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    Clinical Trial Results:
    Safety, tolerability and pharmacokinetics (PKs) of multiple oral doses of GR3027 in healthy male volunteers and single and multiple doses in patients with liver cirrhosis. Preliminary efficacy in cirrhotic patients with evidence of covert hepatic encephalopathy (CHE). A prospective, double-blinded, randomized, placebo-controlled phase I/IIa study.

    Summary
    EudraCT number
    		 2016-003651-30
    Trial protocol
    		 SE   DK   FI   PL   HU  
    Global end of trial date
    20 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2020
    First version publication date
    20 Nov 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UCAB-CT-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Umecrine Cognition AB
    Sponsor organisation address
    Fogdevreten 2, Solna, Sweden, SE-171 65
    Public contact
    Magnus Doverskog, Umecrine Cognition AB, 46 8524 844 84, magnus.doverskog@umecrine.se
    Scientific contact
    Magnus Doverskog, Umecrine Cognition AB, 46 8524 844 84, magnus.doverskog@umecrine.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
    24 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the safety and tolerability of GR3027 after multiple dose administration in healthy male volunteers and after single and multiple dose administration in cirrhotic patients. General information The study consisted of 4 separate parts: A Multiple Ascending Dose (MAD) in healthy subjects for safety and PK. B Single dose in cirrhotic patients Child-Pugh class B for safety, PK and preliminary assessment of EEG findings. C MAD in cirrhotic patients Child-Pugh class A and B for safety and PK and preliminary assessment of EEG findings. D Extended treatment (21 consecutive days) in cirrhotic patients Child-Pugh class A and B with manifestation of CHE for safety and preliminary efficacy. A 4-weeks screening period was applied. In Part A, 5 QD (1st cohort) or 5 BID (2nd and 3rd cohorts) doses were given. In Part C, 5 BID doses were given in all cohorts. In Part D, 21 BID doses were given in all cohorts.
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference of Harmonization (ICH)/Good Clinical Practice (GCP) E6 (R1), European Union (EU) Clinical Trials Directive, and applicable local regulatory requirements. In accordance with the EU Data Protection Directive (95/46/EC), the data will not identify any persons taking part in the study. A pre-defined dosing strategy was applied in the trial, including evaluations of an Internal Safety Review Committee (iSRC), before proceeding to the next cohort or trial part. In parts A and C of the trial, each cohort were divided into at least 3 groups (2+3+3).The subjects remained in the research clinic from the evening before first dosing (Day -1) until 48 h post last dose (Day 3 and Day 7, respectively) and were closely monitored by medical staff. Each group was dosed approximately 48 hours apart. In each group, the subjects/patients were dosed with an interval of at least 90 min between subjects. In each cohort of Part B (single dose, cirrhotic patients) a “sentinel group” of 2 subjects (1 GR3027/1 placebo) was dosed first and closely observed for 48 h before proceeding to dose the remaining subjects with an interval of at least 24 h between subjects. A summary of the safety and PK results from Parts A and B was submitted to the Swedish Competent Authority and the IEC for approval before initiating Parts C and D. In each cohort of Part C (MAD, cirrhotic patients) a “sentinel group” of 2 subjects (1 GR3027/1 placebo) was dosed first and closely observed for 48 h before proceeding to dose the remaining subjects. In Part D (extended treatment, cirrhotic patients) the morning doses on Days 1, 10 and 21 were administered under surveillance. No DLTs, as defined in the Clinical Study Protocol Section 9.1.1.2, occurred.
    Background therapy
    		 In Parts B-D, treatments with lactulose, rifaximin, proton-pump inhibitors (PPIs), diuretics, anti-epileptics, sleep aids, and selective serotonin reuptake inhibitor (SSRI) were allowed, but must be stable during the trial, except for adjustment of lactulose dose (e.g. for diarrhoea).
    Evidence for comparator
    		 This was a placebo-controlled trial vs investigational drug. No other comparators were used. Abbreviations used: AE: Adverse event ANT1: Animal Naming Test BID: Twice daily CHE: Covert hepatic encephalopathy CTCAE: Common Terminology Criteria for Adverse Events HE: Hepatic encephalopathy DTABR: Ratio relative powers of delta and theta to the relative powers of alpha and beta IMP: Investigational medicinal product MAD: Multiple ascending dose MDF: Mean dominant frequency OHE: Overt hepatic encephalopathy PK: Pharmacokinetic PPASC: Per protocol analysis set, Part C PPASD: Per protocol analysis set, Part D QD: Once daily QoL: Quality of life SAE: Serious adverse event SD: Single dose TEAE: Treatment emergent adverse event
    Actual start date of recruitment
    16 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Sweden: 37
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Hungary: 32
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Ukraine: 8
    Worldwide total number of subjects
    101
    EEA total number of subjects
    71
    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)
    86
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Part A: The healthy subjects were recruited from a register of healthy volunteers at the Swedish CRO CTC and from advertising in media. Part B-D: Cirrhotic patients were recruited from a network of referring clinics. 1 subject from Part B participated also in Part C. 5 subjects from Part C participated also in Part D.

    Pre-assignment
    Screening details
    		 Consenting subjects were screened for eligibility to study Parts A to D, according to study-specific inclusion/exclusion criteria within 4 weeks prior to the first administration of IMP. Eligible subjects were randomized on Day 1 to receive either GR3027 or placebo and consecutively included in one of the cohorts in applicable study part.

    Period 1
    Period 1 title
    Overall Trial Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Capsules of GR3027 and placebo were of identical appearance. The IMP dispensing was performed according to the randomisation scheme by 2 un-blinded staff, not involved in the conduct of the study. In Parts A-C, the IMP was administered by blinded study staff at the research clinic. In Part D, the IMP was self-administered by the subjects. A code breaking procedure was available in the eCRF system Viedoc™ with an audit trail. No un-blinding occurred in the study prior to database closure.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part A, A1 50 mg QD
    Arm description
    		 Healthy male subjects recieved an oral dose of 50 mg GR3027 QD for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    5 GR3027 10 mg orange hard gelatine capsules were administered QD

    Arm title
    		 Part A, A2 50 mg BID (100 mg per day)
    Arm description
    		 Healthy male subjects recieved oral doses of 50 mg GR3027 BID for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    5 GR3027 10 mg orange hard gelatine capsules were administered BID

    Arm title
    		 Part A, A3 100 mg BID (200 mg per day)
    Arm description
    		 Healthy male subjects recieved oral doses of 100 mg GR3027 BID for 5 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    10 GR3027 10 mg orange hard gelatine capsules were administered BID

    Arm title
    		 Part A, Placebo
    Arm description
    		 Healthy male subjects recieved placebo capsules QD (cohort A1) or BID (cohorts A2-A3) for 5 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules, with identical appearence to the GR3027 capsules, were administered in a number matching the dose of the active drug

    Arm title
    		 Part B, 10 mg SD
    Arm description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of 10 mg GR3027
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 GR3027 10 mg orange hard gelatine capsule was administered as a single dose

    Arm title
    		 Part B, Placebo
    Arm description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    A placebo capsule, with identical appearence to the GR3027 capsules, were administered as a single dose

    Arm title
    		 Part C, C1 10 mg BID (20 mg per day)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 5 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 GR3027 10 mg orange hard gelatine capsule was administered BID

    Arm title
    		 Part C, C2 40 mg BID (80 mg per day)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 5 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4 GR3027 10 mg orange hard gelatine capsules was administered BID

    Arm title
    		 Part C, C3 80 mg BID (160 mg per day)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 5 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    8 GR3027 10 mg orange hard gelatine capsules was administered BID

    Arm title
    		 Part C, Placebo
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 5 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules, with identical appearence to the GR3027 capsules, were administered in a number matching the dose of the active drug

    Arm title
    		 Part D, D1 10 mg BID (20 mg per day)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 21 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 GR3027 10 mg orange hard gelatine capsule was administered BID

    Arm title
    		 Part D, D2 40 mg BID (80 mg per day)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 21 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    4 GR3027 10 mg orange hard gelatine capsules was administered BID

    Arm title
    		 Part D, D3 80 mg BID (160 mg per day)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 21 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    8 GR3027 10 mg orange hard gelatine capsules was administered BID

    Arm title
    		 Part D, Placebo
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 21 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules, with identical appearence to the GR3027 capsules, were administered in a number matching the dose of the active drug

    Arm title
    		 Part D, Total (D1+D2+D3)
    Arm description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10, 40, or 80 mg GR3027 BID for 21 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    GR3027 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1, 4, or 8 GR3027 10 mg orange hard gelatine capsules were administered BID

    Number of subjects in period 1
    		Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day) Part A, Placebo Part B, 10 mg SD Part B, Placebo Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Started
    6
    6
    6
    6
    6
    2
    6
    6
    6
    6
    10
    10
    13
    12
    33
    Completed
    6
    6
    6
    6
    6
    2
    6
    6
    6
    6
    9
    10
    11
    12
    30
    Not completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    0
    3
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
    1
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A, A1 50 mg QD
    Reporting group description
    		 Healthy male subjects recieved an oral dose of 50 mg GR3027 QD for 5 days.

