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    Clinical Trial Results:
    An open-label, non-controlled, multicentre clinical trial of inhaled molgramostim in autoimmune pulmonary proteinosis patients

    Summary
    EudraCT number
    		 2017-004078-32
    Trial protocol
    		 DK   NL   DE   FR   GB   GR   IT  
    Global end of trial date
    14 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Dec 2022
    First version publication date
    28 Jan 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Change of Sponsor contact person

    Trial information

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    Trial identification
    Sponsor protocol code
    SAV006-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03482752
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Savara Pharmaceuticals
    Sponsor organisation address
    6836 Bee Cave Road, Building 3, Suite 201, Austin, United States, TX 78746
    Public contact
    Chief Medical Officer, Savara Inc, +1 5127848757, ray.pratt@savarapharma.com
    Scientific contact
    Chief Medical Officer, Savara Inc, +1 5127848757, ray.pratt@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
    05 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate safety of long-term use of inhaled molgramostim nebulizer solution.
    Protection of trial subjects
    Subjects were free to discontinue their participation in the trial at any time with no prejudice or effect on the subject’s further care or treatment. Subjects could be discontinued from treatment and assessments at any time, if deemed necessary by the investigator. Pulmonary function and respiratory symptoms were monitored during the trial and treatment were to be discontinued if significant worsening occurred. Pregnancy testing was performed in women of childbearing potential at each trial visit where molgramostim was dispensed and at home at monthly intervals during treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2018
    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
    Turkey: 7
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 9
    Worldwide total number of subjects
    60
    EEA total number of subjects
    38
    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)
    55
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 SAV006-03 was an open-label extension trial for subjects who had completed MOL-PAP-002. Among the 30 sites enrolling subjects in MOL-PAP-002, 13 sites participated in SAV006-03.

    Pre-assignment
    Screening details
    		 SAV006-03 enrolled subjects who had completed MOL-PAP-002. A total of 62 subjects were screened and 60 were enrolled. The same dose regimen was used in SAV006-03 as was used in the follow-up period of MOL-PAP-002 (molgramostim nebulizer solution 300 μg intermittently, repetitive cycles of 7 days of treatment - 7 days off-treatment).

    Period 1
    Period 1 title
    Open-label treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Molgramostim nebulizer solution (300 μg)
    Arm description
    		 Open-label treatment with molgramostim nebulizer solution (300 μg) administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Molgramostim nebulizer solution (300 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and dispersion for nebuliser dispersion
    Routes of administration
    Inhalation use
    Dosage and administration details
    Molgramostim nebulizer solution (300 μg) was administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment). It was administered using an investigational version of the PARI nebulizer system (eFlow), adapted specifically for the delivery of molgramostim nebulizer solution by PARI Pharma GmbH, Germany. Subjects were to administer the first dose at the baseline visit under the supervision of trial personnel, unless they had already dosed within the MOL-PAP-002 trial on the same day, and were retrained in administration and medical device maintenance procedure, if required. The molgramostim nebulizer solution was administered once daily with no defined timing in relation to time of day or meals.

    Number of subjects in period 1
    		Molgramostim nebulizer solution (300 μg)
    Started
    60
    Completed
    0
    Not completed
    60
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    2
         Early termination of trial
    56
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Molgramostim nebulizer solution (300 μg)
    Reporting group description
    		 Open-label treatment with molgramostim nebulizer solution (300 μg) administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment).

    Reporting group values
    		 Molgramostim nebulizer solution (300 μg) Total
    Number of subjects
    		 60 60
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 55 55
        From 65-84 years
    		 5 5
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 36 36
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set included all subjects enrolled into the trial.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included all enrolled subjects who were exposed to molgramostim nebulizer solution in SAV006-03.

    Subject analysis sets values
    		 Full analysis set Safety analysis set
    Number of subjects
    60
    59
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    55
    54
        From 65-84 years
    5
    5
    Age continuous
    Units:
        
    46.8 ± 13.5
    ±
    Gender categorical
    Units: Subjects
        Female
    24
    24
        Male
    36
    35

    End points

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    End points reporting groups
    Reporting group title
    Molgramostim nebulizer solution (300 μg)
    Reporting group description
    		 Open-label treatment with molgramostim nebulizer solution (300 μg) administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment).

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set included all subjects enrolled into the trial.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included all enrolled subjects who were exposed to molgramostim nebulizer solution in SAV006-03.

