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    Clinical Trial Results:
    Phase-Ib/IIa study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of orally inhaled multiple doses of POL6014 (lonodelestat) in patients with Cystic Fibrosis

    Summary
    EudraCT number
    2018-002550-71
    Trial protocol
    DE  
    Global end of trial date
    30 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SNT-I-018
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03748199
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Santhera Pharmaceuticals (Switzerland) Ltd
    Sponsor organisation address
    Hohenrainstrasse 24, Pratteln, Switzerland, 4133
    Public contact
    Julien Gaudias, Santhera Pharmaceuticals (Switzerland) Ltd, +41 798110198, julien.gaudias@santhera.com
    Scientific contact
    Julien Gaudias, Santhera Pharmaceuticals (Switzerland) Ltd, +41 798110198, julien.gaudias@santhera.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To assess the safety and tolerability of up to three multiple ascending dose levels of inhaled POL6014 after 15 days q.d. or b.i.d. -To identify the highest tolerated dose level and associated dose regimen of inhaled POL6014 after 15 days q.d. or b.i.d. treatment.
    Protection of trial subjects
    This study was completed and archived according to the guidelines of Good Clinical Practice (GCP), International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E3 (CPMP/ICH/135/95) and conducted in compliance with the World Medical Assembly Declaration of Helsinki and its most recent amendments.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    32
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 37 patients were enrolled for screening. Of these patients, 33 were randomized whereas 4 patients were screening failures.

    Pre-assignment
    Screening details
    Overall, 37 patients were enrolled for screening. Of these patients, 33 were randomized whereas 4 patients were screening failures.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1A-(80 mg/day)
    Arm description
    80 mg QD lonodelestat or matching placebo for 15 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)
    Arm type
    Experimental

    Investigational medicinal product name
    lonodelestat
    Investigational medicinal product code
    Other name
    POL6014
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    80 mg QD lonodelestat or matching placebo for 15 days, Inhalation use

    Arm title
    Placebo
    Arm description
    Placebo
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    lonodelestat matching Placebo, Inhalation use

    Arm title
    Cohort 2A (160mg/day)
    Arm description
    Cohort 2A - 160mg lonodelestat or matching Placebo QD for 15 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)
    Arm type
    Experimental

    Investigational medicinal product name
    lonodelestat
    Investigational medicinal product code
    Other name
    POL6014
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    160 mg QD lonodelestat or matching placebo for 15 days, Inhalation use

    Arm title
    Cohort 2B (160mg/day)
    Arm description
    Cohort 2B - 80mg lonodelestat or matching Placebo BID for 15 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)
    Arm type
    Experimental

    Investigational medicinal product name
    lonodelestat
    Investigational medicinal product code
    Other name
    POL6014
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    80 mg BID lonodelestat or matching placebo for 15 days, Inhalation use

    Arm title
    Cohort C
    Arm description
    Cohort C - 40mg lonodelestat or matching Placebo QD for 28 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)
    Arm type
    Experimental

    Investigational medicinal product name
    lonodelestat
    Investigational medicinal product code
    Other name
    POL6014
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    40 mg QD lonodelestat or matching placebo for 28 days, Inhalation use

    Number of subjects in period 1
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Started
    6
    8
    6
    6
    6
    Completed
    6
    8
    6
    5
    6
    Not completed
    0
    0
    0
    1
    0
         Consent withdrawn by subject
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Overall, 37 patients were enrolled for screening. Of these patients, 33 were randomized whereas 4 patients were screening failures. 31 patients completed the study according to the protocol. One patient was randomized to the placebo QD group of Cohort C but was not treated due to withdrawal of consent. Another patient randomized to 80 mg lonodelestat BID terminated the study prematurely due to withdrawal of consent.

    Reporting group values
    Overall trial Total
    Number of subjects
    32 32
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    32 32
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        median (standard deviation)
    32 ± 9.7 -
    Gender categorical
    Units: Subjects
        Female
    4 4
        Male
    28 28

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1A-(80 mg/day)
    Reporting group description
    80 mg QD lonodelestat or matching placebo for 15 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group title
    Cohort 2A (160mg/day)
    Reporting group description
    Cohort 2A - 160mg lonodelestat or matching Placebo QD for 15 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)

    Reporting group title
    Cohort 2B (160mg/day)
    Reporting group description
    Cohort 2B - 80mg lonodelestat or matching Placebo BID for 15 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)