    Reporting group title
    Part A, A2 50 mg BID (100 mg per day)
    Reporting group description
    		 Healthy male subjects recieved oral doses of 50 mg GR3027 BID for 5 days.

    Reporting group title
    Part A, A3 100 mg BID (200 mg per day)
    Reporting group description
    		 Healthy male subjects recieved oral doses of 100 mg GR3027 BID for 5 days.

    Reporting group title
    Part A, Placebo
    Reporting group description
    		 Healthy male subjects recieved placebo capsules QD (cohort A1) or BID (cohorts A2-A3) for 5 days.

    Reporting group title
    Part B, 10 mg SD
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of 10 mg GR3027

    Reporting group title
    Part B, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of placebo

    Reporting group title
    Part C, C1 10 mg BID (20 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 5 days

    Reporting group title
    Part C, C2 40 mg BID (80 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 5 days

    Reporting group title
    Part C, C3 80 mg BID (160 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 5 days

    Reporting group title
    Part C, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 5 days.

    Reporting group title
    Part D, D1 10 mg BID (20 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 21 days

    Reporting group title
    Part D, D2 40 mg BID (80 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 21 days

    Reporting group title
    Part D, D3 80 mg BID (160 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 21 days

    Reporting group title
    Part D, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 21 days.

    Reporting group title
    Part D, Total (D1+D2+D3)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10, 40, or 80 mg GR3027 BID for 21 days

    Reporting group values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day) Part A, Placebo Part B, 10 mg SD Part B, Placebo Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3) Total
    Number of subjects
    		 6 6 6 6 6 2 6 6 6 6 10 10 13 12 33
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.33 ( 6.80 ) 31.33 ( 7.63 ) 32.00 ( 8.67 ) 28.50 ( 4.04 ) 63.50 ( 2.07 ) 58.50 ( 4.95 ) 54.7 ( 10.3 ) 55.0 ( 9.8 ) 50.2 ( 11.9 ) 60.5 ( 5.5 ) 53.0 ( 6.8 ) 53.2 ( 12.9 ) 56.3 ( 12.2 ) 59.7 ( 9.4 ) 54.4 ( 10.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0 1 1 1 4 4 3 4 5 11 23
        Male
    		 6 6 6 6 6 2 5 5 5 2 6 7 9 7 22 78

    End points

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    End points reporting groups
    Reporting group title
    Part A, A1 50 mg QD
    Reporting group description
    		 Healthy male subjects recieved an oral dose of 50 mg GR3027 QD for 5 days.

    Reporting group title
    Part A, A2 50 mg BID (100 mg per day)
    Reporting group description
    		 Healthy male subjects recieved oral doses of 50 mg GR3027 BID for 5 days.

    Reporting group title
    Part A, A3 100 mg BID (200 mg per day)
    Reporting group description
    		 Healthy male subjects recieved oral doses of 100 mg GR3027 BID for 5 days.

    Reporting group title
    Part A, Placebo
    Reporting group description
    		 Healthy male subjects recieved placebo capsules QD (cohort A1) or BID (cohorts A2-A3) for 5 days.

    Reporting group title
    Part B, 10 mg SD
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of 10 mg GR3027

    Reporting group title
    Part B, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of placebo

    Reporting group title
    Part C, C1 10 mg BID (20 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 5 days

    Reporting group title
    Part C, C2 40 mg BID (80 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 5 days

    Reporting group title
    Part C, C3 80 mg BID (160 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 5 days

    Reporting group title
    Part C, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 5 days.

    Reporting group title
    Part D, D1 10 mg BID (20 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 21 days

    Reporting group title
    Part D, D2 40 mg BID (80 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 21 days

    Reporting group title
    Part D, D3 80 mg BID (160 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 21 days

    Reporting group title
    Part D, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 21 days.

    Reporting group title
    Part D, Total (D1+D2+D3)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10, 40, or 80 mg GR3027 BID for 21 days

    Primary: Safety as number of subjects with adverse events

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    End point title
    		 Safety as number of subjects with adverse events [1] [2]
    End point description
    Safety was assessed by occurrence and frequency of AEs, changes in laboratory parameters, vital signs, ECG, and physical examination. Medically important abnormalities observed in laboratory parameters, vital signs, ECG, and physical examinations were reported as adverse events. AEs occurring before first administration of IMP were defined as baseline events. AEs starting from first administration of IMP were defined as TEAEs. The grading of the severity of AEs followed the CTCAE v4.03. The CTCAE displays severity Grades 1 through 5.
    End point type
    Primary
    End point timeframe
    From signing of informed consent and until follow-up assessments, 21 days after the last dose.
    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: In this trial, safety was the primary endpoint. In accordance with the trial protocol no statistical analysis was performed, but data were presented as an overview of all subjects with AEs including severity, relationship to the IP, and SAEs.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Arm Total (D1+D2+D3+D4¤) is a combination of the arms in Part D and is not relevant for this endpoint. Safety data are reported for the arms D1-D4 separately.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day) Part A, Placebo Part B, 10 mg SD Part B, Placebo Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Number of subjects analysed
    6
    6
    6
    6
    6
    2
    6
    6
    6
    6
    10
    10
    13
    12
    Units: Subjects with adverse events
        Any AE
    5
    3
    4
    2
    3
    1
    3
    4
    1
    1
    3
    3
    6
    5
        Any SAE
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Any baseline event
    2
    1
    2
    0
    2
    0
    0
    1
    0
    1
    1
    0
    1
    2
        Any TEAE
    4
    2
    4
    2
    3
    1
    3
    3
    1
    0
    2
    3
    6
    4
        Not related TEAEs
    2
    1
    2
    2
    3
    1
    1
    0
    1
    0
    2
    0
    5
    2
        Possibly related TEAEs
    3
    1
    3
    2
    0
    0
    2
    2
    0
    0
    0
    3
    3
    2
        Probably related TEAEs
    0
    0
    2
    1
    0
    0
    0
    1
    0
    0
    0
    0
    2
    0
        TEAEs of Grade 1 severity
    4
    2
    4
    2
    3
    1
    3
    3
    0
    0
    2
    3
    5
    3
        TEAEs of Grade 2 severity
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    1
    1
    2
        TEAEs of Grade 3 severity
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
        TEAEs of Grade 4 severity
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        TEAEs of Grade 5 severity
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Part A: PK - Lambdaz after first dose

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    End point title
    		 Part A: PK - Lambdaz after first dose [3]
    End point description
    Plasma terminal elimination rate constant Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    5 [4]
    Units: /h
        median (full range (min-max))
    0.0650 (0.047 to 0.134)
    0.1425 (0.103 to 0.186)
    0.1401 (0.061 to 0.195)
    Notes
    [4] - For 1 subject in dose group 100 mg BID, Lambdaz could not be calculated following the first dose.
    No statistical analyses for this end point

    Secondary: Part A: PK - T1/2 after first dose

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    End point title
    		 Part A: PK - T1/2 after first dose [5]
    End point description
    Plasma Terminal half-life Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    5 [6]
    Units: hour
        median (full range (min-max))
    10.8237 (5.168 to 14.628)
    4.9197 (3.724 to 6.758)
    4.9477 (3.556 to 11.315)
    Notes
    [6] - For 1 subject in dose group 100 mg BID, T1/2 could not be calculated following the first dose.
    No statistical analyses for this end point

    Secondary: Part A: PK - Tmax after first dose

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    End point title
    		 Part A: PK - Tmax after first dose [7]
    End point description
    Time to maximum plasma concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: hour
        median (full range (min-max))
    1.5000 (1.033 to 2.033)
    1.2500 (1.000 to 2.000)
    1.7500 (1.500 to 6.000)
    No statistical analyses for this end point

    Secondary: Part A: PK - Cmax after first dose

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    End point title
    		 Part A: PK - Cmax after first dose [8]
    End point description
    Maximum plasma concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: ng/mL
        median (full range (min-max))
    740.00 (638.0 to 990.0)
    929.00 (700.0 to 1150.0)
    1395.00 (595.0 to 1750.0)
    No statistical analyses for this end point

    Secondary: Part A: PK - AUC(0-t) after first dose

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    End point title
    		 Part A: PK - AUC(0-t) after first dose [9]
    End point description
    Area under the plasma concentration time curve to last nonzero concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: h*ng/mL
        median (full range (min-max))
    3926.2 (2993 to 5397)
    3415.4 (2546 to 4283)
    5823.0 (5374 to 7816)
    No statistical analyses for this end point

