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    Clinical Trial Results:
    A Phase 2, proof-of-concept, multicentre, double-blind, randomised, dose-ascending, sequential group, placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of 12 weeks twice daily oral administration of alvelestat (MPH966) in participants with alpha-1 antitrypsin deficiency.

    Summary
    EudraCT number
    		 2018-001309-95
    Trial protocol
    		 GB   SE   DK   ES   PL   BE  
    Global end of trial date
    30 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2024
    First version publication date
    27 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MPH966-2-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03636347
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mereo BioPharma
    Sponsor organisation address
    1 Cavendish Place, London, United Kingdom, W1G 0QF
    Public contact
    Mereo BioPharma, Mereo BioPharma, enquiries@mereobiopharma.com
    Scientific contact
    Mereo BioPharma, Mereo BioPharma, enquiries@mereobiopharma.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
    30 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the mechanistic effect of two doses of alvelestat administered twice daily (bid) for 12 weeks on blood markers of Neutrophil Elastase (NE) activity and safety in individuals with alpha-1 antitrypsin deficiency-associated emphysema.
    Protection of trial subjects
    This study was conducted in accordance with the accepted version of the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines and/or all relevant federal regulations as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of the United States Code of Federal Regulations (CFR), in compliance with International Council for Harmonisation (ICH) good clinical practice (GCP) guidelines, and according to the appropriate regulatory requirements in the countries where the study was conducted.
    Background therapy
    		 Standard of Care for Chronic Obstructive Pulmonary Disease
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 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
    United Kingdom: 39
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    99
    EEA total number of subjects
    48
    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)
    77
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were enrolled at 26 sites in the United States, Canada, Belgium, Denmark, Poland, Spain, Sweden and the United Kingdom. 1 participant was randomized to alvelestat 240 milligram (mg) but did not receive study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alvelestat 120 mg
    Arm description
    		 4 × 30 mg alvelestat and 4 × 30 mg placebo oral tablets taken twice daily (BID) 12 hours apart with water for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alvelestat
    Investigational medicinal product code
    Other name
    MPH966
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alvelestat tablets were administered orally

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets were administered orally

    Arm title
    		 Alvelestat 240 mg
    Arm description
    		 8 × 30 mg alvelestat oral tablets BID 12 hours apart with water for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alvelestat
    Investigational medicinal product code
    Other name
    MPH966
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alvelestat tablets were administered orally

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets were administered orally

    Arm title
    		 Placebo
    Arm description
    		 8 × oral placebo tablets BID 12 hours apart with water for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets were administered orally

    Number of subjects in period 1 [1]
    		Alvelestat 120 mg Alvelestat 240 mg Placebo
    Started
    22
    40
    36
    Received at least 1 dose of study drug
    22
    40
    36
    Completed
    14
    29
    33
    Not completed
    8
    11
    3
         Adverse event, non-fatal
    2
    11
    -
         Withdrew due to COVID-19 restrictions
    6
    -
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant was randomized to alvelestat 240 mg but did not receive study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alvelestat 120 mg
    Reporting group description
    		 4 × 30 mg alvelestat and 4 × 30 mg placebo oral tablets taken twice daily (BID) 12 hours apart with water for 12 weeks.

    Reporting group title
    Alvelestat 240 mg
    Reporting group description
    		 8 × 30 mg alvelestat oral tablets BID 12 hours apart with water for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 8 × oral placebo tablets BID 12 hours apart with water for 12 weeks.

    Reporting group values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo Total
    Number of subjects
    		 22 40 36 98
    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)
    		 55.5 ( 9.67 ) 59.8 ( 9.25 ) 55.3 ( 8.05 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 18 27 14 59
        Male
    		 4 13 22 39
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 22 40 36 98
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Alvelestat 120 mg
    Reporting group description
    		 4 × 30 mg alvelestat and 4 × 30 mg placebo oral tablets taken twice daily (BID) 12 hours apart with water for 12 weeks.

