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    Clinical Trial Results:
    A Randomised, Double-Blind, Placebo-Controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients.

    Summary
    EudraCT number
    		 2015-003878-33
    Trial protocol
    		 GB   DK   NL   DE   GR   ES   IT   PT  
    Global end of trial date
    27 Sep 2019

    Results information
    Results version number
    		 v1
    This version publication date
    18 Feb 2021
    First version publication date
    18 Feb 2021
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MOL-PAP-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02702180
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IMPALA: IMPALA
    Sponsors
    Sponsor organisation name
    Savara ApS
    Sponsor organisation address
    Slotsmarken 17, 1.th., Hørsholm, Denmark, DK-2970
    Public contact
    Cecilia Ganslandt, Savara ApS, +45 79301414, info@savarapharma.com
    Scientific contact
    Cecilia Ganslandt, Savara ApS, +45 79301414, info@savarapharma.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
    08 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare efficacy of inhaled molgramostim on the Alveolar-arterial oxygen difference ((A-a)DO2) with placebo after 24-weeks treatment.
    Protection of trial subjects
    Subjects could be discontinued from treatment and assessments at any time, if deemed necessary by the investigator. Potential reasons for discontinuation of treatment included lack of efficacy/worsening of disease and unacceptable AE. WLL was applied as rescue therapy. The criterion for performing WLL was clinical worsening of aPAP based on symptoms, reduced exercise capacity and/or findings of hypoxemia or desaturation according to the investigator’s judgement.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2016
    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
    Switzerland: 1
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 13
    Worldwide total number of subjects
    138
    EEA total number of subjects
    61
    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)
    113
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Key incl. criteria: aPAP (diagnosed by CT/biopsy/BAL, and increased GM-CSF autoantibodies); confirmed stable/progressive for ≥2 months prior to Baseline; (A-a)DO2 ≥25 mmHg; PaO2 <75 mmHg at rest/desaturation >4 % points in 6MWT. 235 were screened. 138 entered the DB period. Most Scr. failures were related to key incl. criteria listed above.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MOL-OD
    Arm description
    		 Molgramostim 300 µg nebuliser solution administered once-daily; referred to as MOL-OD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Molgramostim nebuliser solution 300 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Molgramostim nebuliser solution 300 μg, administered once-daily by inhalation using an investigational eFlow® Nebuliser System.

    Arm title
    		 MOL-INT
    Arm description
    		 Molgramostim 300 µg nebuliser solution and matching placebo administered intermittently (12 cycles of 7 days molgramostim nebuliser solution, 7 days placebo; both administered once-daily); referred to as MOL-INT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Molgramostim nebuliser solution 300 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Molgramostim nebuliser solution 300 μg, administered once-daily every other week by inhalation using an investigational eFlow® Nebuliser System.

    Investigational medicinal product name
    Placebo nebuliser solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo nebuliser solution administered once-daily every other week by inhalation using an investigational eFlow® Nebuliser System.

    Arm title
    		 Placebo
    Arm description
    		 Placebo nebuliser solution administered once-daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo nebuliser solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo nebuliser solution administered once-daily by inhalation using an investigational eFlow® Nebuliser System.

    Number of subjects in period 1
    		MOL-OD MOL-INT Placebo
    Started
    46
    45
    47
    Completed
    45
    44
    43
    Not completed
    1
    1
    4
         Consent withdrawn by subject
    1
    1
    -
         Adverse event, non-fatal
    -
    -
    1
         Lack of efficacy
    -
    -
    1
         Protocol deviation
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MOL-OD
    Reporting group description
    		 Molgramostim 300 µg nebuliser solution administered once-daily; referred to as MOL-OD.

    Reporting group title
    MOL-INT
    Reporting group description
    		 Molgramostim 300 µg nebuliser solution and matching placebo administered intermittently (12 cycles of 7 days molgramostim nebuliser solution, 7 days placebo; both administered once-daily); referred to as MOL-INT.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo nebuliser solution administered once-daily.