    Secondary: Part A: PK - AUCinf after first dose

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    End point title
    		 Part A: PK - AUCinf after first dose [10]
    End point description
    Area under the plasma concentration time curve to infinity (observed value) Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    5 [11]
    Units: h*ng/mL
        median (full range (min-max))
    4785.5 (3093 to 6219)
    4059.1 (3112 to 5603)
    7400.0 (6887 to 9705)
    Notes
    [11] - For 1 subject in dose group 100 mg BID, AUCinf could not be calculated following the first dose.
    No statistical analyses for this end point

    Secondary: Part A: PK - Vz/F after first dose

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    End point title
    		 Part A: PK - Vz/F after first dose [12]
    End point description
    Volume of distribution Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    5 [13]
    Units: litre
        median (full range (min-max))
    158.9 (90 to 185)
    80.9 (72 to 111)
    96.5 (69 to 169)
    Notes
    [13] - For 1 subject in dose group 100 mg BID, Vz/F could not be calculated following the first dose.
    No statistical analyses for this end point

    Secondary: Part A: PK - CL/F after first dose

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    End point title
    		 Part A: PK - CL/F after first dose [14]
    End point description
    Total apparent clearance of drug from plasma/serum Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose, 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    5 [15]
    Units: L/h
        median (full range (min-max))
    10.4 (8 to 16)
    12.4 (9 to 16)
    13.5 (10 to 15)
    Notes
    [15] - For 1 subject in dose group 100 mg BID, Cl/F could not be calculated following the first dose.
    No statistical analyses for this end point

    Secondary: Part A: PK - Ae after first dose

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    End point title
    		 Part A: PK - Ae after first dose [16]
    End point description
    Urine recovery of GR3027
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter Urine recovery (Ae) was only measured in Part A of the trial.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    0 [17]
    6
    6
    Units: µg
        median (full range (min-max))
    ( to )
    2.31 (0.0 to 20.1)
    16.92 (0.0 to 48.5)
    Notes
    [17] - For the first dose in group 50 mg QD, assessment of Ae was not performed due to analytical problems.
    No statistical analyses for this end point

    Secondary: Part A: PK - Fe after first dose

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    End point title
    		 Part A: PK - Fe after first dose [18]
    End point description
    Fraction of the dose excreted in urine for GR3027
    End point type
    Secondary
    End point timeframe
    Predose to 24 h for dose group 50mg QD. Predose to 12 h for dose group 50mg BID and 100 mg BID.
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter Fraction of dose extracted in urine (Fe) was only measured in Part A of the trial.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    0 [19]
    6
    6
    Units: percent (%)
        median (full range (min-max))
    ( to )
    0.0046 (0.000 to 0.040)
    0.0169 (0.000 to 0.049)
    Notes
    [19] - For the first dose in group 50 mg QD, assessment of Fe was not performed due to analytical problems.
    No statistical analyses for this end point

    Secondary: Part A: PK - Lambdaz after last dose

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    End point title
    		 Part A: PK - Lambdaz after last dose [20]
    End point description
    Plasma terminal elimination rate constant Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: /h
        median (full range (min-max))
    0.0619 (0.055 to 0.135)
    0.0613 (0.040 to 0.087)
    0.0639 (0.035 to 0.090)
    No statistical analyses for this end point

    Secondary: Part A: PK - T1/2 after last dose

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    End point title
    		 Part A: PK - T1/2 after last dose [21]
    End point description
    Plasma terminal half-life Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: hour
        median (full range (min-max))
    11.2292 (5.117 to 12.623)
    11.6258 (7.930 to 17.248)
    10.9620 (7.703 to 19.723)
    No statistical analyses for this end point

    Secondary: Part A: PK - Tmax after last dose

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    End point title
    		 Part A: PK - Tmax after last dose [22]
    End point description
    Time to maximum plasma concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: hour
        median (full range (min-max))
    1.7500 (1.000 to 2.000)
    1.5000 (1.000 to 4.000)
    2.5000 (2.000 to 4.000)
    No statistical analyses for this end point

    Secondary: Part A: PK - Cmax, ss, after last dose

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    End point title
    		 Part A: PK - Cmax, ss, after last dose [23]
    End point description
    Maximum plasma concentration at steady-state Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: ng/mL
        median (full range (min-max))
    848.50 (705.0 to 1190.0)
    870.50 (595.0 to 1350.0)
    1365.00 (1300.0 to 1850.0)
    No statistical analyses for this end point

    Secondary: Part A: PK - Cmin, ss, after last dose

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    End point title
    		 Part A: PK - Cmin, ss, after last dose [24]
    End point description
    Minimum plasma concentration at steady-state Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: ng/mL
        median (full range (min-max))
    64.25 (16.9 to 86.7)
    204.00 (147.0 to 409.0)
    455.00 (312.0 to 825.0)
    No statistical analyses for this end point

    Secondary: Part A: PK - Vz/F after last dose

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    End point title
    		 Part A: PK - Vz/F after last dose [25]
    End point description
    Volume of distribution for dose interval Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: litre(s)
        median (full range (min-max))
    145.5 (72 to 176)
    148.3 (123 to 234)
    322.9 (215 to 591)
    No statistical analyses for this end point

    Secondary: Part A: PK - % fluctuation after last dose

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    End point title
    		 Part A: PK - % fluctuation after last dose [26]
    End point description
    Peak trough fluctuation within one dosing interval at steady state Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: percent (%)
        median (full range (min-max))
    402.43 (285.4 to 471.9)
    165.28 (113.3 to 207.4)
    120.00 (48.7 to 204.0)
    No statistical analyses for this end point

    Secondary: Part A: PK - AUC over dosing interval after last dose, and dose proportionality

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    End point title
    		 Part A: PK - AUC over dosing interval after last dose, and dose proportionality [27]
    End point description
    Area under the plasma concentration time curve over dosing interval Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Group A1 (50 mg QD): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post last dose. Groups A2 and A3 (50 mg BID and 100 mg BID): Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose. Dose proportionality given in attached Table 12.1.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: h*ng/mL
        median (full range (min-max))
    5400.6 (3627 to 5929)
    4548.2 (4062 to 8207)
    9337.2 (8629 to 12927)
    Attachments
    		 Table 12.1 Dose proportionalty
    No statistical analyses for this end point

    Secondary: Part A: PK - Ae after last dose

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    End point title
    		 Part A: PK - Ae after last dose [28]
    End point description
    Urine recovery of GR3027
    End point type
    Secondary
    End point timeframe
    Predose to 24h post last dose.
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter Urine recovery (Ae) was only measured in Part A of the trial.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    3 [29]
    6
    6
    Units: µg
        median (full range (min-max))
    19.00 (0.0 to 30.6)
    0.00 (0.0 to 29.8)
    45.00 (24.6 to 63.5)
    Notes
    [29] - For the last dose in group 50 mg QD, complete assessment of Ae was performed for 3 subjects.
    No statistical analyses for this end point

    Secondary: Part A: PK - Fe after last dose

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    End point title
    		 Part A: PK - Fe after last dose [30]
    End point description
    Fraction of the dose excreted in urine for GR3027
    End point type
    Secondary
    End point timeframe
    Predose to 24 h post last dose.
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter Fraction of dose extracted in urine (Fe) was only measured in Part A of the trial.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    3 [31]
    6
    6
    Units: percent (%)
        median (full range (min-max))
    0.0380 (0.000 to 0.061)
    0.0000 (0.000 to 0.060)
    0.0450 (0.025 to 0.063)
    Notes
    [31] - For the last dose in group 50 mg QD, complete assessment of Fe was performed for 3 subjects.
    No statistical analyses for this end point

    Secondary: Part A: PK - Accumulation ratio, Cmax, after last dose

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    End point title
    		 Part A: PK - Accumulation ratio, Cmax, after last dose [32]
    End point description
    Accumulation ratio for Cmax between first and last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: no unit
        median (full range (min-max))
    1.14 (1.00 to 1.32)
    0.93 (0.79 to 1.57)
    1.03 (0.78 to 2.27)
    No statistical analyses for this end point

    Secondary: Part A: PK - Accumulation ratio, AUC, after last dose

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    End point title
    		 Part A: PK - Accumulation ratio, AUC, after last dose [33]
    End point description
    Accumulation ratio for AUC between first and last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients.
    End point values
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: no unit
        median (full range (min-max))
    1.23 (1.10 to 1.42)
    1.34 (1.28 to 1.98)
    1.54 (1.32 to 2.41)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - Lambdaz after first dose

