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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-group, Multi-center Study of an Inhaled Pan-Janus Kinase Inhibitor, TD-0903, to Treat Symptomatic Acute Lung Injury Associated with COVID-19

    Summary
    EudraCT number
    		 2020-001807-18
    Trial protocol
    		 GB   RO   FI  
    Global end of trial date
    21 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2022
    First version publication date
    13 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TD-0903-0188
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04402866
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Theravance Biopharma
    Sponsor organisation address
    Connaught House, 1 Burlington Road, Dublin, Ireland, D04 C5Y6
    Public contact
    Medical Monitor, Theravance Biopharma, 1 855-633-8479 , medinfo@theravance.com
    Scientific contact
    Medical Monitor, Theravance Biopharma, 1 855-633-8479 , medinfo@theravance.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
    21 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to characterize the efficacy of TD-0903 as measured by respiratory failure-free days (RFDs) through Day 28.
    Protection of trial subjects
    This trial was designed and monitored in accordance with Sponsor procedures, which comply with the ethical principles of good clinical practice as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    Moldova, Republic of: 72
    Country: Number of subjects enrolled
    Ukraine: 108
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    235
    EEA total number of subjects
    5
    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)
    155
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 235 participants were enrolled across 18 sites in the United States, Brazil, Finland, the Republic of Moldova, Ukraine and the United Kingdom.

    Pre-assignment
    Screening details
    		 235 participants were enrolled and 230 participants were randomized and treated with study drug. Within each cohort in Part 1 (multiple-ascending dose design), participants were randomized 3:1, TD-0903 to placebo. During Part 2 (parallel-group design), participants were randomized 1:1, TD-0903 to placebo.

    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
    		 Part 1: Matching Placebo
    Arm description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo was administered by oral inhalation.

    Arm title
    		 Part 1: TD-0903 - 1 mg
    Arm description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TD-0903
    Investigational medicinal product code
    Other name
    nezulcitinib
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TD-0903 was administered by oral inhalation.

    Arm title
    		 Part 1: TD-0903 - 3 mg
    Arm description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TD-0903
    Investigational medicinal product code
    Other name
    nezulcitinib
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TD-0903 was administered by oral inhalation.

    Arm title
    		 Part 1: TD-0903 - 10 mg
    Arm description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TD-0903
    Investigational medicinal product code
    Other name
    nezulcitinib
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TD-0903 was administered by oral inhalation.

    Arm title
    		 Part 2: Matching Placebo
    Arm description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo was administered by oral inhalation.

    Arm title
    		 Part 2: TD-0903 - 3 mg
    Arm description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TD-0903
    Investigational medicinal product code
    Other name
    nezulcitinib
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TD-0903 was administered by oral inhalation.

    Number of subjects in period 1
    		Part 1: Matching Placebo Part 1: TD-0903 - 1 mg Part 1: TD-0903 - 3 mg Part 1: TD-0903 - 10 mg Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Started
    6
    6
    7
    6
    104
    106
    Randomized and Treated With Study Drug
    6
    6
    7
    6
    102
    103
    Completed
    4
    5
    6
    6
    89
    92
    Not completed
    2
    1
    1
    0
    15
    14
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    2
         Adverse event, non-fatal
    2
    1
    -
    -
    13
    8
         Discontinued Prior to Treatment
    -
    -
    -
    -
    2
    3
         Miscellaneous
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Matching Placebo
    Reporting group description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.

    Reporting group title
    Part 1: TD-0903 - 1 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1.

    Reporting group title
    Part 1: TD-0903 - 3 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.

    Reporting group title
    Part 1: TD-0903 - 10 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.

    Reporting group title
    Part 2: Matching Placebo
    Reporting group description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.

    Reporting group title
    Part 2: TD-0903 - 3 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.

    Reporting group values
    		 Part 1: Matching Placebo Part 1: TD-0903 - 1 mg Part 1: TD-0903 - 3 mg Part 1: TD-0903 - 10 mg Part 2: Matching Placebo Part 2: TD-0903 - 3 mg Total
    Number of subjects
    		 6 6 7 6 104 106 235
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.2 ( 16.94 ) 59.5 ( 15.49 ) 62.0 ( 3.27 ) 52.8 ( 13.41 ) 58.1 ( 12.54 ) 58.3 ( 12.42 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 3 1 41 41 90
        Male
    		 3 5 4 5 63 65 145
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 10 14 24
        Not Hispanic or Latino
    		 6 6 7 6 90 89 204
        Unknown or Not Reported
    		 0 0 0 0 4 3 7
    Race
    Units: Subjects
        Asian
    		 1 0 0 0 0 0 1
        Black or African American
    		 0 0 0 0 0 2 2
        White
    		 5 6 7 6 102 104 230
        More Than One Race
    		 0 0 0 0 1 0 1
        Other
    		 0 0 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Matching Placebo
    Reporting group description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.