    Reporting group values
    		 MOL-OD MOL-INT Placebo Total
    Number of subjects
    		 46 45 47 138
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 34 38 41 113
        From 65-84 years
    		 12 7 6 25
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.0 ( 13.32 ) 49.2 ( 14.06 ) 46.1 ( 14.84 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 19 22 59
        Male
    		 28 26 25 79

    End points

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    End points reporting groups
    Reporting group title
    MOL-OD
    Reporting group description
    		 Molgramostim 300 µg nebuliser solution administered once-daily; referred to as MOL-OD.

    Reporting group title
    MOL-INT
    Reporting group description
    		 Molgramostim 300 µg nebuliser solution and matching placebo administered intermittently (12 cycles of 7 days molgramostim nebuliser solution, 7 days placebo; both administered once-daily); referred to as MOL-INT.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo nebuliser solution administered once-daily.

    Primary: Absolute change from baseline of (A-a)DO2

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    End point title
    		 Absolute change from baseline of (A-a)DO2
    End point description
    Absolute change from baseline of (A-a)DO2 after 24 weeks of treatment.
    End point type
    Primary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    45
    43
    43
    Units: mmHg
        arithmetic mean (standard deviation)
    -12.1 ( 14.58 )
    -11.7 ( 17.06 )
    -8.8 ( 16.14 )
    Statistical analysis title
    		 Analysis of primary endpoint (FAS)
    Comparison groups
    MOL-OD v Placebo
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1688
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.1
         upper limit
    		 2
    Statistical analysis title
    		 Analysis of primary endpoint (FAS)
    Comparison groups
    MOL-INT v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3968
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 3.7

    Secondary: Change from baseline in 6 minute walking distance (6MWD)

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    End point title
    		 Change from baseline in 6 minute walking distance (6MWD)
    End point description
    Change from baseline in 6MWD after 24 weeks of treatment. This was a Key Secondary Endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    43
    43
    43
    Units: meters
        arithmetic mean (standard deviation)
    39.6 ( 95.89 )
    11.3 ( 81.94 )
    6.0 ( 110.46 )
    Statistical analysis title
    		 Analysis of key secondary endpoint (FAS)
    Comparison groups
    MOL-OD v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3159 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    20.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.8
         upper limit
    		 61
    Notes
    [1] - Not adjusted for multiplicity.
    Statistical analysis title
    		 Analysis of key secondary endpoint (FAS)
    Comparison groups
    MOL-INT v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7809 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.1
         upper limit
    		 45.2
    Notes
    [2] - Not adjusted for multiplicity.

    Secondary: Change from baseline in the St. George’s Respiratory Questionnaire (SGRQ) total score

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    End point title
    		 Change from baseline in the St. George’s Respiratory Questionnaire (SGRQ) total score
    End point description
    Change from baseline in SGRQ total score after 24 weeks of treatment. SGRQ scores (total and components) range from 0 to 100, with higher scores indicating more limitations. This was a Key Secondary Endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    45
    44
    43
    Units: Score
        arithmetic mean (standard deviation)
    -12.3 ( 14.30 )
    -12.0 ( 15.12 )
    -4.7 ( 12.83 )
    Statistical analysis title
    		 Analysis of key secondary endpoint (FAS)
    Comparison groups
    MOL-OD v Placebo
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0103 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    -7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 -1.8
    Notes
    [3] - Not adjusted for multiplicity.
    Statistical analysis title
    		 Analysis of key secondary endpoint (FAS)
    Comparison groups
    MOL-INT v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0173 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    -7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.7
         upper limit
    		 -1.3
    Notes
    [4] - Not adjusted for multiplicity.