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    End point title
    		 Parts B and C: PK - Lambdaz after first dose [34]
    End point description
    Plasma terminal elimination rate constant Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose. Due to a short PK sampling interval on Day 1 (0-12h), calculated values for Lambdaz are uncertain for Day 1 in Part C.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: /h
        median (full range (min-max))
    0.0522 (0.021 to 0.058)
    0.0778 (0.061 to 0.169)
    0.0791 (0.062 to 0.129)
    0.0827 (0.062 to 0.099)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - T1/2 after first dose

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    End point title
    		 Parts B and C: PK - T1/2 after first dose [35]
    End point description
    Plasma terminal half-life Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose. Due to a short PK sampling interval on Day 1 (0-12h), calculated values for T1/2 are uncertain for Day 1 in Part C.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: hour
        median (full range (min-max))
    13.2789 (11.936 to 32.925)
    8.9314 (4.106 to 11.398)
    8.7809 (5.374 to 11.227)
    8.3816 (6.975 to 11.123)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - Tmax after first dose

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    End point title
    		 Parts B and C: PK - Tmax after first dose [36]
    End point description
    Time to maximum plasma concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: hour
        median (full range (min-max))
    0.8500 (0.667 to 1.017)
    1.000 (0.33 to 3.00)
    1.000 (0.67 to 2.00)
    1.515 (1.00 to 2.85)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - Cmax after first dose

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    End point title
    		 Parts B and C: PK - Cmax after first dose [37]
    End point description
    Maximum plasma concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: ng/mL
        median (full range (min-max))
    107.50 (80.1 to 116.0)
    109.25 (53.9 to 262.0)
    467.50 (289.0 to 833.0)
    861.00 (462.0 to 1260.0)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - AUC(0-t) after first dose

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    End point title
    		 Parts B and C: PK - AUC(0-t) after first dose [38]
    End point description
    Area under the plasma concentration time curve Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10 mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: h*ng/mL
        median (full range (min-max))
    740.6 (628 to 1319)
    394.09 (292.9 to 616.5)
    1944.75 (1247.0 to 3008.0)
    3792.25 (2762.5 to 6012.2)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - AUCinf after first dose

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    End point title
    		 Parts B and C: PK - AUCinf after first dose [39]
    End point description
    Area under the plasma concentration time curve, predicted to infinity Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose. Due to a short PK sampling interval on Day 1 (0-12h), calculated values for AUCinf are uncertain for Day 1 in Part C.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: h*ng/mL
        median (full range (min-max))
    1114.8 (830 to 1951)
    600.23 (362.6 to 964.2)
    2954.32 (1754.8 to 4988.8)
    5822.83 (4952.5 to 9756.5)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - Vz/F after first dose

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    End point title
    		 Parts B and C: PK - Vz/F after first dose [40]
    End point description
    Volume of distribution Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose. Due to a short PK sampling interval on Day 1 (0-12h), calculated values for Vz/F are uncertain for Day 1 in Part C.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: litre(s)
        median (full range (min-max))
    214.0 (157 to 243)
    181.25 (137.2 to 296.2)
    183.86 (99.0 to 304.4)
    154.25 (101.2 to 237.3)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - CL/F after first dose

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    End point title
    		 Parts B and C: PK - CL/F after first dose [41]
    End point description
    Total apparent clearance of drug from plasma/serum Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points. Part B: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, and 48 hours post first dose. Part C: Predose , 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post first dose. Due to a short PK sampling interval on Day 1 (0-12h), calculated values forCL/F are uncertain for Day 1 in Part C.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    6
    Units: L/h
        median (full range (min-max))
    9.0 (5 to 12)
    16.77 (10.3 to 27.4)
    13.44 (8.2 to 22.8)
    13.80 (8.2 to 16.1)
    No statistical analyses for this end point

    Secondary: Parts B and C: PK - Fraction unbound after first dose

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    End point title
    		 Parts B and C: PK - Fraction unbound after first dose [42]
    End point description
    The fraction of drug in serum that is not bound to a carrier protein or other molecule.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h for dose group B, 10 mg. Predose to 12 h for dose groups C1, 10mg BID; C2, 40 mg BID; and C3, 80 mg BID.
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The parameter fraction unbound was only measured in Trial parts B and C, why no values are available for parts A or D.
    End point values
    		 Part B, 10 mg SD Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    4 [43]
    6
    6
    Units: percent (%)
        median (full range (min-max))
    0.966 (0.72 to 1.08)
    0.76340 (0.6873 to 0.9713)
    0.69550 (0.5613 to 1.6230)
    0.91955 (0.6455 to 1.9155)
    Notes
    [43] - For 2 subjects in the 10 mg BID group, data on unbound drug conc were missing at all timepoints.
    No statistical analyses for this end point

    Secondary: Part C: PK - Lambdaz after last dose

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    End point title
    		 Part C: PK - Lambdaz after last dose [44]
    End point description
    Plasma terminal elimination rate constant Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: /h
        median (full range (min-max))
    0.0465 (0.038 to 0.108)
    0.0515 (0.026 to 0.087)
    0.0481 (0.019 to 0.066)
    No statistical analyses for this end point

    Secondary: Part C: PK - T1/2 after last dose

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    End point title
    		 Part C: PK - T1/2 after last dose [45]
    End point description
    Plasma terminal half-life Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: hour
        median (full range (min-max))
    14.9476 (6.440 to 18.475)
    13.4681 (7.970 to 26.626)
    14.5413 (10.553 to 37.362)
    No statistical analyses for this end point

    Secondary: Part C: PK - Tmax after last dose

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    End point title
    		 Part C: PK - Tmax after last dose [46]
    End point description
    Time to maximum plasma concentration Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: hour
        median (full range (min-max))
    2.50 (1.0 to 4.0)
    1.50 (1.0 to 4.0)
    1.00 (1.0 to 3.0)
    No statistical analyses for this end point

    Secondary: Part C: PK - Cmax after last dose, and dose proportionality

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    End point title
    		 Part C: PK - Cmax after last dose, and dose proportionality [47]
    End point description
    Maximum plasma concentration at steady-state Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose. Dose proportionality given in attached Table 14.61.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: ng/mL
        median (full range (min-max))
    101.80 (64.5 to 158.0)
    473.5 (197.0 to 699.0)
    1470.0 (610.0 to 1820.0)
    Attachments
    		 Dose proportionalty Cmax
    No statistical analyses for this end point

    Secondary: Part C: PK - AUCinf after last dose

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    End point title
    		 Part C: PK - AUCinf after last dose [48]
    End point description
    Area under the plasma concentration time curve, predicted to infinity Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: h*ng/mL
        median (full range (min-max))
    1897.90 (618.5 to 4096.3)
    8340.95 (3818.8 to 16127.8)
    20501.200 (9787.0 to 59817.9)
    No statistical analyses for this end point

    Secondary: Part C: PK - AUC(% Extrapolation) after last dose

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    End point title
    		 Part C: PK - AUC(% Extrapolation) after last dose [49]
    End point description
    Area under the plasma concentration time curve, % extrapolation Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: percent (%)
        median (full range (min-max))
    24.694 (8.41 to 32.92)
    7.619 (1.65 to 28.18)
    9.328 (4.20 to 42.03)
    No statistical analyses for this end point

    Secondary: Part C: PK - Cmin after last dose

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    End point title
    		 Part C: PK - Cmin after last dose [50]
    End point description
    Minimum plasma concentration at steady-state Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: ng/mL
        median (full range (min-max))
    42.35 (14.2 to 83.2)
    203.50 (89.3 to 278.0)
    449.50 (239.0 to 824.0)
    No statistical analyses for this end point

    Secondary: Part C: PK - % fluctuation after last dose

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    End point title
    		 Part C: PK - % fluctuation after last dose [51]
    End point description
    Peak trough fluctuation within one dosing interval at steady state. Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: percent (%)
        median (full range (min-max))
    101.6 (28.7 to 165.1)
    91.85 (57.4 to 158.0)
    107.31 (27.6 to 206.8)
    No statistical analyses for this end point

    Secondary: Part C: PK - Vz/F after last dose

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    End point title
    		 Part C: PK - Vz/F after last dose [52]
    End point description
    Volume of distribution for dose interval Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: litre(s)
        median (full range (min-max))
    255.21 (191.6 to 403.0)
    273.66 (101.9 to 408.1)
    243.85 (100.0 to 407.4)
    No statistical analyses for this end point

    Secondary: Part C: PK - AUC over dosing interval after last dose and dose proportionality