    Primary: Number of adverse events (AEs)

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    End point title
    		 Number of adverse events (AEs) [1]
    End point description
    The primary objective of this trial was safety assessed by AE reporting. Definitions and reporting procedures for AEs were done according to current regulatory standards. AEs were collected by the investigator by a non-leading question and by reporting events directly observed or spontaneously volunteered by subjects. Subjects were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns.
    End point type
    Primary
    End point timeframe
    AEs were collected from the baseline visit up to a follow-up telephone call, which ocurred 2 weeks after trial completion (i.e. Week 158).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: According to the protocol, no hypothesis/statistical testing was planned for any of the endpoints of this long-term safety extension study but only descriptive statistics were to be used.
    End point values
    		 Molgramostim nebulizer solution (300 μg) Safety analysis set
    Number of subjects analysed
    59
    59
    Units: event
    165
    165
    No statistical analyses for this end point

    Primary: Number of serious adverse events (SAEs)

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    End point title
    		 Number of serious adverse events (SAEs) [2]
    End point description
    End point type
    Primary
    End point timeframe
    SAEs were collected from the baseline visit up to a follow-up telephone call, which ocurred 2 weeks after trial completion (i.e. Week 158).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: According to the protocol, no hypothesis/statistical testing was planned for any of the endpoints of this long-term safety extension study but only descriptive statistics were to be used.
    End point values
    		 Molgramostim nebulizer solution (300 μg) Safety analysis set
    Number of subjects analysed
    59
    59
    Units: events
    8
    8
    No statistical analyses for this end point

    Primary: Number of adverse drug reactions (ADRs)

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    End point title
    		 Number of adverse drug reactions (ADRs) [3]
    End point description
    All AEs were assessed by the investigator for causality (unlikely, possible, probable, not applicable) according to current regulatory standards. AEs which had a 'possible' or 'probable' cauality were classified as ADRs.
    End point type
    Primary
    End point timeframe
    AEs were collected from the baseline visit up to a follow-up telephone call, which ocurred 2 weeks after trial completion (i.e. Week 158).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: According to the protocol, no hypothesis/statistical testing was planned for any of the endpoints of this long-term safety extension study but only descriptive statistics were to be used.
    End point values
    		 Molgramostim nebulizer solution (300 μg) Safety analysis set
    Number of subjects analysed
    59
    59
    Units: events
    3
    3
    No statistical analyses for this end point

    Primary: Number of adverse events leading to treatment discontinuation

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    End point title
    		 Number of adverse events leading to treatment discontinuation [4]
    End point description
    End point type
    Primary
    End point timeframe
    AEs were collected from the baseline visit up to a follow-up telephone call, which ocurred 2 weeks after trial completion (i.e. Week 158).
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: According to the protocol, no hypothesis/statistical testing was planned for any of the endpoints of this long-term safety extension study but only descriptive statistics were to be used.
    End point values
    		 Molgramostim nebulizer solution (300 μg) Safety analysis set
    Number of subjects analysed
    59
    59
    Units: events
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the baseline visit up to a follow-up telephone call, which ocurred 2 weeks after trial completion (i.e. Week 158).
    Adverse event reporting additional description
    AEs were collected by the investigator by a non-leading question and by reporting events directly observed or spontaneously volunteered by subjects. Subjects were also encouraged to contact the clinic in between visits if they experienced adverse events or had any concerns.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    		 -

    Serious adverse events
    		 Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 59 (13.56%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Alveolar proteinosis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    HIV infection CDC Group IV subgroup A
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 59 (64.41%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 59 (11.86%)
         occurrences all number
    7
    Alveolar proteinosis
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    5
    Dyspnoea
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 59 (11.86%)
         occurrences all number
    7
    Respiratory tract infection
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    7
    COVID-19
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Bronchitis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    6
    Pneumonia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2018
    Changes implemented in 2 local amendments were made global in substantial global amendment 3.0. In addition: - Revision of note to inclusion criterion 2. - Exploratory endpoint added for GM-CSF levels before and 2 hours after dosing. - Clarification that spirometry and DLCO should be performed in accordance with ERS/ATS guidance.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Jan 2021
    SAV006-03 was initiated before the evaluation and advice on the MOL-PAP-002 results which investigated an intermittent dosing regimen as well as continuous (daily) dosing regimen. The continuous daily dosing regimen did demonstrate clinical improvements in patients with aPAP and will continue to be investigated in a phase 3 confirmatory study. Considering the MOL-PAP-002 results and the authority advice, there would not be adequate efficacy and safety data on the intermittent dosing regimen to support a marketing authorization application for this regimen. Consequently, the sponsor decided to discontinue SAV006-03. At the point of termination, 60 subjects were enrolled in the trial. As expected, due to the early termination, the number of subjects decreased during the trial. However, 44 subjects (74.6%) reached ≥12 months of exposure and 15 subjects (25.4%) reached ≥24 months of exposure.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Efficacy endpoints were secondary and no hypothesis testing was carried out. Due to early termination, limited efficacy data were available for evaluation an in general, firm conclusion based on efficacy data are not applicable.
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    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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