    Secondary: Time to WLL during 24 weeks of treatment

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    End point title
    		 Time to WLL during 24 weeks of treatment
    End point description
    Time to need for WLL during 24 weeks of treatment. This was a Key Secondary Endpoint. The median time to WLL could not be estimated due to the small number of events.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    46
    45
    47
    Units: Number of subjects in need of WLL
    4
    4
    6
    Statistical analysis title
    		 Analysis of key secondary endpoint (FAS)
    Comparison groups
    MOL-OD v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4934 [5]
    Method
    		 Logrank
    Confidence interval
    Notes
    [5] - Not adjusted for multiplicity.
    Statistical analysis title
    		 Analysis of key secondary endpoint (FAS)
    Comparison groups
    MOL-INT v Placebo
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4787 [6]
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - Not adjusted for multiplicity.

    Secondary: Change from baseline in DLCO (% predicted)

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    End point title
    		 Change from baseline in DLCO (% predicted)
    End point description
    Absolute change from baseline in DLCO (% predicted) after 24 weeks of treatment. Hemoglobin-adjusted values were used. This was a Further Secondary Endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    43
    43
    42
    Units: % predicted
        arithmetic mean (standard deviation)
    11.6 ( 17.30 )
    7.7 ( 11.41 )
    3.9 ( 10.86 )
    Statistical analysis title
    		 Analysis of further secondary endpoint (FAS)
    Comparison groups
    MOL-OD v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0074 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    7.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 13.6
    Notes
    [7] - No adjustment for multiplicity.
    Statistical analysis title
    		 Analysis of further secondary endpoint (FAS)
    Comparison groups
    MOL-INT v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3097 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LSmean difference
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 8.7
    Notes
    [8] - No adjustment for multiplicity.

    Secondary: Number of serious adverse events (SAEs)

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    End point title
    		 Number of serious adverse events (SAEs)
    End point description
    Number of SAEs reported during 24 weeks of treatment
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    46
    45
    47
    Units: Number of events
    13
    5
    16
    No statistical analyses for this end point

    Secondary: Number of adverse drug reactions (ADRs)

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    End point title
    		 Number of adverse drug reactions (ADRs)
    End point description
    Number of ADRs (AEs with relation to IP = probable or possible) reported during 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    46
    45
    47
    Units: Number of events
    53
    27
    33
    No statistical analyses for this end point

    Secondary: Number of severe adverse events

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    End point title
    		 Number of severe adverse events
    End point description
    Number of severe AEs reported during 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    46
    45
    47
    Units: Number of events
    28
    11
    38
    No statistical analyses for this end point

    Secondary: Adverse events leading to treatment discontinuation

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    End point title
    		 Adverse events leading to treatment discontinuation
    End point description
    Number of subjects with one or more AEs leading to treatment discontinuation during 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    46
    45
    47
    Units: Number of subjects with events
    2
    1
    1
    No statistical analyses for this end point

    Secondary: Number of adverse events

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    End point title
    		 Number of adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 24.
    End point values
    		 MOL-OD MOL-INT Placebo
    Number of subjects analysed
    46
    45
    47
    Units: Number of events
    215
    191
    192
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Week 24.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    MOL-OD
    Reporting group description
    		 Molgramostim 300 µg nebuliser solution administered once-daily (referred to as MOL-OD)

    Reporting group title
    MOL-INT
    Reporting group description
    		 Molgramostim 300 µg nebuliser solution and matching placebo administered intermittently (12 cycles of 7 days molgramostim nebuliser solution, 7 days placebo; both administered once daily); referred to as MOL-INT.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo nebuliser solution administered once-daily.