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    End point title
    		 Part C: PK - AUC over dosing interval after last dose and dose proportionality [53]
    End point description
    Area under the plasma concentration time curve over the dosing interval Venous blood samples for the determination of GR3027 in plasma were collected at pre-specified time-points: Predose Day 5 (last dose), 20, 40, 60, 90, 120, 180 min, 4, 6, 9, 12, 18, 24, 36, and 48 hours post last dose. Dose proportionality given in attached Table 14.60.
    End point type
    Secondary
    End point timeframe
    Predose Day 5 (last dose) to 48 h post last dose.
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: h*ng/mL
        median (full range (min-max))
    763.35 (428.6 to 1162.3)
    3843.09 (1864.1 to 4514.8)
    8922.97 (4934.3 to 13227.6)
    Attachments
    		 Dose proportionalty AUC
    No statistical analyses for this end point

    Secondary: Part C: PK - Accumulation ratio, Cmax, after last dose

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    End point title
    		 Part C: PK - Accumulation ratio, Cmax, after last dose [54]
    End point description
    Accumulation ratio for Cmax between first and last dose
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: no unit
        median (full range (min-max))
    0.85 (0.42 to 2.00)
    1.15 (0.55 to 1.40)
    1.96 (0.48 to 2.32)
    No statistical analyses for this end point

    Secondary: Part C: PK - Accumulation ratio, AUC, after last dose

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    End point title
    		 Part C: PK - Accumulation ratio, AUC, after last dose [55]
    End point description
    Accumulation ratio for AUC between first and last dose.
    End point type
    Secondary
    End point timeframe
    Predose to 48 h post last dose.
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetics for Part A (healthy volunteers) are reported in separate endpoints as the results are not comparable to PK results in cirrhotic patients. Only 1 dose was given in Part B No pharmacokinetic parameters but exposure were calculated for Part D.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day)
    Number of subjects analysed
    6
    6
    6
    Units: no unit
        median (full range (min-max))
    1.84 (1.46 to 2.29)
    1.68 (1.41 to 2.51)
    2.06 (1.37 to 3.87)
    No statistical analyses for this end point

    Secondary: Part D: PK - Exposure

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    End point title
    		 Part D: PK - Exposure [56]
    End point description
    Exposure as plasma concentration at Day 1 (predose), Day 10 (predose), Day 21 (predose). A 12 h post last dose sample on Day 21 in dose groups D2 and D3 should be collected if accepted by the subject, but only 1 subject agreed and data are not shown for this time point.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to 12 h post last dose (Day 21).
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter Exposure was only calculated for Part D of the trial.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day)
    Number of subjects analysed
    10 [57]
    10
    12 [58]
    Units: ng/mL
    median (full range (min-max))
        Day 1, predose
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
        Day 10, predose
    69.10 (15.3 to 120.0)
    186.50 (54.9 to 448.0)
    416.50 (182.0 to 716.0)
        Day 21, predose
    42.75 (0.0 to 94.4)
    146.50 (42.0 to 189.0)
    465.00 (0.0 to 582.0)
    Notes
    [57] - On Day 10, samples were collected from only 9 subjects,
    [58] - On Day 10, samples were collected from only 11 subjects,
    No statistical analyses for this end point

    Secondary: Part C, Change in EEG parameters (MDF) from baseline

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    End point title
    		 Part C, Change in EEG parameters (MDF) from baseline [59]
    End point description
    Change from baseline in EEG parameters: Mean Dominant Frequency, MDF-US (average of T3-O1 and T4-O2) (PPASC). The data are presented by “Dose group” (Per dose group overall, all timepoints), by timepoint (each specific time-point from all 5 days combined), by day (all time-points a specific day combined, “Post-dose” is combined Day 1 data), and by Days 2-5 combined (= After Day 1). Change from pre-dose at consecutive days has been evaluated (using MMRM). Using the least square mean estimate, no statistically significant difference from placebo was achieved.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 5, 8 hours post dose
    Notes
    [59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Part A of the trial (healthy volunteers), no efficacy endpoints were evaluated. In Part B of the trial (single dose), only exploratory measurements of EEG were performed. No comparison with placebo was possible due to lack of evaluable data. No results are therefore presented. In Part D of the trial (extended treatment), different measurement timepoints were used and EEG data for Part D are described in separate endpoints.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo
    Number of subjects analysed
    5
    5
    5
    5
    Units: Hz
    least squares mean (confidence interval 95%)
        Dose group
    -0.2694 (-1.2323 to 0.6935)
    -0.3911 (-1.3474 to 0.5652)
    -0.1494 (-1.0905 to 0.7917)
    -0.6181 (-1.65167 to 0.4154)
        Post-dose
    -0.3073 (-1.2746 to 0.6600)
    -0.3640 (-1.3242 to 0.5963)
    -0.2184 (-1.1632 to 0.7265)
    -0.5733 (-1.6110 to 0.4644)
        90 min
    -0.0730 (-1.0857 to 0.9398)
    -0.3878 (-1.3917 to 0.6161)
    -0.0819 (-1.0716 to 0.9079)
    -0.6135 (-1.6934 to 0.4664)
        180 min
    -0.2018 (-1.2115 to 0.8080)
    -0.3953 (-1.3992 to 0.6086)
    -0.0400 (-1.0266 to 0.9465)
    -0.6350 (-1.7205 to 0.4505)
        6-8 hours
    -0.6471 (-1.6606 to 0.3663)
    -0.3088 (-1.3096 to 0.6921)
    -0.5332 (-1.5198 to 0.4533)
    -0.4713 (-1.5619 to 0.6193)
        After Day 1
    -0.1568 (-1.1264 to 0.8128)
    -0.4151 (-1.3776 to 0.5474)
    -0.2348 (-1.1821 to 0.7124)
    -0.7065 (-1.7474 to 0.3344)
        Day 2
    -0.1240 (-1.2034 to 0.9554)
    -0.2406 (-1.3149 to 0.8337)
    -0.2481 (-1.3142 to 0.8180)
    -0.0484 (-1.2105 to 1.1136)
        Day 3
    -0.4484 (-1.5451 to 0.6483)
    -0.5256 (-1.5999 to 0.5487)
    -0.0042 (-1.0654 to 1.0569)
    -0.4301 (-1.5845 to 0.7243)
        Day 4
    0.0997 (-0.9847 to 1.1840)
    -0.4396 (-1.5139 to 0.6347)
    -0.3060 (-1.3722 to 0.7601)
    -1.0671 (-2.2363 to 0.1022)
        Day 5
    -0.1544 (-1.2466 to 0.9379)
    -0.4547 (-1.5457 to 0.6364)
    -0.3810 (-1.4422 to 0.6802)
    -1.2803 (-2.4386 to -0.1220)
    No statistical analyses for this end point

    Secondary: Part C, Change in EEG parameters (relative power of theta frequencies) from baseline

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    End point title
    		 Part C, Change in EEG parameters (relative power of theta frequencies) from baseline [60]
    End point description
    Change from baseline in EEG parameters: Relative power of theta frequencies (average of T3-O1 and T4-O2) (PPASC). The data are presented by “Dose group” (Per dose group overall, all timepoints), by timepoint (each specific time-point from all 5 days combined), by day (all time-points a specific day combined, “Post-dose” is combined Day 1 data), and by Days 2-5 combined (= After Day 1). Change from pre-dose at consecutive days has been evaluated (using MMRM). Using the least square mean estimate, no statistically significant difference from placebo was achieved.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 5, 8 hours post dose
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Part A of the trial (healthy volunteers), no efficacy endpoints were evaluated. In Part B of the trial (single dose), only exploratory measurements of EEG were performed. No comparison with placebo was possible due to lack of evaluable data. No results are therefore presented. In Part D of the trial (extended treatment), different measurement timepoints were used and EEG data for Part D are described in separate endpoints.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo
    Number of subjects analysed
    5
    5
    5
    5
    Units: percent (%)
    least squares mean (confidence interval 95%)
        Dose group
    1.1082 (-3.8616 to 6.0781)
    -1.9506 (-6.9313 to 3.0300)
    3.4475 (-1.0908 to 7.9858)
    -0.1210 (-5.1054 to 4.8634)
        Post-dose
    0.8595 (-4.1240 to 5.8430)
    -1.9939 (-6.9863 to 2.9986)
    3.5691 (-0.9795 to 8.1176)
    -0.1968 (-5.1957 to 4.8021)
        90 min
    1.3056 (-3.8162 to 6.4273)
    -1.9689 (-7.0928 to 3.1550)
    4.2620 (-0.4066 to 8.9306)
    0.1682 (-4.9727 to 5.3092)
        180 min
    1.1782 (-3.9338 to 6.2902)
    -1.4291 (-6.5530 to 3.6948)
    2.5538 (-2.1077 to 7.2153)
    0.4910 (-4.6597 to 5.6417)
        6-8 hours
    0.0947 (-5.0275 to 5.2169)
    -2.5836 (-7.6980 to 2.5307)
    3.8914 (-0.7700 to 8.5529)
    -1.2496 (-6.4166 to 3.9175)
        After Day 1
    1.5961 (-3.3911 to 6.5833)
    -1.8770 (-6.8735 to 3.1195)
    3.5229 (-1.0293 to 8.0751)
    0.1009 (-4.9024 to 5.1042)
        Day 2
    2.3078 (-2.9626 to 7.5782)
    -2.1113 (-7.3934 to 3.1708)
    3.6616 (-1.1645 to 8.4876)
    -1.8738 (-7.2201 to 3.4724)
        Day 3
    1.3031 (-4.0198 to 6.6261)
    -1.7383 (-7.0204 to 3.5438)
    3.9723 (-0.8426 to 8.7872)
    0.0403 (-5.2816 to 5.3622)
        Day 4
    1.8476 (-3.4377 to 7.1328)
    -2.1406 (-7.4227 to 3.1415)
    2.7183 (-2.1077 to 7.5444)
    1.3873 (-3.9797 to 6.7542)
        Day 5
    0.9259 (-4.3809 to 6.2327)
    -1.5177 (-6.8516 to 3.8162)
    3.7396 (-1.0753 to 8.5544)
    0.8499 (-4.4812 to 6.1810)
    No statistical analyses for this end point