    Reporting group title
    Part 1: TD-0903 - 1 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1.

    Reporting group title
    Part 1: TD-0903 - 3 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.

    Reporting group title
    Part 1: TD-0903 - 10 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.

    Reporting group title
    Part 2: Matching Placebo
    Reporting group description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.

    Reporting group title
    Part 2: TD-0903 - 3 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.

    Primary: Part 2: Number of RFDs From Randomization to Day 28

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    End point title
    		 Part 2: Number of RFDs From Randomization to Day 28 [1]
    End point description
    An RFD was defined as a day that a participant was alive and did not require the use of any respiratory support (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow oxygen devices, or oxygen supplementation) from randomization through Day 28. The number of RFDs was 0 for participants who used respiratory support for 28 days or longer or for participants who died on or before Day 28. A clinical status score of ≤ 4 on a given day was equivalent to an RFD. The clinical status categories and associated scores ranged from 1-8 where a higher score represented a worse outcome. A clinical status score of 4 was defined as a participant who was hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (whether or not related to COVID-19). Intent-to-Treat (ITT) analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
    End point type
    Primary
    End point timeframe
    Randomization to Day 28
    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: Statistical analysis was pre-specified for Part 2 only.
    End point values
    		 Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Number of subjects analysed
    102
    100
    Units: days
        median (inter-quartile range (Q1-Q3))
    21.0 (15.0 to 23.0)
    21.0 (17.5 to 23.0)
    Statistical analysis title
    		 Part 2: Matching Placebo versus (vs) TD-0903 3 mg
    Statistical analysis description
    Common Odds Ratio (TD-0903 vs placebo) and corresponding 95% Wald confidence interval were obtained from the proportional odds regression model of RFD adjusting for baseline age strata (≤ 60 years vs > 60 years).
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6137
    Method
    		 Van Elteren test
    Parameter type
    		 Common Odds Ratio
    Point estimate
    1.142
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.706
         upper limit
    		 1.846

    Secondary: Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7

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    End point title
    		 Part 2: Change From Baseline in SaO2/FiO2 Ratio on Day 7 [2]
    End point description
    SaO2/FiO2 ratio was calculated as SaO2 divided by FiO2. ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was pre-specified for Part 2 only.
    End point values
    		 Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Number of subjects analysed
    86
    90
    Units: ratio measure
        least squares mean (standard error)
    88.97 ( 7.769 )
    88.46 ( 7.654 )
    Statistical analysis title
    		 Part 2: Matching Placebo vs TD-0903 3 mg
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.962
    Method
    		 Mixed model repeated measures model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.95
         upper limit
    		 20.92
    Notes
    [3] - Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.