    Reporting group title
    Alvelestat 240 mg
    Reporting group description
    		 8 × 30 mg alvelestat oral tablets BID 12 hours apart with water for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 8 × oral placebo tablets BID 12 hours apart with water for 12 weeks.

    Primary: Percent Change from Baseline to End of Treatment in Blood Neutrophil Elastase Activity

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    End point title
    		 Percent Change from Baseline to End of Treatment in Blood Neutrophil Elastase Activity
    End point description
    Percent change of Blood Neutrophil Elastase (NE) Activity is reported. To fulfil the residual normality assumptions of the model for NE serum, a log transformation was applied. The log ratio defined as log (visit value or EndPoint value / baseline value) was used as the dependent variable in place of the percentage change in the MMRM model. Therefore, the back-transformed least squares mean (LSM) values were obtained by applying the formula [exp(LSM) -1]×100%.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, and 12
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo
    Number of subjects analysed
    17
    28
    32
    Units: Percent change from Baseline
    least squares mean (standard error)
        Week 4
    -90.0 ( 0.68 )
    -90.0 ( 0.54 )
    -18.1 ( 0.42 )
        Week 8
    -86.5 ( 0.80 )
    -93.3 ( 0.52 )
    -25.9 ( 0.44 )
        Week 12
    -83.5 ( 0.83 )
    -93.3 ( 0.53 )
    -18.1 ( 0.38 )
    Statistical analysis title
    		 Alvelestat 120mg vs Placebo at Week 12
    Statistical analysis description
    Analysis was performed on the Per-Protocol analysis set. 42 participants were evaluable at the Week 12 time point.
    Comparison groups
    Alvelestat 120 mg v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed Models Repeated Measures
    Confidence interval
    Statistical analysis title
    		 Alvelestat 240mg vs Placebo at Week 12
    Statistical analysis description
    Analysis was performed on the Per-Protocol analysis set. 52 participants were evaluable at the Week 12 time point.
    Comparison groups
    Alvelestat 240 mg v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed Models Repeated Measures
    Confidence interval

    Primary: Percent Change From Baseline to End of Treatment in Plasma Aα-Val360

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    End point title
    		 Percent Change From Baseline to End of Treatment in Plasma Aα-Val360
    End point description
    Percent change of Plasma Aα-Val360 is reported as [(measure at time t - measure at baseline)/measure at baseline * 100%]
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, and 12
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo
    Number of subjects analysed
    15
    25
    31
    Units: Percent change from Baseline
    least squares mean (standard error)
        Week 4
    -18.7 ( 8.98 )
    -2.0 ( 8.36 )
    10.3 ( 6.96 )
        Week 8
    -11.3 ( 8.84 )
    -15.0 ( 7.85 )
    17.0 ( 9.57 )
        Week 12
    4.1 ( 13.60 )
    -22.7 ( 7.46 )
    11.7 ( 8.24 )
    Statistical analysis title
    		 Alvelestat 120mg vs Placebo at Week 12
    Statistical analysis description
    Analysis was performed on the Per-Protocol analysis set. 41 participants were evaluable at the Week 12 time point.
    Comparison groups
    Alvelestat 120 mg v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.533
    Method
    		 Mixed Models Repeated Measures
    Confidence interval
    Statistical analysis title
    		 Alvelestat 240mg vs Placebo at Week 12
    Statistical analysis description
    Analysis was performed on the Per-Protocol analysis set. 49 participants were evaluable at the Week 12 time point.
    Comparison groups
    Alvelestat 240 mg v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed Models Repeated Measures
    Confidence interval