    Secondary: Part C, Change in EEG parameters (DTABR) from baseline

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    End point title
    		 Part C, Change in EEG parameters (DTABR) from baseline [61]
    End point description
    Change from baseline in EEG parameters: Ratio relative powers of delta and theta to the relative powers of alpha and beta, DTABR (average of T3-O1 and T4-O2, Part C (PPASC). The data are presented by “Dose group” (Per dose group overall, all timepoints), by timepoint (each specific time-point from all 5 days combined), by day (all time-points a specific day combined, “Post-dose” is combined Day 1 data), and by Days 2-5 combined (= After Day 1). Change from pre-dose at consecutive days has been evaluated (using MMRM). Using the least square mean estimate, no statistically significant difference from placebo was achieved.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 5, 8 hours post dose
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Part A of the trial (healthy volunteers), no efficacy endpoints were evaluated. In Part B of the trial (single dose), only exploratory measurements of EEG were performed. No comparison with placebo was possible due to lack of evaluable data. No results are therefore presented. In Part D of the trial (extended treatment), different measurement timepoints were used and EEG data for Part D are described in separate endpoints.
    End point values
    		 Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo
    Number of subjects analysed
    5
    5
    5
    5
    Units: no unit
    least squares mean (confidence interval 95%)
        Dose group
    -0.0257 (-0.4877 to 0.4363)
    -0.1113 (-0.5758 to 0.3533)
    0.0291 (-0.4315 to 0.4898)
    0.0987 (-0.3719 to 0.5692)
        Post-dose
    -0.0014 (-0.4656 to 0.4627)
    -0.0875 (-0.5540 to 0.3790)
    0.0626 (-0.3998 to 0.5250)
    0.0911 (-0.3819 to 0.5640)
        90 min
    -0.0486 (-0.5353 to 0.4382)
    -0.1595 (-0.6474 to 0.3283)
    -0.0156 (-0.4997 to 0.4686)
    0.1671 (-0.3286 to 0.6628)
        180 min
    -0.0900 (-0.5751 to 0.3952)
    -0.0741 (-0.5620 to 0.4138)
    -0.0495 (-0.5321 to 0.4331)
    0.0804 (-0.4170 to 0.5779)
        6-8 hours
    0.1342 (-0.3527 to 0.6211)
    -0.0290 (-0.5153 to 0.4573)
    0.2529 (-0.2297 to 0.7355)
    0.0256 (-0.4746 to 0.5257)
        After Day 1
    -0.0429 (-0.5080 to 0.4223)
    -0.0962 (-0.5637 to 0.3713)
    0.0567 (-0.4068 to 0.5201)
    0.1071 (-0.3670 to 0.5811)
        Day 2
    0.0350 (-0.4824 to 0.5524)
    0.0659 (-0.4541 to 0.5859)
    0.1652 (-0.3538 to 0.6843)
    -0.0696 (-0.6047 to 0.4654)
        Day 3
    0.1050 (-0.4211 to 0.6310)
    -0.1471 (-0.6671 to 0.3729)
    -0.0895 (-0.6061 to 0.4271)
    0.0110 (-0.5201 to 0.5421)
        Day 4
    -0.1748 (-0.6946 to 0.3451)
    -0.1021 (-0.6221 to 0.4179)
    0.0279 (-0.4910 to 0.5469)
    0.1463 (-0.3927 to 0.6853)
        Day 5
    -0.1366 (-0.6601 to 0.3869)
    -0.2013 (-0.7295 to 0.3269)
    0.1230 (-0.3936 to 0.6396)
    0.3406 (-0.1922 to 0.8733)
    No statistical analyses for this end point

    Secondary: Part D, Change in EEG parameters (MDF) from Day 1

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    End point title
    		 Part D, Change in EEG parameters (MDF) from Day 1 [62]
    End point description
    Change from Day 1 to Day 21 in the EEG parameter Mean Dominant Frequency, MDF-US (average of T3-O1 and T4-O2) The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Part A of the trial (healthy volunteers), no efficacy endpoints were evaluated. In Part B of the trial (single dose), only exploratory measurements of EEG were performed. No comparison with placebo was possible due to lack of evaluable data. No results are therefore presented. In Part C of the trial (5 Days treatment), different measurement timepoints were used and EEG data for Part C are described in separate endpoints.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    4
    9
    9
    7
    22
    Units: Hz
        least squares mean (confidence interval 95%)
    0.7544 (-0.6957 to 2.2045)
    0.2244 (-0.7313 to 1.1801)
    0.3366 (-0.6832 to 1.3564)
    -0.5716 (-1.7486 to 0.6054)
    0.4385 (-0.2340 to 1.1109)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, D1 10 mg BID (20 mg per day) v Part D, Total (D1+D2+D3)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1417 [63]
    Method
    		 Mixed models analysis
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [63] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.1614 D2 40 mg BID vs placebo: P-value = 0.2953 D3 80 mg BID vs placebo: P-value = 0.2474

    Secondary: Part D, Change in EEG parameters (relative power of theta frequencies) from Day 1

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    End point title
    		 Part D, Change in EEG parameters (relative power of theta frequencies) from Day 1 [64]
    End point description
    Change from Day 1 to Day 21 in the EEG parameter Relative power of theta frequencies (average of T3-O1 and T4-O2). The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Part A of the trial (healthy volunteers), no efficacy endpoints were evaluated. In Part B of the trial (single dose), only exploratory measurements of EEG were performed. No comparison with placebo was possible due to lack of evaluable data. No results are therefore presented. In Part C of the trial (5 Days treatment), different measurement timepoints were used and EEG data for Part C are described in separate endpoints.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    4
    9
    9
    7
    22
    Units: percent (%)
        least squares mean (confidence interval 95%)
    -2.7864 (-12.3875 to 6.8147)
    2.4518 (-3.7654 to 8.6690)
    2.3061 (-4.0957 to 8.7079)
    12.3025 (5.0502 to 19.5548)
    0.6572 (-3.6615 to 4.9758)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D1 10 mg BID (20 mg per day) v Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, Total (D1+D2+D3)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0086 [65]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [65] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.0161 D2 40 mg BID vs placebo: P-value = 0.0436 D3 80 mg BID vs placebo: P-value = 0.0429

    Secondary: Part D, Change in EEG parameters (DTABR) from Day 1

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    End point title
    		 Part D, Change in EEG parameters (DTABR) from Day 1 [66]
    End point description
    Change from Day 1 to Day 21 in the EEG parameter Ratio relative powers of delta and theta to the relative powers of alpha and beta, DTABR (average of T3-O1 and T4-O2. The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Part A of the trial (healthy volunteers), no efficacy endpoints were evaluated. In Part B of the trial (single dose), only exploratory measurements of EEG were performed. No comparison with placebo was possible due to lack of evaluable data. No results are therefore presented. In Part C of the trial (5 Days treatment), different measurement timepoints were used and EEG data for Part C are described in separate endpoints.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    4
    9
    9
    7
    22
    Units: no unit
        least squares mean (confidence interval 95%)
    -0.3527 (-0.8891 to 0.1836)
    -0.0443 (-0.4043 to 0.3157)
    -0.2313 (-0.6133 to 0.1507)
    0.3904 (-0.0489 to 0.8296)
    -0.2094 (-0.4586 to 0.0398)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D1 10 mg BID (20 mg per day) v Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, Total (D1+D2+D3)
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0209 [67]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [67] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.0360 D2 40 mg BID vs placebo: P-value = 0.1318 D3 80 mg BID vs placebo: P-value = 0.0360

