IMPALA: Efficacy and Safety of Inhaled Molgramostim (rhGM-CSF) in Autoimmune Pulmonary Alveolar Proteinosis

Sponsor
Savara Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02702180
Collaborator
(none)
139
30
4
42.2
4.6
0.1

Study Details

Study Description

Brief Summary

This study evaluates inhaled molgramostim (recombinant human granulocyte macrophage-colony stimulating factor [rhGM-CSF]) in the treatment of autoimmune pulmonary alveolar proteinosis (aPAP) patients. A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

The trial is a phase 2, randomized, double-blind, placebo-controlled multicentre clinical trial investigating efficacy and safety of inhaled molgramostim (rhGM-CSF) in patients with aPAP.

The trial will include 2 periods; a double-blind treatment period consisting of up to 8 trial visits (Screening, Baseline, and at Weeks 4, 8,12, 16, 20 and 24 after randomisation) and a open-label follow-up period consisting of up to 5 trial visits (at Weeks 4, 12, 24, 36 and 48 post-treatment).

In the double-blind treatment period, eligible subjects will be randomised to treatment for up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily (MOL-OD), 2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (7 days on and 7 days off) (MOL-INT) or 3) inhaled placebo once daily (PBO). During the follow-up period, all participants will receive inhaled molgramostim intermittently (7 days on, 7 days off). During the trial, whole lung lavage (WLL) may be applied as rescue therapy in case of significant clinical worsening.

Study Design

Study Type:
Interventional
Actual Enrollment :
139 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomised, Double-blind, Placebo-controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients
Actual Study Start Date :
Mar 21, 2016
Actual Primary Completion Date :
Apr 19, 2019
Actual Study Completion Date :
Sep 27, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Double-blind molgramostim once daily

Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks

Drug: Molgramostim
300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation
Other Names:
  • rhGM-CSF
  • Device: PARI eFlow nebulizer system
    PARI eFlow nebulizer system

    Experimental: Double-blind molgramostim intermittent

    Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles)

    Drug: Molgramostim
    300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation
    Other Names:
  • rhGM-CSF
  • Device: PARI eFlow nebulizer system
    PARI eFlow nebulizer system

    Placebo Comparator: Double-blind placebo

    Inhalation of placebo nebuliser solution once daily for 24 weeks

    Drug: Placebo
    Placebo nebulizer solution for inhalation

    Device: PARI eFlow nebulizer system
    PARI eFlow nebulizer system

    Experimental: Open-label molgramostim intermittent

    Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period

    Drug: Molgramostim
    300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation
    Other Names:
  • rhGM-CSF
  • Device: PARI eFlow nebulizer system
    PARI eFlow nebulizer system

    Outcome Measures

    Primary Outcome Measures

    1. Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment [From baseline to 24 weeks]

      Measurement of (A-a)DO2 was done by blood gas analysis. An arterial blood sample was collected in the supine position, after resting for at least 10 minutes (or longer if required to achieve stable oxygen saturation). The sample was analyzed for arterial oxygen tension (PaO2) and partial pressure of carbon dioxide (PaCO2). The calculation of (A-a)DO2 was done centrally by using a formula described in the protocol.

    Secondary Outcome Measures

    1. Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment [From baseline to 24 weeks]

      The 6MWD was assessed by the use of 6-minute walking test (6MWT). The 6MWT was performed in accordance with the 2014 ATS/ERS guideline "field walking tests in chronic respiratory disease" (Holland et al. 2014) by technicians with documented training and experience. Where possible, the test was conducted with the participant breathing ambient atmospheric air. If the participant required oxygen supplementation at rest, a titration procedure was carried out as part of the 6MWT at screening in order to determine the oxygen flow rate required for the participant to complete the test. This flow rate was to be used during subsequent tests, if possible.

    2. Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment [From baseline to 24 weeks]

      The SGRQ is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It consists of two parts, where Part 1 covers the participants' recollection of their symptoms over the preceding period (1 month recall used in this trial, Symptoms component) and Part 2 addresses the participants' current state in terms of disturbances to their daily physical activity (Activity component) and a wide range of disturbances of psycho-social function (Impact component). A total score as well as individual component scores were calculated. Scores (total and component) range from 0 to 100, with higher scores indicating more limitations.

    3. Number of Whole Lung Lavage During 24 Weeks of Treatment [From baseline to 24 weeks]

      In all versions of the protocol (no participants were recruited under version 1.0), whole lung lavage (single lung or both lungs) was applied as rescue therapy. In protocol version 2.0, the criterion for performing whole lung lavage was an increase in (A-a)DO2 by more than 10 mmHg/1.33 kilopascal compared to baseline. In protocol version 3.0 onwards, the criterion for performing whole lung lavage was clinical worsening of aPAP based on symptoms, reduced exercise capacity and/or findings of hypoxemia or desaturation according to the investigator's judgement. In protocol versions 2.0 and 3.0, participants undergoing whole lung lavage during the double-blind period were to discontinue double-blind treatment, encouraged to continue to follow the same visit schedule and, if required, receive further whole lung lavage at the investigator's discretion. In protocol version 4.0 and 5.0, participants undergoing whole lung lavage were to continue double-blind treatment.

    4. Number of Adverse Events (AEs) During 24 Weeks of Treatment [From baseline to 24 weeks]

      Treatment-emergent adverse events (AEs) were assessed on or after the first dose of trial drug to 28 days after last dose. Information about AEs was collected by the investigator by a non-leading question such as "have you experienced any new health problems or worsening of existing conditions" and by reporting events directly observed or spontaneously volunteered by participants (e.g., in the Subject Diary Card, where subjects were asked to record any AEs and answer questions regarding lung toxicity and known systemic effects). Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. All AEs were assessed by the investigator for severity (mild, moderate, severe), outcome (recovered, not recovered, recovered with sequelae, fatal, unknown) and causality (unlikely, possible, probable, not applicable) according to current regulatory standards.