    Reporting group title
    Cohort C
    Reporting group description
    Cohort C - 40mg lonodelestat or matching Placebo QD for 28 days,8 patients per cohort (6 patients on verum, 2 patients on placebo)

    Primary: 6-Proportion of patients with local irritation of the nose or pharynx by visual inspection

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    End point title
    6-Proportion of patients with local irritation of the nose or pharynx by visual inspection [1]
    End point description
    Local irritation of the nose or pharynx by visual inspection and symptomatology
    End point type
    Primary
    End point timeframe
    TEAEs were defined as AEs that started or worsened after the 1st dose of the IMP until the follow-up visit.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: Subjects
        Patients with event
    1
    0
    1
    1
    0
        Respiratory, thoracic and mediastinal disorders
    1
    0
    1
    1
    0
        Epistaxis
    0
    0
    1
    0
    0
        Oropharyngeal pain
    1
    0
    0
    0
    0
        Rhinorrhoea
    0
    0
    1
    1
    0
    No statistical analyses for this end point

    Primary: 7-Proportion of patients with bronchospasm by symptoms such as dyspnoea, wheezing, chest tightness, cough

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    End point title
    7-Proportion of patients with bronchospasm by symptoms such as dyspnoea, wheezing, chest tightness, cough [2]
    End point description
    Bronchospasm by symptoms such as dyspnea, wheezing, chest tightness, and/or cough
    End point type
    Primary
    End point timeframe
    TEAEs were defined as AEs that started or worsened after the 1st dose of the IMP until the follow-up visit.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8
    6
    6
    6
    Units: Patients
        Patients with any event
    1
    1
    3
    6
    2
        General disorders and administration site conditio
    1
    0
    1
    3
    0
        Chest discomfort
    1
    0
    1
    3
    0
        Investigations
    0
    0
    0
    1
    0
        Forced expiratory volume decreased
    0
    0
    0
    1
    0
        Respiratory, thoracic and mediastinal disorders
    1
    1
    3
    6
    2
        Bronchospasm
    0
    0
    1
    0
    0
        Chest discomfort.
    0
    0
    0
    1
    0
        Cough
    1
    0
    2
    1
    0
        Dyspnoea
    1
    0
    1
    4
    1
        Obstructive airways disorder
    0
    0
    0
    3
    0
        Oropharyngeal pain
    0
    0
    0
    1
    1
        Productive cough
    0
    1
    0
    0
    0
        Wheezing
    1
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: 9-Changes from baseline in oxygen saturation in peripheral blood as measured by pulse

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    End point title
    9-Changes from baseline in oxygen saturation in peripheral blood as measured by pulse [3]
    End point description
    End point type
    Primary
    End point timeframe
    15 days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8 [4]
    6
    6 [5]
    6
    Units: Oxygen Saturation [%]
    arithmetic mean (standard deviation)
        Change D8 - Baseline
    0.5 ± 1.38
    0.5 ± 1.41
    -1.2 ± 2.86
    0.5 ± 2.59
    -1.3 ± 3.78
        Change D15 - Baseline
    0.8 ± 1.33
    1.0 ± 1.31
    -2.8 ± 1.33
    -2.6 ± 3.29
    0.0 ± 0.89
        Change Follow-up - Baseline
    0.5 ± 0.84
    1.2 ± 2.48
    -1.2 ± 2.23
    1.3 ± 1.21
    0.0 ± 0.63
    Notes
    [4] - Change Follow-up - Baseline: N=6
    [5] - Change D15 - Baseline: N=5
    No statistical analyses for this end point

    Primary: 8A-Changes from baseline and pre-dose in lung function parameters by spirometry-FVC