    Secondary: Part D, Change in CRT index from Day 1

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    End point title
    		 Part D, Change in CRT index from Day 1 [68]
    End point description
    Change in cognitive function from Day 1 to Day 21, compared to placebo, as measured by the Continuous Reaction Time (CRT) test (PPASD). The CRT method is a computerised registration of a series of motor reaction times to an auditory stimulus. The CRT test outputs a single number, the CRT-index which is calculated on the basis of the percentiles of the reaction times (50 percentile / (90-10) percentile). This index is a measure of the reaction time and attention stability and can be used to assess deficits in attention and cognition. A value of the CRT Index of <1.9 discriminates between organic brain damage and HE with a sensitivity and specificity well above 90% and is used as a normal value threshold by the software. The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A (healthy volunteers) and B (single dose) of the trial, CRT was not evaluated. In Part C of the trial (5 Days treatment), only Day 1 data were collected and no change was evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    8
    9
    11
    12
    28
    Units: index
        least squares mean (confidence interval 95%)
    0.2925 (-0.1222 to 0.7072)
    0.3588 (-0.0363 to 0.7540)
    0.3425 (-0.0111 to 0.6962)
    0.3957 (0.0543 to 0.7372)
    0.3313 (0.1070 to 0.5556)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, Total (D1+D2+D3) v Part D, D1 10 mg BID (20 mg per day)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7543 [69]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [69] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.7011 D2 40 mg BID vs placebo: P-value = 0.8890 D3 80 mg BID vs placebo: P-value = 0.8295

    Secondary: Part D, Change in PHES from Day 1

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    End point title
    		 Part D, Change in PHES from Day 1 [70]
    End point description
    Change in cognitive function from Day 1 to Day 21, compared to placebo, as measured by Portosystemic Hepatic Encephalopathy Score (PHES), (PPASD). The PHES is a paper-pencil test, which assesses motor speed, motor accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction and memory, which are related to most of neuropsychological impairments in Covert hepatic encephalopathy (CHE). The sub-tests are scored according to a scoring manual. The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A (healthy volunteers) and B (single dose) of the trial, PHES was not evaluated. In Part C of the trial (5 Days treatment), only Day 1 data were collected and no change was evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    8
    9
    11
    12
    28
    Units: score
        least squares mean (confidence interval 95%)
    3.6 (2.0 to 5.1)
    1.1 (-0.4 to 2.6)
    2.0 (0.7 to 3.3)
    1.9 (0.7 to 3.2)
    2.2 (1.4 to 3.0)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, Total (D1+D2+D3) v Part D, D1 10 mg BID (20 mg per day)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7019 [71]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [71] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.1050 D2 40 mg BID vs placebo: P-value = 0.3979 D3 80 mg BID vs placebo: P-value = 0.9516

    Secondary: Part D, Change in ANT1 from Day 1

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    End point title
    		 Part D, Change in ANT1 from Day 1 [72]
    End point description
    Change in cognitive function from Day 1 to Day 21, compared to placebo, as measured by the Animal Naming Test (ANT1), (PPASD). The ANT1 is a semantic fluency test that can appraise the cognitive functions impaired in the early stages of HE, mainly executive functions. Study subjects were asked to list as many animals as they could during 1 minute. All repetitions and errors (non-animal words) were excluded from the calculations. The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, ANT1 was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    8
    9
    11
    12
    28
    Units: score
        least squares mean (confidence interval 95%)
    4.2 (1.2 to 7.2)
    2.2 (-0.5 to 4.9)
    2.2 (-0.2 to 4.6)
    1.9 (-0.5 to 4.4)
    2.9 (1.3 to 4.5)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D1 10 mg BID (20 mg per day) v Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, Total (D1+D2+D3)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5396 [73]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [73] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.2616 D2 40 mg BID vs placebo: P-value = 0.8977 D3 80 mg BID vs placebo: P-value = 0.8788

    Secondary: Part D, Change in ESS from Day 1

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    End point title
    		 Part D, Change in ESS from Day 1 [74]
    End point description
    Change in daytime sleepiness from Day 1 to Day 21, compared to placebo, as measured by the Epworth Sleepiness Scale (ESS), (PPASD). The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in 8 different activities. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person’s average sleep propensity in daily life, or their ‘daytime sleepiness’. The change from Day 1 to Day 21 is presented by Dose group and in Total (all dose groups D1-D3 combined).
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, EES was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo Part D, Total (D1+D2+D3)
    Number of subjects analysed
    8
    9
    11
    12
    28
    Units: score
        least squares mean (confidence interval 95%)
    -0.7 (-2.4 to 0.9)
    -3.0 (-4.6 to -1.3)
    -1.4 (-2.8 to 0.0)
    -0.0 (-1.4 to 1.3)
    -1.7 (-2.6 to -0.8)
    Statistical analysis title
    		 MMRM
    Statistical analysis description
    A Mixed Model Repeated Measures (MMRM) analysis was used to estimate the statistics presented.
    Comparison groups
    Part D, D1 10 mg BID (20 mg per day) v Part D, D2 40 mg BID (80 mg per day) v Part D, D3 80 mg BID (160 mg per day) v Part D, Placebo v Part D, Total (D1+D2+D3)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0448 [75]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [75] - = Group Total (D1+D2+D3) vs placebo D1 10 mg BID vs placebo: P-value = 0.5263 D2 40 mg BID vs placebo: P-value = 0.0075 D3 80 mg BID vs placebo: P-value = 0.1703

    Secondary: Part D, Change in caregiver QoL (time dependency) from Day 1

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    End point title
    		 Part D, Change in caregiver QoL (time dependency) from Day 1 [76]
    End point description
    Change in caregiver quality of life (QoL) from Day 1 to Day 21, as measured by the CGBI questionnaire (PPASD). The CGBI is a standardised questionnaire consisting of 24 questions grouped into 5 dimensions (time dependency, development, physical health, emotional health, social relationships). There are 5 items in each dimension, except for physical burden which has 4 items. A higher score indicates a greater caregiver burden. The change in time dependency from Day 1 to Day 21 is presented by Dose group. No general trend of dose dependent better improvement in the GR3027 dose groups as compared to placebo was seen for time dependency.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, caregiver QoL was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Number of subjects analysed
    8
    9
    11
    12
    Units: score
        arithmetic mean (standard deviation)
    -0.1 ( 0.4 )
    0.0 ( 0.5 )
    -0.5 ( 1.2 )
    -0.5 ( 1.0 )
    No statistical analyses for this end point

    Secondary: Part D, Change in caregiver QoL (development) from Day 1

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    End point title
    		 Part D, Change in caregiver QoL (development) from Day 1 [77]
    End point description
    Change in caregiver quality of life (QoL) from Day 1 to Day 21, as measured by the CGBI questionnaire (PPASD). The CGBI is a standardised questionnaire consisting of 24 questions grouped into 5 dimensions (time dependency, development, physical health, emotional health, social relationships). There are 5 items in each dimension, except for physical burden which has 4 items. A higher score indicates a greater caregiver burden. The change in development from Day 1 to Day 21 is presented by Dose group. No general trend of dose dependent better improvement in the GR3027 dose groups as compared to placebo was seen for development .
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, caregiver QoL was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Number of subjects analysed
    8
    9
    11
    12
    Units: score
        arithmetic mean (standard deviation)
    -0.4 ( 1.1 )
    0.0 ( 0.0 )
    0.0 ( 0.4 )
    0.1 ( 1.3 )
    No statistical analyses for this end point

    Secondary: Part D, Change in caregiver QoL (physical health) from Day 1

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    End point title
    		 Part D, Change in caregiver QoL (physical health) from Day 1 [78]
    End point description
    Change in caregiver quality of life (QoL) from Day 1 to Day 21, as measured by the CGBI questionnaire (PPASD). The CGBI is a standardised questionnaire consisting of 24 questions grouped into 5 dimensions (time dependency, development, physical health, emotional health, social relationships). There are 5 items in each dimension, except for physical burden which has 4 items. A higher score indicates a greater caregiver burden. The change in time physical health from Day 1 to Day 21 is presented by Dose group. No general trend of dose dependent better improvement in the GR3027 dose groups as compared to placebo was seen for physical health.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [78] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, caregiver QoL was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Number of subjects analysed
    8
    9
    11
    12
    Units: score
        arithmetic mean (standard deviation)
    -0.6 ( 1.4 )
    0.2 ( 0.7 )
    -0.1 ( 0.7 )
    -0.3 ( 0.7 )
    No statistical analyses for this end point