    Primary: Percent Change From Baseline to End of Treatment in Plasma Desmosine

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    End point title
    		 Percent Change From Baseline to End of Treatment in Plasma Desmosine
    End point description
    Percent change of Plasma Desmosine is reported as [(measure at time t - measure at baseline)/measure at baseline * 100%]
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, and 12
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo
    Number of subjects analysed
    17
    28
    32
    Units: Percent change from Baseline
    least squares mean (standard error)
        Week 4
    9.3 ( 10.47 )
    -11.0 ( 7.65 )
    10.1 ( 5.77 )
        Week 8
    23.2 ( 11.93 )
    -14.0 ( 7.65 )
    17.9 ( 6.65 )
        Week 12
    29.2 ( 11.59 )
    -13.2 ( 7.42 )
    18.1 ( 6.64 )
    Statistical analysis title
    		 Alvelestat 120mg vs Placebo at Week 12
    Statistical analysis description
    Analysis was performed on the Per-Protocol analysis set. 43 participants were evaluable at the Week 12 time point.
    Comparison groups
    Alvelestat 120 mg v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.922
    Method
    		 Mixed Models Repeated Measures
    Confidence interval
    Statistical analysis title
    		 Alvelestat 240mg vs Placebo at Week 12
    Statistical analysis description
    Analysis was performed on the Per-Protocol analysis set. 53 participants were evaluable at the Week 12 time point.
    Comparison groups
    Alvelestat 240 mg v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041
    Method
    		 Mixed Models Repeated Measures
    Confidence interval

    Secondary: Number of Participants with Active Neutrophil Elastase Concentration Below the Limit of Detection (<LLOQ)

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    End point title
    		 Number of Participants with Active Neutrophil Elastase Concentration Below the Limit of Detection (<LLOQ)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to week 12
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo
    Number of subjects analysed
    18
    34
    32
    Units: Participants
        Baseline
    1
    2
    3
        Week 4
    8
    14
    8
        Week 8
    6
    15
    8
        Week 12
    5
    15
    5
    Statistical analysis title
    		 Alvelestat 120mg vs Placebo at Week 12
    Comparison groups
    Alvelestat 120 mg v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.729
    Method
    		 Mixed Models Repeated Measures
    Confidence interval
    Statistical analysis title
    		 Alvelestat 240mg vs Placebo at Week 12
    Comparison groups
    Alvelestat 240 mg v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed Models Repeated Measures
    Confidence interval

    Secondary: Alvelestat Plasma Concentrations by Visit

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    End point title
    		 Alvelestat Plasma Concentrations by Visit [1]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    Notes
    [1] - 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: Only study-drug arms were analyzed for this measure.
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg
    Number of subjects analysed
    22
    40
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Baseline - Predose
    4.5494 ( 136.1 )
    0.5410 ( 99999 )
        Baseline - Post-dose 1-2 hours(h)
    904.4804 ( 40.3 )
    1126.7272 ( 56.3 )
        Week 4 - Predose
    356.83 ( 79.5 )
    661.31 ( 53.4 )
        Week 4 - Post-dose 1-2 h
    1241.03 ( 40.4 )
    2242.14 ( 37.2 )
        Week 8 - Predose
    402.5 ( 43.1 )
    670.1 ( 50.9 )
        Week 8 - Post-dose 1-2 h
    1327.7 ( 32.3 )
    2342.9 ( 35.2 )
        Week 12 - Predose
    350.0140 ( 57.3 )
    120.2227 ( 100.8 )
    No statistical analyses for this end point

    Secondary: Numbers of Participants Who Experienced At Least 1 Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Numbers of Participants Who Experienced At Least 1 Treatment-emergent Adverse Event (TEAE)
    End point description
    An Adverse Event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical (investigational) product and which did not necessarily have to have a causal relationship with this treatment. TEAEs were events with start dates on or after the date of the first dose of study treatment and up to 28 days after the date of the last dose of study treatment or events with start dates prior to the date of the first dose of study treatment whose severity worsened on or after the date of the first dose of study treatment. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo
    Number of subjects analysed
    22
    40
    36
    Units: Participants
    22
    37
    32
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events of Special Interest (AESI)

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    End point title
    		 Number of Participants with Adverse Events of Special Interest (AESI)
    End point description
    Adverse events of special interest (AESIs) were defined as AEs associated with liver function abnormalities, corrected QT interval (QTc)/cardiac, infections, and neutropenia.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Alvelestat 120 mg Alvelestat 240 mg Placebo
    Number of subjects analysed
    22
    40
    36
    Units: Participants
    5
    11
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to 28 days after date of last dose (Up to Week 16)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Alvelestat 120 mg
    Reporting group description
    		 4 × 30 mg alvelestat and 4 × 30 mg placebo oral tablets taken twice daily (BID) 12 hours apart with water for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 8 × oral placebo tablets BID 12 hours apart with water for 12 weeks.