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    End point title
    8A-Changes from baseline and pre-dose in lung function parameters by spirometry-FVC [6]
    End point description
    End point type
    Primary
    End point timeframe
    15 days
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    6
    6
    6
    6
    Units: Percent Predicted FVC according to GLI f
    arithmetic mean (standard deviation)
        Screening
    74.294 ± 10.7952
    95.127 ± 23.8408
    85.572 ± 6.0049
    77.191 ± 11.2056
    78.216 ± 16.9532
        D1 - 1h post-morning dose
    71.836 ± 12.0833
    92.746 ± 24.2705
    79.743 ± 7.2022
    73.967 ± 8.4247
    74.139 ± 18.2907
        D8 - pre-morning dose
    72.433 ± 12.8110
    96.897 ± 25.0244
    78.357 ± 5.6837
    71.115 ± 12.9275
    77.999 ± 16.9712
        D8 - 3h post-morning dose
    71.239 ± 11.8307
    95.354 ± 24.0326
    78.548 ± 6.1711
    68.465 ± 14.5707
    75.124 ± 18.9872
        D15 - pre-morning dose
    69.353 ± 11.9325
    92.459 ± 25.8670
    74.207 ± 8.1306
    68.452 ± 8.9347
    73.607 ± 16.2156
        D15 - 3h post-morning dose
    68.211 ± 10.1422
    91.685 ± 21.7058
    75.463 ± 8.1343
    67.012 ± 10.5575
    72.722 ± 17.1640
        Follow-up
    71.670 ± 12.1342
    95.529 ± 27.6120
    84.944 ± 2.4961
    74.611 ± 12.7714
    74.337 ± 17.3027
    No statistical analyses for this end point

    Primary: 8B-Changes from baseline and pre-dose in lung function parameters by spirometry- FEV1

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    End point title
    8B-Changes from baseline and pre-dose in lung function parameters by spirometry- FEV1 [7]
    End point description
    FEV1 [%] - absolute change from baseline
    End point type
    Primary
    End point timeframe
    15 days
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8
    6
    6
    6
    Units: Percent Predicted FEV1 according to GLI
    arithmetic mean (standard deviation)
        Change D1 - 1h post-morning dose-Baseline
    -1.327 ± 2.7409
    2.188 ± 6.3432
    -1.253 ± 2.7017
    -3.643 ± 1.9381
    -1.167 ± 4.1864
        Change D8 - pre-morning dose - Baseline
    -2.150 ± 4.6335
    4.816 ± 6.9112
    -6.343 ± 9.1191
    -8.683 ± 6.1120
    3.381 ± 2.5686
        Change D15 - pre-morning dose - Baseline
    -7.285 ± 6.6758
    0.852 ± 5.6222
    -11.734 ± 7.9541
    -14.005 ± 9.6930
    -2.901 ± 3.2141
        Change Follow-up - Baseline
    -2.848 ± 7.4268
    6.878 ± 6.6505
    -1.153 ± 7.9842
    -4.979 ± 4.9556
    -1.590 ± 3.3609
    No statistical analyses for this end point

    Primary: 1-Proportion of patients with abnormal physical examination findings

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    End point title
    1-Proportion of patients with abnormal physical examination findings [8]
    End point description
    End point type
    Primary
    End point timeframe
    trial duration
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8
    6
    6
    6
    Units: Subjects
        Subjects
    2
    0
    2
    5
    4
    No statistical analyses for this end point

    Primary: 4-Changes from baseline and pre-dose in ECG parameters

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    End point title
    4-Changes from baseline and pre-dose in ECG parameters [9]
    End point description
    ECG Mean Ventricular Rate [beats/min]
    End point type
    Primary
    End point timeframe
    trial duraction
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8
    6
    6
    6
    Units: beats/min
    arithmetic mean (standard deviation)
        Change D1 - 4h post-morning dose - Baseline
    1.7 ± 12.91
    5.1 ± 8.18
    6.2 ± 7.25
    3.0 ± 7.97
    0.8 ± 4.62
        Change D8 - pre-morning dose - Baseline
    2.0 ± 8.60
    0.9 ± 7.85
    1.0 ± 4.20
    3.3 ± 13.50
    -1.3 ± 8.71
        Change D8 - 4h post-morning dose - Baseline
    0.7 ± 13.26
    0.4 ± 7.41
    9.3 ± 4.59
    1.5 ± 11.26
    1.0 ± 4.38
        Change D15 - pre-morning dose - Baseline
    0.7 ± 12.21
    -0.6 ± 5.55
    -2.0 ± 11.63
    12.2 ± 15.94
    3.7 ± 5.61
        Change D15 - 4h post-morning dose - Baseline
    5.5 ± 14.79
    0.4 ± 5.29
    7.2 ± 12.56
    9.4 ± 21.07
    2.7 ± 6.59
        Change Follow-up - Baseline
    3.3 ± 8.31
    7.5 ± 16.02
    0.3 ± 10.03
    2.7 ± 16.15
    -3.0 ± 8.72
    No statistical analyses for this end point