    Secondary: Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28

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    End point title
    		 Part 2: Number of Participants in Each Category of the 8-point Ordinal Clinical Status Scale on Days 7, 14, 21, and 28 [4]
    End point description
    The clinical status categories and associated scores ranged from 1-8 where a higher score represented a worse outcome. The scale was as follows: • Score 1: Not hospitalized, no limitations on activities • Score 2: Not hospitalized, but with limitations on activities and/or requiring home oxygen • Score 3: Hospitalized, not requiring supplemental oxygen, and no longer requiring ongoing medical care • Score 4: Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (whether or not related to COVID-19) • Score 5: Hospitalized, requiring supplemental oxygen • Score 6: Hospitalized, on non-invasive ventilation or high-flow oxygen devices • Score 7: Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation • Score 8: Death. ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21 and 28
    Notes
    [4] - 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: Statistical analysis was pre-specified for Part 2 only.
    End point values
    		 Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Number of subjects analysed
    102 [5]
    100 [6]
    Units: participants
        Day 7: Score 1
    6
    8
        Day 7: Score 2
    12
    9
        Day 7: Score 3
    1
    1
        Day 7: Score 4
    25
    23
        Day 7: Score 5
    42
    48
        Day 7: Score 6
    7
    7
        Day 7: Score 7
    7
    2
        Day 7: Score 8
    2
    1
        Day 14: Score 1
    57
    52
        Day 14: Score 2
    6
    11
        Day 14: Score 3
    2
    7
        Day 14: Score 4
    14
    13
        Day 14: Score 5
    10
    7
        Day 14: Score 6
    1
    2
        Day 14: Score 7
    6
    5
        Day 14: Score 8
    6
    2
        Day 21: Score 1
    72
    72
        Day 21: Score 2
    4
    9
        Day 21: Score 3
    4
    6
        Day 21: Score 4
    4
    0
        Day 21: Score 5
    3
    4
        Day 21: Score 6
    1
    0
        Day 21: Score 7
    2
    3
        Day 21: Score 8
    12
    5
        Day 28: Score 1
    79
    78
        Day 28: Score 2
    5
    11
        Day 28: Score 3
    0
    1
        Day 28: Score 4
    1
    1
        Day 28: Score 5
    3
    1
        Day 28: Score 6
    0
    0
        Day 28: Score 7
    1
    2
        Day 28: Score 8
    13
    6
    Notes
    [5] - Day 7: n = 102 Day 14: n = 102 Day 21: n = 102 Day 28: n = 102
    [6] - Day 7: n = 99 Day 14: n = 99 Day 21: n = 99 Day 28: n = 100
    Statistical analysis title
    		 Part 2: Matching Placebo vs TD-0903 3 mg on Day 7
    Statistical analysis description
    Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs > 60 years).
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.5918
    Method
    		 Van Elteren test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.153
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.692
         upper limit
    		 1.922
    Notes
    [7] - Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
    Statistical analysis title
    		 Part 2: Matching Placebo vs TD-0903 3 mg on Day 14
    Statistical analysis description
    Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs > 60 years).
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.6978
    Method
    		 Van Elteren test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.651
         upper limit
    		 1.878
    Notes
    [8] - Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
    Statistical analysis title
    		 Part 2: Matching Placebo vs TD-0903 3 mg on Day 21
    Statistical analysis description
    Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs > 60 years).
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.399
    Method
    		 Van Elteren test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.295
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.702
         upper limit
    		 2.388
    Notes
    [9] - Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
    Statistical analysis title
    		 Part 2: Matching Placebo vs TD-0903 3 mg on Day 28
    Statistical analysis description
    Between-group comparisons analyzed using a proportional odds model adjusting for baseline age strata (≤ 60 years vs > 60 years).
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.6445
    Method
    		 Van Elteren test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.605
         upper limit
    		 2.299
    Notes
    [10] - Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.

    Secondary: Part 2: Number of Participants Alive and Respiratory Failure-free on Day 28

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    End point title
    		 Part 2: Number of Participants Alive and Respiratory Failure-free on Day 28 [11]
    End point description
    Defined as participants who were alive and did not require the use of any respiratory support (invasive mechanical ventilation, non-invasive positive pressure ventilation, high-flow oxygen devices, or oxygen supplementation) on Day 28. ITT analysis set (Part 2) - all participants with analyzable data who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    Day 28
    Notes
    [11] - 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: Statistical analysis was pre-specified for Part 2 only.
    End point values
    		 Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Number of subjects analysed
    104
    106
    Units: participants
    85
    92
    Statistical analysis title
    		 Part 2: Matching Placebo vs TD-0903 3 mg
    Comparison groups
    Part 2: Matching Placebo v Part 2: TD-0903 - 3 mg
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.3005 [13]
    Method
    		 Cochran-Mantel-Haenszel chi-square test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 14.63
    Notes
    [12] - Since this was a Phase 2 study, it was not powered for any of the secondary endpoints.
    [13] - The p-value was calculated using the Cochran-Mantel-Haenszel chi-square test stratified by baseline age group (≤ 60 years vs > 60 years).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Day 28
    Adverse event reporting additional description
    Safety analysis set - all participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Part 1: Matching Placebo
    Reporting group description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.

    Reporting group title
    Part 1: TD-0903 - 1 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 1 mg. Participants were administered a 2 mg loading dose as the total dose on Day 1.

    Reporting group title
    Part 1: TD-0903 - 3 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.

    Reporting group title
    Part 1: TD-0903 - 10 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 10 mg.

    Reporting group title
    Part 2: Matching Placebo
    Reporting group description
    		 Matching placebo inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system.