    Reporting group title
    Alvelestat 240 mg
    Reporting group description
    		 8 × 30 mg alvelestat oral tablets BID 12 hours apart with water for 12 weeks.

    Serious adverse events
    		 Alvelestat 120 mg Placebo Alvelestat 240 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    3 / 40 (7.50%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Alvelestat 120 mg Placebo Alvelestat 240 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    32 / 36 (88.89%)
    37 / 40 (92.50%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    1
    1
    2
    Hypertension
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Varicose vein
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Fatigue
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    1
    1
    2
    Feeling hot
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Malaise
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Sensation of foreign body
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Thirst
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Vaccination site pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Amenorrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Breast calcifications
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 36 (8.33%)
    4 / 40 (10.00%)
         occurrences all number
    1
    3
    4
    Cough
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    1
    Cough decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 36 (2.78%)
    3 / 40 (7.50%)
         occurrences all number
    2
    1
    3
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    1
    Hypoxia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Lung disorder
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Sputum increased
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Investigations
    Platelet count increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Eosinophil count increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Escherichia test positive
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Foreign body in respiratory tract
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Post procedural haematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Tendon injury
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 36 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    4
    0
    5
    Dizziness postural
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Head discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    0
    Headache
         subjects affected / exposed
    7 / 22 (31.82%)
    11 / 36 (30.56%)
    20 / 40 (50.00%)
         occurrences all number
    13
    32
    35
    Migraine
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Syncope
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Ear pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Glaucoma
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Eye swelling
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 36 (8.33%)
    0 / 40 (0.00%)
         occurrences all number
    0
    3
    0
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    2
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    2
    Enteritis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Eructation
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Flatulence
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    3
    1
    Frequent bowel movements
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    5
    Nausea
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 36 (2.78%)
    5 / 40 (12.50%)
         occurrences all number
    4
    1
    8
    Vomiting
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    3
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Acne
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Alopecia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Polyuria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    1
    Back pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    0
    2
    Costochondritis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    3
    0
    Myalgia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Tooth abscess
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 22 (0.00%)
    4 / 36 (11.11%)
    2 / 40 (5.00%)
         occurrences all number
    0
    4
    2
    Cystitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    Erysipelas
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    3 / 40 (7.50%)
         occurrences all number
    0
    1
    4
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 22 (0.00%)
    4 / 36 (11.11%)
    4 / 40 (10.00%)
         occurrences all number
    0
    4
    4
    Oral candidiasis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 36 (5.56%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 36 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    2
    0
    2
    Rhinitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Viral infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 36 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 36 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    1
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 36 (2.78%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2018
    Clarifications and corrections.
    02 Jul 2018
    Amendments to inclusion/exclusion criteria and treatment discontinuation criteria for liver function tests at request of FDA.
    15 Aug 2018
    Amendments to the exclusion criteria and description of a potential non-clinical safety risk of phototoxicity and the protective measures for participants to minimize exposure to UV radiation at the request of the FDA.
    30 Jul 2019
    Clarifications and corrections. Amendments to remove the procedures for phototoxicity and the protective measures for participants to minimize exposure to UV radiation.
    05 Dec 2019
    Introduction of within participant dose escalation to improve participant tolerability of the 240 mg bid dose. Simplifications of the protocol.
    07 Jun 2021
    Clarifications and corrections. Amendments to inclusion/exclusion criteria and Concomitant Therapy information
    16 Nov 2021
    Clarifications and corrections. Change to study design from single primary endpoint proof of concept design to multiple (3 mechanistic) primary endpoint, signal-seeking, weight of evidence design with related changes throughout.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Mar 2022
    Trial terminated early due to recruitment difficulties during COVID-19.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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