    Primary: 5- Occurrence and severity of AEs

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    End point title
    5- Occurrence and severity of AEs [10]
    End point description
    End point type
    Primary
    End point timeframe
    trial duration
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8
    6
    6
    6
    Units: number of adverse events
        Total number of TEAE
    19
    13
    18
    36
    19
        Number of TEAE possibly related to study drug
    2
    3
    9
    16
    8
        Number of local TEAE related to inhalation
    3
    1
    2
    13
    7
        Number of TEAE of severity grade 3, 4 or 5
    0
    0
    0
    0
    0
        Number of serious TEAE
    0
    0
    0
    0
    0
        Number of TEAE leading to study drug interruption
    0
    0
    1
    2
    0
        Number of TEAE leading to study drug discontinuati
    0
    0
    0
    2
    0
    No statistical analyses for this end point

    Primary: 2 Changes from baseline in laboratory safety assessments (clinical chemistry, haematology, urinalysis)

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    End point title
    2 Changes from baseline in laboratory safety assessments (clinical chemistry, haematology, urinalysis) [11]
    End point description
    representative for the laboratory parameters collected only the albumin data is presented here,full summary of laboratory parameters is provided in appendix 14.3.5-1 of the CSR
    End point type
    Primary
    End point timeframe
    trial duration
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8 [12]
    6
    6 [13]
    6
    Units: g/dl
    arithmetic mean (standard deviation)
        Change D8 - Baseline
    0.12 ± 0.306
    0.03 ± 0.176
    0.10 ± 0.176
    0.17 ± 0.225
    -0.19 ± 0.267
        Change D15 - Baseline
    -0.12 ± 0.160
    0.03 ± 0.194
    -0.11 ± 0.209
    0.08 ± 0.084
    -0.16 ± 0.245
        Change Follow-up - Baseline
    0.05 ± 0.187
    0.14 ± 0.093
    0.08 ± 0.223
    0.17 ± 0.082
    -0.02 ± 0.318
    Notes
    [12] - subjects change follow up- baseline: 6
    [13] - subjects change D15-baseline=5
    No statistical analyses for this end point

    Primary: 3 Changes from baseline and pre-dose in vital signs (blood pressure, pulse, respiratory rate body temperature)

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    End point title
    3 Changes from baseline and pre-dose in vital signs (blood pressure, pulse, respiratory rate body temperature) [14]
    End point description
    representative for the vital signs parameters collected only the temperature data is presented here,full summary of vital signs parameters is provided in appendix 14.3.6-1 of the CSR
    End point type
    Primary
    End point timeframe
    trial duration
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The sample size of each cohort was too small to perform statistical tests on any of the components of the PEP. Descriptive analysis was conducted for these groups.
    End point values
    Cohort 1A-(80 mg/day) Placebo Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    8 [15]
    6
    6 [16]
    6
    Units: celcius
    arithmetic mean (standard deviation)
        Change D1 - 1h post-morning dose - Baseline
    0.12 ± 0.319
    0.04 ± 0.374
    0.02 ± 0.098
    0.25 ± 0.226
    -0.02 ± 0.256
        Change D1 - 4h post-morning dose - Baseline
    -0.07 ± 0.367
    0.08 ± 0.276
    0.13 ± 0.225
    0.38 ± 0.264
    0.02 ± 0.248
        Change D8 - pre-morning dose - Baseline
    0.08 ± 0.306
    -0.16 ± 0.302
    0.07 ± 0.234
    0.02 ± 0.392
    -0.08 ± 0.462
        Change D8 - 4h post-morning dose - Baseline
    0.00 ± 0.415
    0.01 ± 0.304
    0.00 ± 0.179
    0.20 ± 0.335
    0.02 ± 0.488
        Change D15 - pre-morning dose - Baseline
    0.12 ± 0.449
    -0.23 ± 0.266
    0.15 ± 0.266
    0.10 ± 0.292
    -0.03 ± 0.339
        Change D15 - 4h post-morning dose - Baseline
    0.22 ± 0.799
    0.05 ± 0.424
    0.10 ± 0.237
    0.28 ± 0.327
    -0.05 ± 0.226
        Change Follow-up - Baseline
    0.07 ± 0.308
    0.00 ± 0.00
    0.02 ± 0.133
    -0.08 ± 0.475
    0.10 ± 0.341
    Notes
    [15] - Change Follow-up C - Baseline (n=2) not avialbale, therefore stated 0.00
    [16] - subjects day 15 changes:n=5
    No statistical analyses for this end point

