    		 ALT
    End point description
    ALT was summarised descriptively by treatment group and overall at baseline, 10 h and 20 h. Change from baseline was also summarised.
    End point type
    Secondary
    End point timeframe
    Baseline, 10 and 20 hours after
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: U/L
    geometric mean (standard deviation)
        Baseline
    42.5 ( 3.6 )
    24.6 ( 2.1 )
    29.4 ( 2.3 )
    17.7 ( 1.5 )
    27.2 ( 2.4 )
        10 hours
    41.4 ( 3.3 )
    22.9 ( 1.8 )
    25.3 ( 2.1 )
    15.0 ( 1.3 )
    24.5 ( 2.2 )
        20 hours
    43.3 ( 3.8 )
    20.4 ( 1.9 )
    25.4 ( 1.8 )
    16.4 ( 1.5 )
    24.6 ( 2.3 )
        Change from baseline
    1.02 ( 1.62 )
    0.83 ( 1.25 )
    0.87 ( 1.34 )
    0.92 ( 1.58 )
    0.91 ( 1.45 )
    No statistical analyses for this end point

    Secondary: INR

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    End point title
    		 INR
    End point description
    Relative change from baseline to 20 h - ratio was also assessed
    End point type
    Secondary
    End point timeframe
    Baseline, 10 and 20 hours and Relative change from baseline to 20 h - ratio
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: NA
    arithmetic mean (standard deviation)
        Baseline
    1.02 ( 0.04 )
    1.00 ( 0.12 )
    0.98 ( 0.04 )
    1.05 ( 0.14 )
    1.01 ( 0.09 )
        10 hours
    1.30 ( 0.18 )
    1.17 ( 0.20 )
    1.20 ( 0.00 )
    1.22 ( 0.25 )
    1.22 ( 0.18 )
        20 hours
    1.18 ( 0.21 )
    1.07 ( 0.19 )
    1.08 ( 0.04 )
    1.17 ( 0.23 )
    1.13 ( 0.18 )
        Relative change from baseline to 20 h - ratio
    1.15 ( 1.17 )
    1.07 ( 1.12 )
    1.10 ( 1.07 )
    1.10 ( 1.10 )
    1.11 ( 1.11 )
    No statistical analyses for this end point

    Secondary: Number of additional NAC infusions after 12 h regimen

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    End point title
    		 Number of additional NAC infusions after 12 h regimen
    End point description
    End point type
    Secondary
    End point timeframe
    After 12 hours NAC regimen
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: subjects
        None
    3
    5
    6
    5
    19
        One
    1
    1
    0
    1
    3
        Two
    2
    0
    0
    0
    2
    No statistical analyses for this end point

    Secondary: K18

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    End point title
    		 K18
    End point description
    Relative change from baseline to 20 h – ratio was also assessed
    End point type
    Secondary
    End point timeframe
    Baseline, 10 hours and 20 hours
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: U/L
    geometric mean (standard deviation)
        Baseline (2 h)
    187 ( 2.20 )
    177 ( 1.82 )
    193 ( 1.56 )
    128 ( 1.25 )
    169 ( 1.72 )
        10h
    182 ( 1.95 )
    152 ( 1.56 )
    170 ( 1.42 )
    111 ( 1.18 )
    151 ( 1.58 )
        20h
    347 ( 3.18 )
    229 ( 1.94 )
    172 ( 1.45 )
    181 ( 1.73 )
    223 ( 2.12 )
        Relative change from baseline to 20 h – ratio
    1.85 ( 1.47 )
    1.29 ( 1.89 )
    0.89 ( 1.57 )
    1.41 ( 1.83 )
    1.32 ( 1.75 )
    No statistical analyses for this end point

    Secondary: ccK18

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    End point title
    		 ccK18
    End point description
    Relative change from baseline to 20 h - ratio
    End point type
    Secondary
    End point timeframe
    At Baseline, 10 hours and 20 hours
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: U/L
    geometric mean (standard deviation)
        Baseline (2 h)
    67 ( 1.99 )
    45 ( 1.33 )
    84 ( 1.80 )
    104 ( 2.44 )
    71 ( 1.99 )
        10h
    72 ( 2.24 )
    53 ( 1.25 )
    56 ( 1.57 )
    78 ( 2.12 )
    64 ( 1.80 )
        20h
    149 ( 3.34 )
    66 ( 1.34 )
    85 ( 1.62 )
    111 ( 2.56 )
    98 ( 2.27 )
        Relative change from baseline to 20 h - ratio
    2.22 ( 1.77 )
    1.49 ( 1.55 )
    1.02 ( 1.79 )
    1.08 ( 2.44 )
    1.38 ( 1.97 )
    No statistical analyses for this end point

    Secondary: miR-122 (DCt)