    Reporting group title
    Part 2: TD-0903 - 3 mg
    Reporting group description
    		 TD-0903 inhalation solution (1 mL) was administered once daily for up to 7 days via oral inhalation using the Aerogen Solo nebulizer system at a dose of 3 mg. Participants were administered a 6 mg loading dose as the total dose on Day 1.

    Serious adverse events
    		 Part 1: Matching Placebo Part 1: TD-0903 - 1 mg Part 1: TD-0903 - 3 mg Part 1: TD-0903 - 10 mg Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    16 / 102 (15.69%)
    10 / 103 (9.71%)
         number of deaths (all causes)
    2
    1
    0
    0
    13
    6
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 102 (1.96%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 102 (1.96%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    Sudden death
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 102 (2.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    4 / 102 (3.92%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    5 / 102 (4.90%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 102 (2.94%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    COVID-19
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic bacterial infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Matching Placebo Part 1: TD-0903 - 1 mg Part 1: TD-0903 - 3 mg Part 1: TD-0903 - 10 mg Part 2: Matching Placebo Part 2: TD-0903 - 3 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    4 / 6 (66.67%)
    1 / 7 (14.29%)
    5 / 6 (83.33%)
    18 / 102 (17.65%)
    15 / 103 (14.56%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    4 / 103 (3.88%)
         occurrences all number
    0
    1
    0
    0
    0
    4
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 102 (0.98%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    3 / 6 (50.00%)
    1 / 102 (0.98%)
    3 / 103 (2.91%)
         occurrences all number
    0
    0
    0
    4
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    6 / 102 (5.88%)
    5 / 103 (4.85%)
         occurrences all number
    0
    0
    0
    1
    6
    5
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 102 (0.98%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    7 / 102 (6.86%)
    3 / 103 (2.91%)
         occurrences all number
    1
    0
    0
    0
    7
    3
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
         occurrences all number
    3
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 102 (1.96%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vascular device infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 102 (1.96%)
    3 / 103 (2.91%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2020
    Amendment 2, dated 16 May 2020, was classified as a substantial amendment, and included the following non-administrative changes to Amendment 1: - Revisions to the secondary and exploratory objectives. - Reduction in enrollment. - Revisions to blood oxygenation measurements. - Revisions to inclusion and exclusion criteria. - Revisions to dose escalation stopping rules. - Specification that a major violation of the protocol was grounds for study withdrawal by the investigator.
    18 May 2020
    Amendment 2, Revision 1, dated 18 May 2020, was classified as a substantial amendment, and included all of the non-administrative changes listed for Amendment 2, and the following non-administrative changes: - Clarifications on the informed consent procedure. - Revisions to inclusion criteria.
    25 Jun 2020
    Amendment 3, dated 25 June 2020, was classified as a substantial amendment, and included the following non-administrative changes to Amendment 2, Revision 1: - Revisions to inclusion and exclusion criteria. - Revisions to the clinical status scale based on feedback from the United States Food and Drug Administration. - Removal of nasal swab restrictions for COVID-19 testing. - Revisions to the primary, secondary and exploratory objectives. - Revisions to the blinding details. - Removal of discharge criteria language. - Revisions to the informed consent procedure. - Safety Assessment Committee were added. - Revisions to the pharmacokinetic sampling time intervals. - Revision of the assumptions associated with the sample size. - Potential of pooling data from Parts 1 and 2 was removed. - Additional collection, analysis, and storage of plasma samples. - Revisions to the withdrawal criteria.
    18 Sep 2020
    Amendment 4, dated 18 September 2020, was a substantial amendment that consolidated changes from Amendment 3 and Amendment 3.1, and included the following non-administrative changes: - Introduction updated. - Revisions to the primary, secondary and exploratory objectives. - Revisions to the study design. - Modified randomization schedule. - Revisions to the inclusion and exclusion criteria. - Clarification of loading doses. - Revisions to the schedule of study procedures. - Revisions to the assessments associated with clinical outcomes. - Revisions to the list of biomarkers. - Revisions to the list of prohibited concomitant medications. - Clarification of renal disease study equation. - Added language regarding partners of study participants reporting pregnancy. - Clarification that the Safety Assessment Committee was no longer independent of the Sponsor. - Revisions of the assumptions associated with the sample size. - Revisions to the analysis sets.

    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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