    Secondary: renal clearance from plasma (CLr)

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    End point title
    renal clearance from plasma (CLr) [17]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15, 0-12h
    Notes
    [17] - 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: Placebo values not reported
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    6
    4
    6
    Units: l/h
    geometric mean (standard deviation)
        CLR d15, 0-12h
    2.604 ± 1.412
    2.502 ± 1.966
    3.482 ± 1.367
    2.092 ± 1.263
    No statistical analyses for this end point

    Secondary: Tmax of POL6014 after q.d. dosing

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    End point title
    Tmax of POL6014 after q.d. dosing [18]
    End point description
    End point type
    Secondary
    End point timeframe
    on D1,D15 and D28 (only Cohort C)
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported. cmaxDue to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [19]
    6 [20]
    6
    Units: hour
    geometric mean (standard deviation)
        Day 1
    1.787 ± 1.318
    1.904 ± 1.426
    1.904 ± 1.426
        Day 15
    1.261 ± 1.735
    2.152 ± 1.581
    1.523 ± 1.605
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    1.620 ± 1.428
    Notes
    [19] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [20] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    No statistical analyses for this end point

    Secondary: Cmax of POL6014after QD dosing

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    End point title
    Cmax of POL6014after QD dosing [21]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 1, day 15, day 28 (Cohort C only)
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [22]
    6 [23]
    6
    Units: ng/ml
    geometric mean (standard deviation)
        Day 1
    74.36 ± 2.290
    297.0 ± 1.685
    69.77 ± 1.390
        Day 15
    91.56 ± 1.600
    263.3 ± 1.842
    69.76 ± 1.496
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    82.25 ± 1.543
    Notes
    [22] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [23] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    Statistical analysis title
    ANOVA of Cmax,D15 and dose after q.d. dosing
    Statistical analysis description
    ANOVA of Cmax,D15 and dose after q.d. dosing
    Comparison groups
    Cohort 2A (160mg/day) v Cohort 1A-(80 mg/day)
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    other [24]
    P-value
    = 0.0024 [25]
    Method
    ANOVA
    Confidence interval
    Notes
    [24] - other
    [25] - comparison 160mg QD : 80mg QD

    Secondary: Cmax,norm of POL6014 after q.d. dosing

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    End point title
    Cmax,norm of POL6014 after q.d. dosing [26]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 1, day 15 and day 28 (Cohort C only)
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [27]
    6 [28]
    6
    Units: ng/mL/(mg/kg)
    geometric mean (standard deviation)
        Day 1
    68.62 ± 2.049
    146.8 ± 1.800
    124.0 ± 1.560
        Day 15
    84.48 ± 1.553
    130.1 ± 2.009
    123.9 ± 1.620
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    146.1 ± 1.593
    Notes
    [27] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [28] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    No statistical analyses for this end point

    Secondary: AUCτ of POL6014 after q.d. dosing

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    End point title
    AUCτ of POL6014 after q.d. dosing [29]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 1, day 15, day 28 (cohort C only)
    Notes
    [29] - 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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [30]
    6 [31]
    6
    Units: h*ng/ml
    geometric mean (standard deviation)
        Day 1
    513.2 ± 2.249
    1971 ± 1.614
    471.7 ± 1.407
        Day 15
    559.0 ± 1.726
    1636 ± 1.787
    437.5 ± 1.787
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    562.3 ± 1.386
    Notes
    [30] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [31] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    No statistical analyses for this end point

    Secondary: AUCτ,norm of POL6014 after q.d. dosing

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    End point title
    AUCτ,norm of POL6014 after q.d. dosing [32]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 1, day 15 and day 28 (Cohort C only)
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [33]
    6 [34]
    6
    Units: h*ng/mL/(mg/kg)
    geometric mean (standard deviation)
        Day 1
    473.6 ± 1.986
    974.2 ± 1.714
    838.0 ± 1.552
        Day 15
    515.8 ± 1.597
    808.4 ± 1.961
    777.3 ± 1.501
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    999.1 ± 1.411
    Notes
    [33] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [34] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    No statistical analyses for this end point