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    End point title
    		 miR-122 (DCt)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 10 hours and 20 hours
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC Full analysis
    Number of subjects analysed
    6
    6
    6
    6
    24
    Units: DCt
    arithmetic mean (standard deviation)
        Baseline (2 h)
    5.58 ( 3.36 )
    5.85 ( 1.50 )
    4.43 ( 3.92 )
    8.73 ( 2.36 )
    6.15 ( 3.18 )
        10h
    5.41 ( 3.86 )
    6.14 ( 1.99 )
    5.01 ( 3.36 )
    9.00 ( 1.45 )
    6.39 ( 3.09 )
        20h
    4.85 ( 3.97 )
    7.12 ( 2.26 )
    4.49 ( 2.93 )
    8.44 ( 1.50 )
    6.22 ( 3.11 )
    No statistical analyses for this end point

    Secondary: miR-122 (copies/mcL)

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    End point title
    		 miR-122 (copies/mcL)
    End point description
    Relative change from baseline to 20 h - ratio was also assessed
    End point type
    Secondary
    End point timeframe
    Baseline, 10 hours and 20 hours
    End point values
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC
    Number of subjects analysed
    6
    6
    6
    6
    Units: copies/mcL
    geometric mean (standard deviation)
        Baseline (2h)
    146363 ( 11.7 )
    116749 ( 2.4 )
    194075 ( 13.5 )
    36051 ( 3.9 )
        10h
    206205 ( 13.0 )
    109882 ( 3.3 )
    196732 ( 9.4 )
    37066 ( 2.2 )
        20 h
    216256 ( 10.8 )
    57664 ( 3.8 )
    202271 ( 7.7 )
    40745 ( 3.2 )
        Relative change from baseline to 20 h - ratio
    1.48 ( 5.71 )
    0.49 ( 1.98 )
    1.04 ( 8.28 )
    1.13 ( 2.96 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were collected 7, 30 and 90 days after randomisation
    Adverse event reporting additional description
    As were events of special interest: representation to hospital (any reason), representation with liver injury, repeat overdose, death and transfer to liver transplantation unit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4
    Reporting groups
    Reporting group title
    NAC alone
    Reporting group description
    		 NAC infusion 100mg/kg in 200ml 'loading dose' at timepoint '0'. 12 hour NAC regime will be continued with the second dose: 200mg/kg NAC in 1000ml i.v. over 10hr as per standard care protocol in NHS Lothian.

    Reporting group title
    Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: Group A: PP100-01 (2 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group title
    Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (5 umol/kg calmangafodipir) after the "loading" dose of NAC. PP100-01 treatment is administered intravenously over 5 minutes.

    Reporting group title
    Group C: PP001-01 (Calmangafodipir) + NAC
    Reporting group description
    		 In addition to the standard care NAC regime, participants will be allocated into a dosing cohort to receive: PP100-01 (10 umol/kg calmangafodipir) after the "loading" dose of NAC PP100-01 treatment is administered intravenously over 5 minutes.

    Serious adverse events
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
    Additional description: There were 9 repeat overdoses for 4 participants, with one subject (11019 (NAC + 10 μmol/kg PP100-01)) presenting to hospital with 5 separate overdoses
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    cardiac disorders
    Additional description: Adverse event of 'Death - caused by bronchopneumonia (possible aspiration) and ischaemic heart disease' experienced by participant 11015 (NAC+5 μmol/kg PP100-01)
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric disorders
    Additional description: 3 participants recorded SAEs relating to psychiatric disorders (depressive episode (11018 (NAC alone)), mental health crisis (11005 (NAC + 2 μmol/kg PP100-01)), mental health issue (11006 NAC + 2 μmol/kg PP100-01))
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
    Additional description: Adverse event of 'Death - caused by bronchopneumonia (possible aspiration) and ischaemic heart disease' experienced by participant 11015 (NAC+5 μmol/kg PP100-01)
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 NAC alone Group A: PP100-01 (2 umol/kg calmangafodipir) +NAC Group B: PP100-01 (Calmangafodipir) 5 umol/kg + NAC Group C: PP001-01 (Calmangafodipir) + NAC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    1
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    2
    0
    1
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
         occurrences all number
    1
    2
    1
    3
    Cardiac disorders
    Cardiac disorderd
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    2
    1
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    4 / 6 (66.67%)
    5 / 6 (83.33%)
         occurrences all number
    5
    6
    4
    5
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
         occurrences all number
    0
    1
    1
    3
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2017
    There was one substantial amendment to the protocol after study start to provide clarification around timing of assessments and ensure alignment of the protocol with relevant SOPs and instructions. The protocol and PIS-ICF were updated accordingly and this amendment were approved and implemented on 10th August 2017

    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.
    No pts developed hepatotoxicity (ALT over 1000 U/L) or ALF. Pts not stratified at randomisation by risk of developing hepatoxicity or ALF. Small pts No per group should be considered when interpreting the effect of calmangafodipir

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30621764
    http://www.ncbi.nlm.nih.gov/pubmed/31311721
    For support, Contact us.
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