    Serious adverse events
    		 MOL-OD MOL-INT Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 46 (17.39%)
    5 / 45 (11.11%)
    8 / 47 (17.02%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Drug detoxification
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Alveolar proteinosis
         subjects affected / exposed
    3 / 46 (6.52%)
    3 / 45 (6.67%)
    6 / 47 (12.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Gambling disorder
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia bacterial
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 45 (2.22%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 45 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 45 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 MOL-OD MOL-INT Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 46 (84.78%)
    41 / 45 (91.11%)
    40 / 47 (85.11%)
    Investigations
    Weight increased
         subjects affected / exposed
    3 / 46 (6.52%)
    5 / 45 (11.11%)
    0 / 47 (0.00%)
         occurrences all number
    4
    6
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 46 (13.04%)
    7 / 45 (15.56%)
    7 / 47 (14.89%)
         occurrences all number
    9
    9
    16
    Dizziness
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 45 (4.44%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    4
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    10 / 46 (21.74%)
    2 / 45 (4.44%)
    1 / 47 (2.13%)
         occurrences all number
    11
    2
    2
    Pyrexia
         subjects affected / exposed
    2 / 46 (4.35%)
    3 / 45 (6.67%)
    3 / 47 (6.38%)
         occurrences all number
    2
    3
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 46 (0.00%)
    6 / 45 (13.33%)
    3 / 47 (6.38%)
         occurrences all number
    0
    6
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 46 (32.61%)
    12 / 45 (26.67%)
    11 / 47 (23.40%)
         occurrences all number
    22
    18
    12
    Dyspnoea
         subjects affected / exposed
    5 / 46 (10.87%)
    7 / 45 (15.56%)
    4 / 47 (8.51%)
         occurrences all number
    8
    7
    5
    Alveolar proteinosis
         subjects affected / exposed
    3 / 46 (6.52%)
    5 / 45 (11.11%)
    8 / 47 (17.02%)
         occurrences all number
    4
    5
    18
    Productive cough
         subjects affected / exposed
    4 / 46 (8.70%)
    3 / 45 (6.67%)
    3 / 47 (6.38%)
         occurrences all number
    5
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 46 (4.35%)
    3 / 45 (6.67%)
    1 / 47 (2.13%)
         occurrences all number
    5
    4
    1
    Arthralgia
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 45 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    2
    0
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 46 (15.22%)
    10 / 45 (22.22%)
    6 / 47 (12.77%)
         occurrences all number
    10
    12
    6
    Respiratory tract infection
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 45 (4.44%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 45 (6.67%)
    3 / 47 (6.38%)
         occurrences all number
    0
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jan 2016
    Additions reflecting 1) the implementation of a data safety monitoring board and 2) new data from long-term toxicity study.
    11 Oct 2016
    Exclusion criteria regarding immunosuppressive treatment updated to only include treatment causing significant immunosuppression. Exclusion criterion regarding liver impairment changed to from 3 to 4 times the upper limit of aspartate aminotransferase and alanine aminotransferase. Open-label FU treatment changed from only to be given in case of worsening of (A-a)DO2 of more than 10 mmHg from baseline, to be given according to investigator’s discretion and if so, dosed intermittently 7-days on / 7-days off treatment for 24 weeks, thereafter dosing according to investigator’s judgement. Criterion for rescue treatment revised to comprise an overall evaluation of treatment requirement by the investigator, including symptoms reported by the patient, rather than only in case of worsening of (A-a)DO2 of more than 10 mmHg from baseline. Analysis for antibodies against the excipients polyethylene glycol and recombinant human albumin were added.
    06 Jun 2017
    Sample size increased to 90 randomized. Updates to key efficacy objectives/endpoints (3 key secondary: 6MWT, SGRQ, WLL). Key secondary objective for safety added. FU for subjects included after this amendment is 24 weeks. FU for subjects included before is 48 weeks. Molgramostim treatment in the FU period applied for all subjects. Additional efficacy assessments (dyspnea, cough, quality of life) and safety laboratory assessments added in the FU period. Possibility to conduct WLL in the screening period removed. Exclusion criterion re. time since last WLL reduced to 1 month, criteria re. liver/renal impairment removed. Statistical methods updated (e.g., to account for multiplicity of key secondary endpoints). Assessment of anti-drug-antibodies added at week 4.
    01 Dec 2017
    Plan for blinded sample size re-estimation added. Statistical methodology for the primary analyses aligned across regions.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32897035
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