    Secondary: Aeτ of POL6014 after q.d. dosing

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    End point title
    Aeτ of POL6014 after q.d. dosing [35]
    End point description
    End point type
    Secondary
    End point timeframe
    d1,d15 and d28
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [36]
    6 [37]
    6 [38]
    Units: microgram(s)
    geometric mean (standard deviation)
        day 1,0-12h
    1301 ± 2.402
    6070 ± 2.163
    942.1 ± 1.382
        day 1,12-24h
    0.00 ± 0.00
    631.9 ± 1.839
    109.5 ± 1.299
        day 15, 0-12h
    1456 ± 1.734
    4093 ± 2.465
    1075 ± 1.427
        day 15, 12-24h
    215.7 ± 1.288
    1328 ± 3.297
    1.217 ± 1.357
        day 28, 0-12h
    0.00 ± 0.00
    0.00 ± 0.00
    1176 ± 1.347
        day 28,12-24h
    0.00 ± 0.00
    0.00 ± 0.00
    119.9 ± 1.957
    Notes
    [36] - D1 0-12h:N=6 D1 12-24h:N=2 D15 0-12h:N=6 D15 12-24h:N=3 D1,12-24h not available,no D28 treatment
    [37] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [38] - Day 1 0-12h:N=6 Day 1 12-24h:N=3 D15 0-12h:N=6 D15 12-24h:N=3 D28 0-12h:N=6 D28 12-24h:N=3
    No statistical analyses for this end point

    Secondary: %Aeτ,D1 of POL6014

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    End point title
    %Aeτ,D1 of POL6014 [39]
    End point description
    End point type
    Secondary
    End point timeframe
    day 1
    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: no placebo values reported
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6 [40]
    6
    6
    6 [41]
    Units: percent
    geometric mean (standard deviation)
        day 1,0-12h
    1.626 ± 2.402
    3.794 ± 2.163
    3.195 ± 2.380
    2.355 ± 1.382
        day 1,12-24h
    0.00 ± 0.00
    0.395 ± 1.839
    2.287 ± 1.969
    0.274 ± 1.299
    Notes
    [40] - day 1,12-24h: N=2
    [41] - day1,12-24h: N=3
    No statistical analyses for this end point

    Secondary: AUCτ of POL6014 after b.i.d. dosing

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    End point title
    AUCτ of POL6014 after b.i.d. dosing [42]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    6
    Units: [h*ng/ml]
    geometric mean (standard deviation)
        day 15 moning
    663.1 ± 2.102
        day 15 evening
    734.1 ± 1.560
    No statistical analyses for this end point

    Secondary: AUCτ,norm of POL6014 after b.i.d. dosing

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    End point title
    AUCτ,norm of POL6014 after b.i.d. dosing [43]
    End point description
    End point type
    Secondary
    End point timeframe
    trial duration
    Notes
    [43] - 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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    5
    Units: [h*ng/ml]
    geometric mean (standard deviation)
        day 15 moning
    488.8 ± 2.946
        day 15 evening
    586.0 ± 1.747
        day 1 morning
    546 ± 2.350
        day 1 evening
    611.6 ± 1.619
    No statistical analyses for this end point

    Secondary: Cmax of POL6014 after b.i.d. dosing

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    End point title
    Cmax of POL6014 after b.i.d. dosing [44]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    6
    Units: ng/mL
    geometric mean (standard deviation)
        day15 morning
    101.8 ± 2.987
        day 15 evening
    115.2 ± 1.997
    No statistical analyses for this end point

    Secondary: Cmax,norm of POL6014 after b.i.d. dosing

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    End point title
    Cmax,norm of POL6014 after b.i.d. dosing [45]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    5
    Units: [ng/mL/mg/kg)]
    geometric mean (standard deviation)
        day 15 morning
    79.16 ± 2.979
        day 15 evening
    98.58 ± 1.984
    No statistical analyses for this end point

    Secondary: Tmax of POL6014 after b.i.d. dosing

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    End point title
    Tmax of POL6014 after b.i.d. dosing [46]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    5
    Units: hour
    geometric mean (standard deviation)
        day 15 morning
    1.151 ± 1.368
        day 15 evening
    1.001 ± 1.127
    No statistical analyses for this end point

    Secondary: Cmin of POL6014 after b.i.d. dosing

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    End point title
    Cmin of POL6014 after b.i.d. dosing [47]
    End point description
    End point type
    Secondary
    End point timeframe
    on day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    5
    Units: ng/ml
    geometric mean (standard deviation)
        day 15 morning
    7.187 ± 2.078
        day 15 evening
    25.84 ± 2.678
    No statistical analyses for this end point