    Secondary: Part D, Change in caregiver QoL (emotional health) from Day 1

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    End point title
    		 Part D, Change in caregiver QoL (emotional health) from Day 1 [79]
    End point description
    Change in caregiver quality of life (QoL) from Day 1 to Day 21, as measured by the CGBI questionnaire (PPASD). The CGBI is a standardised questionnaire consisting of 24 questions grouped into 5 dimensions (time dependency, development, physical health, emotional health, social relationships). There are 5 items in each dimension, except for physical burden which has 4 items. A higher score indicates a greater caregiver burden. The change in emotional health from Day 1 to Day 21 is presented by Dose group. No general trend of dose dependent better improvement in the GR3027 dose groups as compared to placebo was seen for emotional health.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [79] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, caregiver QoL was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Number of subjects analysed
    8
    9
    11
    12
    Units: score
        arithmetic mean (standard deviation)
    -0.3 ( 0.5 )
    0.4 ( 1.7 )
    -0.2 ( 0.4 )
    0.0 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Part D, Change in caregiver QoL (social relationships) from Day 1

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    End point title
    		 Part D, Change in caregiver QoL (social relationships) from Day 1 [80]
    End point description
    Change in caregiver quality of life (QoL) from Day 1 to Day 21, as measured by the CGBI questionnaire (PPASD). The CGBI is a standardised questionnaire consisting of 24 questions grouped into 5 dimensions (time dependency, development, physical health, emotional health, social relationships). There are 5 items in each dimension, except for physical burden which has 4 items. A higher score indicates a greater caregiver burden. The change in social relationships from Day 1 to Day 21 is presented by Dose group. No general trend of dose dependent better improvement in the GR3027 dose groups as compared to placebo was seen for social relationships.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 to Day 21
    Notes
    [80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: In Parts A, B, and C of the trial, caregiver QoL was not evaluated.
    End point values
    		 Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Number of subjects analysed
    8
    9
    11
    12
    Units: score
        arithmetic mean (standard deviation)
    -0.3 ( 0.5 )
    0.0 ( 0.0 )
    -0.2 ( 1.0 )
    0.0 ( 0.9 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were collected from the first administration of the IMP, Day 1, and until 21 days past the last dose in all trial parts.
    Adverse event reporting additional description
    TEAEs, physical examination, laboratory values, vital signs, and ECG parameters reported during the study were summarized for all subjects. Abnormal, clinically significant findings during physical examinations and ECG assessments were to be reported as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Part A, A1 50 mg QD
    Reporting group description
    		 Healthy male subjects recieved an oral dose of 50 mg GR3027 QD for 5 days.

    Reporting group title
    Part A, A2 50 mg BID (100 mg per day)
    Reporting group description
    		 Healthy male subjects recieved oral doses of 50 mg GR3027 BID for 5 days.

    Reporting group title
    Part A, A3 100 mg BID (200 mg per day)
    Reporting group description
    		 Healthy male subjects recieved oral doses of 100 mg GR3027 BID for 5 days.

    Reporting group title
    Part A, Placebo
    Reporting group description
    		 Healthy male subjects recieved placebo capsules QD (cohort A1) or BID (cohorts A2-A3) for 5 days.

    Reporting group title
    Part B, 10 mg SD
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of 10 mg GR3027

    Reporting group title
    Part B, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class B, recieved a single oral dose of placebo

    Reporting group title
    Part C, C1 10 mg BID (20 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 5 days

    Reporting group title
    Part C, C2 40 mg BID (80 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 5 days

    Reporting group title
    Part C, C3 80 mg BID (160 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 5 days

    Reporting group title
    Part C, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 5 days.

    Reporting group title
    Part D, D1 10 mg BID (20 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 10 mg GR3027 BID for 21 days

    Reporting group title
    Part D, D2 40 mg BID (80 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 40 mg GR3027 BID for 21 days

    Reporting group title
    Part D, D3 80 mg BID (160 mg per day)
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved oral doses of 80 mg GR3027 BID for 21 days

    Reporting group title
    Part D, Placebo
    Reporting group description
    		 Cirrhotic patients, Child-Pugh class A and B, recieved placebo capsules BID for 21 days.

    Serious adverse events
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day) Part A, Placebo Part B, 10 mg SD Part B, Placebo Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Toxic encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A, A1 50 mg QD Part A, A2 50 mg BID (100 mg per day) Part A, A3 100 mg BID (200 mg per day) Part A, Placebo Part B, 10 mg SD Part B, Placebo Part C, C1 10 mg BID (20 mg per day) Part C, C2 40 mg BID (80 mg per day) Part C, C3 80 mg BID (160 mg per day) Part C, Placebo Part D, D1 10 mg BID (20 mg per day) Part D, D2 40 mg BID (80 mg per day) Part D, D3 80 mg BID (160 mg per day) Part D, Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 2 (50.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    6 / 13 (46.15%)
    4 / 12 (33.33%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Thirst
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    2
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Cardiac disorders
    Metabolic cardiomyopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    3
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    9
    0
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Vertigo CNS origin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    4
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    2
    2
    2
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Flatulence
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    2
    2
    0
    0
    0
    0
    0
    0
    0
    2
    3
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2017
    Revised upper age limit for cirrhotic patients: The upper age limit was revised from 65 to 70 years.
    22 Nov 2017
    1 Starting dose in Part C Based on safety and PK data from trial Parts A and B, the dose of GR3027 to be administered in the first dose group in part C was 10 mg BID. 2 Exclusion of Quality of Life assessment in Part D It was decided to exclude the Sickness Impact Profile (SIP) questionnaire for preliminary effect on Quality of Life from the trial as it was not validated for use in Ukraine. 3 Additional efficacy assessment in Part D Assessment of Animal Naming Test (ANT1) was added to the battery of tests for the evaluation of preliminary efficacy in the trial as it was expected to increase the opportunity to evaluate cognitive function in patients with HE. 4 Inclusion of women of non-childbearing potential Inclusion of women of non-childbearing potential in Parts C and D of the trial was proposed based on non-clinical data and the safety profile of GR3027 as seen in Parts A and B of the trial. 5 Deletion of exclusion criterion reg. transplantation list (cirrhotic patients) Exclusion criterion No. 10 (Expected to undergo transplantation within 6 months after randomization) was deleted as it was considered to be covered by the exclusion criterion Any planned major surgery within the duration of the trial. 6 No urine PK in Part C As very low concentrations of GR3027 were detected in urine in healthy subjects (Part A) in this trial, a low degree of renal elimination was indicated. Therefore, urine was not to be collected for PK analysis in Part C. 7 Re-screening procedure A procedure for re-screening was defined to allow for re-assessment/re-screening, to a limited extent, of subjects based on parameters expected to fluctuate over time in the target patient population. 8 Portable EEG device to be used in Part C To facilitate the procedures at the sites and to minimize the burden on the subjects in terms of efficacy assessments, it was decided that the portable EEG device intended for trial Part D was to be used already in Part C.
    31 Jan 2018
    Change of PI at the CTC Clinic in Linköping, Sweden. (Site was not initiated.)
    22 Mar 2018
    The upper BMI limit for inclusion of subjects with liver cirrhosis in parts C and D was increased from 35 to 40 kg/m2 to allow more complete representation of obese subjects while excluding those with morbid obesity. This modification was intended to enhance the scientific value of the study with respect to the population at risk for covert HE without compromising subject safety. The upper weight limit was also excluded.
    24 Oct 2018
    1 Inclusion of Child-Pugh A patients in trial Part C Enrolment of up to 50% Child-Pugh A patients into each dose group of Part C was introduced. This allowed evaluation of safety and PK in a trial population more representative of the target population of cirrhotic patients with CHE. 2 Revision of inclusion criterion No. 8 (inclusion based on manifestations of CHE) The ANT1 was included as a test for screening subjects for the presence of CHE. 3 Revision of exclusion criterion no. 2 (GI bleeding) The required period with no active GI bleeding or a history of GI bleeding requiring blood transfusion prior to randomization was shortened from 12 to 3 months. 4 Revision of exclusion criterion no. 13 (vital signs ranges at screening) The exclusion criterion was modified to reflect the range observed by continuous 24 h recording in an unselected population of clinically stable subjects with cirrhosis. The lower limit of systolic blood pressure was set to <90 mm Hg, the lower limit of diastolic blood pressure was set to <50 mm Hg, and the limit of heart rate were set to <50 or >110 beats per minute. 5 Sample size modification in Part D At the discretion of the Sponsor, the sample size of 1 or more cohorts in Part D could be increased from 14 up to 21 (placebo/GR3027; 1:2.5) to maximize the likelihood of achieving the Part D objectives, in particular to increase the statistical likelihood of distinguishing among doses and identifying the optimal efficacy measure.

    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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