    Secondary: Cav of POL6014 after b.i.d. dosing

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    End point title
    Cav of POL6014 after b.i.d. dosing [48]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    5
    Units: ng/ml
    geometric mean (standard deviation)
        day 15 morning
    2.946 ± 148.8
        day 15 evening
    1.747 ± 60.44
    No statistical analyses for this end point

    Secondary: Aeτ of POL6014 after b.i.d. dosing

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    End point title
    Aeτ of POL6014 after b.i.d. dosing [49]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    5 [50]
    Units: microgram(s)
    geometric mean (standard deviation)
        day 15 morning
    2549 ± 2.330
        day 15 evening
    1268 ± 4.381
    Notes
    [50] - D15 morning:N=4 D15 evening:N=5
    No statistical analyses for this end point

    Secondary: CLR of POL6014 after b.i.d. dosing

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    End point title
    CLR of POL6014 after b.i.d. dosing [51]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 2B (160mg/day)
    Number of subjects analysed
    4 [52]
    Units: L/h
    geometric mean (standard deviation)
        day 15 morning
    3.482 ± 1.367
        day 15 evening
    2.165 ± 3.153
    Notes
    [52] - day 15 evening:N=5
    No statistical analyses for this end point

    Secondary: Cmin of POL6014 after q.d. dosing

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    End point title
    Cmin of POL6014 after q.d. dosing [53]
    End point description
    End point type
    Secondary
    End point timeframe
    Day15 and Day 28
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [54]
    6 [55]
    6
    Units: ng/ml
    geometric mean (standard deviation)
        Day 15
    2.836 ± 1.574
    5.410 ± 1.473
    1.945 ± 2.387
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    1.209 ± 1.266
    Notes
    [54] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [55] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    No statistical analyses for this end point

    Secondary: Cav of POL6014 after q.d. dosing

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    End point title
    Cav of POL6014 after q.d. dosing [56]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15 and Day 28 (cohort C only)
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [57]
    6 [58]
    6
    Units: ng/ml
    geometric mean (standard deviation)
        Day 15
    23.29 ± 1.726
    68.16 ± 1.787
    18.23 ± 1.385
        Day 28
    0.00 ± 0.00
    0.00 ± 0.00
    23.43 ± 1.386
    Notes
    [57] - As per protocol Cohort A did not have a Day28 dosing , hence no results are included (0.00).
    [58] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    No statistical analyses for this end point

    Secondary: %PTF of POL6014

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    End point title
    %PTF of POL6014 [59]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15 and day 28 (cohort C only)
    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: Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort 2B (160mg/day) Cohort C
    Number of subjects analysed
    6
    6
    5 [60]
    6
    Units: percent
    geometric mean (standard deviation)
        day 15
    378.0 ± 1.260
    376.6 ± 1.333
    26.68 ± 228.3
    364.1 ± 1.201
        day 28
    0.00 ± 0.00
    0.00 ± 0.00
    0.00 ± 0.00
    345.8 ± 1.201
    Notes
    [60] - %PTF evening dose day 15: 88.55/SD4.804
    No statistical analyses for this end point

    Secondary: CLR of POL6014 after q.d. dosing

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    End point title
    CLR of POL6014 after q.d. dosing [61]
    End point description
    End point type
    Secondary
    End point timeframe
    day 15 and day 28
    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: Due to BD dosing in Cohort 2 B and registry limitations reflecting different dosing time points cohorts 1A, 2A and C (all OD dosing) are reflected in a separate EP entry. Placebo values not reported.
    End point values
    Cohort 1A-(80 mg/day) Cohort 2A (160mg/day) Cohort C
    Number of subjects analysed
    6 [62]
    6 [63]
    6 [64]
    Units: litre/hour
    geometric mean (standard deviation)
        day 15, 0-12h
    2.604 ± 1.412
    2.502 ± 1.966
    2.458 ± 1.299
        day 15 12-24h
    0.254 ± 1.407
    0.812 ± 2.285
    0.221 ± 1.359
        day 28, 0-12h
    0.00 ± 0.00
    0.00 ± 0.00
    2.092 ± 1.263
        day 28 12-24h
    0.00 ± 0.00
    0.00 ± 0.00
    0.204 ± 1.683
    Notes
    [62] - day15 0-12h N=6 day15 12-24h N=3 As per protocol Cohort A did not have a Day28 dosing.
    [63] - As per protocol Cohort 2A did not have a Day28 dosing , hence no results are included (0.00).
    [64] - day 15 0-12hN=6 day 15 12-24hN=3 day 28 0-12hN=6 day 28 12-24hN=3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Comprehensive assessment of any apparent toxicity experienced by the patient will be performed throughout the course of the trial, from the time of the patient’s signature of informed consent till the final study visit.
    Adverse event reporting additional description
    No SAEs were reported during the whole study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Cohort 1A -80mgQD
    Reporting group description
    -

    Reporting group title
    Cohort 2A-160mgQD
    Reporting group description
    -

    Reporting group title
    Cohort 2B - 80mgBID
    Reporting group description
    -

    Reporting group title
    Cohort C- 40mgQD
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Total
    Reporting group description
    -

    Serious adverse events
    Cohort 1A -80mgQD Cohort 2A-160mgQD Cohort 2B - 80mgBID Cohort C- 40mgQD Placebo Total
    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 / 8 (0.00%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Cohort 1A -80mgQD Cohort 2A-160mgQD Cohort 2B - 80mgBID Cohort C- 40mgQD Placebo Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    3 / 6 (50.00%)
    6 / 6 (100.00%)
    4 / 6 (66.67%)
    7 / 8 (87.50%)
    26 / 32 (81.25%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Forced expiratory flow decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    6 / 32 (18.75%)
         occurrences all number
    3
    2
    1
    2
    0
    8
    Dyspnoea
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    8 / 32 (25.00%)
         occurrences all number
    2
    1
    6
    1
    0
    11
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    0
    1
    2
    0
    3
    Increased viscosity of upper respiratory secretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Obstructive airways disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    0
    5
    0
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    1
    0
    1
    1
    0
    3
    Pharyngeal paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    Sputum increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    4 / 32 (12.50%)
         occurrences all number
    2
    1
    0
    0
    1
    4
    Sputum retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    3 / 8 (37.50%)
    8 / 32 (25.00%)
         occurrences all number
    0
    2
    4
    0
    3
    9
    Intercostal neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Eye disorders
    Eye swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    5 / 32 (15.63%)
         occurrences all number
    1
    1
    6
    0
    0
    8
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Eructation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Product issues
    Product taste abnormal
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    6 / 32 (18.75%)
         occurrences all number
    2
    3
    1
    1
    0
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    5 / 32 (15.63%)
         occurrences all number
    4
    2
    1
    0
    0
    7
    Rash pustular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2018
    Amendment 1 resulted in protocol Version 2.0. The main changes implemented are listed below: - Clarification on different procedures required by the protocol - Addition of Appendix 2 to explain the “Guidance for DMC Assessment Criteria” - Clarification of sputum bacteriology assessments timing in Appendix 1 - Change of the interval for screening from D-21 to D-1 to D-21 to D-10
    20 Aug 2019
    Amendment 2 resulted in protocol Version 3.0. The main change implemented is listed below: - Analysis of the unblinded data was performed by the Sponsor at the end of each cohort. Accordingly, text was modified in Sections 3.1, 5.4, 9, 9.6, and 11.1.
    03 Mar 2020
    Amendment 3 resulted in protocol Version 4.0. The main changes implemented are listed below: - Modification and renaming of pre-planned Cohort 1B to Cohort C, at lower dose of 40 mg QD in 8 patients (6 on verum, 2 on placebo) for 28 days instead of 40 mg BID in 16 patients for 15 days. The respective sections on study design and schedule of assessment were updated. - Complete removal of DL3 (320 mg daily) as well as study Part II which had been provisionally kept but not precisely defined so far - Modification of inclusion criterion no.7 (applicable to upcoming Cohort C): patient had to have an FEV1% predicted value at screening ≥50% instead of 40% to decrease potential risk and impact in case of FEV1 decline. - Inclusion of additional criteria related to lung function for AE/SAE grading and patient discontinuation from the IMP - Summary information from unblinded interim data of completed Cohorts 1A, 2A, and 2B had been incorporated to the protocol (especially benefit-risk assessment) to inform about further conduct of the study by investigators.
    23 Jun 2020
    Amendment 4 resulted in protocol Version 5.0. The main change implemented is listed below: - Administrative change: Dr. med. O. Kornmann (IKF Pneumologie GmbH & Co. KG) replaced Dr. med. W. Timmer (Inamed GmbH) as Coordinating Investigator

    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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