    5. Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment [From baseline to 24 weeks]

      SAEs are defined as any untoward medicinal occurrence or effect that at any dose: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Is a congenital anomaly or birth defect May jeopardise the subject or may require intervention to prevent one or more of the other outcomes listed above (Important Medical Events)

    6. Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment [From baseline to 24 weeks]

      All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as ADRs. The expression reasonable causal relationship means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility i.e. the relationship cannot be ruled out.

    7. Number of Severe AEs During 24 Weeks of Treatment [From baseline to 24 weeks]

      All AEs were assessed by the investigator for severity (mild, moderate, severe) according to current regulatory standards: Mild: The AE is easily tolerated and does not interfere with daily activity. Moderate: The AE interferes with daily activity, but the subject is still able to function. Medical intervention may be considered. Severe: The AE is incapacitating and requires medical intervention.

    8. Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment [From baseline to 24 weeks]

      Participants could be discontinued from treatment and assessments at any time, if deemed necessary by the investigator. Potential reasons for discontinuation of treatment included e.g. unacceptable AE.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • aPAP diagnosed by computed tomography, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by increased GM-CSF autoantibodies in serum.

    • Stable or progressive aPAP during a minimum period of 2 months prior to the Baseline visit.

    • Arterial oxygen tension (PaO2) <75 mmHg/<10 kilo Pascal (kPa) at rest, OR desaturation of >4 percentage points on the 6MWT

    • An alveolar-arterial oxygen difference [(A-a)DO2] of minimum 25 mmHg/3.33 kPa

    • Female or male ≥18 years of age

    • Females who have been post-menopausal for >1 year or females of childbearing potential after a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with <1% failure rate such as combined hormonal contraception, progesterone-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence), during and until 30 days after last dose of double-blind trial treatment. Females of childbearing potential must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit

    1. and must not be lactating
    • Males agreeing to use condoms during and until 30 days after last dose of double-blind medication, or males having a female partner who is using adequate contraception as described above

    • Willing and able to provide signed informed consent

    • Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures specified in the protocol as judged by the investigator

    Exclusion Criteria:
    • Diagnosis of hereditary or secondary PAP

    • WLL within 1 month of Baseline

    • Treatment with GM-CSF within 3 months of Baseline

    • Treatment with rituximab within 6 months of Baseline

    • Treatment with plasmapheresis within 3 months of Baseline

    • Treatment with any investigational medicinal product within 4 weeks of Screening

    • Concomitant use of sputum modifying drugs such as carbocysteine or ambroxol

    • History of allergic reactions to GM-CSF

    • Connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring treatment associated with significant immunosuppression, e.g. more than 10 mg/day systemic prednisolone

    • Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product

    • History of, or present, myeloproliferative disease or leukaemia

    • Known active infection (viral, bacterial, fungal or mycobacterial)

    • Apparent pre-existing concurrent pulmonary fibrosis

    • Any other serious medical condition which in the opinion of the investigator would make the participant unsuitable for the trial

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UCLA Los Angeles California United States 90095
    2 University of Florida Gainesville Florida United States 32610
    3 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    4 Royal Prince Alfred Hospital Sydney New South Wales Australia 2050
    5 Aarhus University Hospital Aarhus Denmark
    6 CHU Rennes Hospital Pontchaillou Rennes France
    7 Westdeutsches Lungenzentrum am Universitätsklinikum Essen Essen Germany
    8 Asklepios Fachkliniken München - Gauting Gauting Germany 82131
    9 Thoraxklinik am Universitätsklinikum Heidelberg Heidelberg Germany
    10 Universitätsklinikum Schleswig-Holstein Zentralklinikum, Lübeck Medizinische Klinik III, Pneumologie Lübeck Germany 23538
    11 Attikon University Hospital Athens Greece
    12 Rabin Medical Center Petaẖ Tiqwa Israel
    13 IRCCS Policlinico San Matteo Pavia Italy
    14 Niigata University Medical and Dental Hospital Niigata Japan
    15 National Hospital Organization Kinki-Chuo Osaka Japan
    16 Tohoku University Hospital Sendai Japan
    17 Aichi Medical University Hospital Toyohashi Japan
    18 Kanagawa Cardiovascular and Respiratory Center Yokohama Japan
    19 Seoul National University Hospital Seoul Korea, Republic of 0 3080
    20 Asan Medical Center, Division of Pulmonary and Critical Care Medicine Seoul Korea, Republic of 05505
    21 Samsung Medical Center, Division of Pulmonary and Critical Care Medicine Seoul Korea, Republic of 135-710
    22 St. Antonius Hospital Nieuwegein Netherlands
    23 Hospital de dia de Pneumologia Lisboa Portugal
    24 Hospital Sao Joao Porto Portugal 4200-319
    25 City Hospital St. Petersburg St. Petersburg Russian Federation
    26 II. Pulmonary Department National Institut for TB, Lung Diseases and Chest Surgery Vyšné Hágy Slovakia 05984
    27 Hospital University de Bellvitge (HUB) Barcelona Spain 08907
    28 Centre Hospitalier Universitaire Vaudois Lausanne Switzerland
    29 Yedikule Pulmonary Diseases and Pulmonary Surgery Training and Research Hospital İstanbul Turkey 34020
    30 Royal Brompton Hospital London United Kingdom

    Sponsors and Collaborators

    • Savara Inc.

    Investigators

    • Principal Investigator: Cliff Morgan, MD, Royal Brompton Hospital London

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Savara Inc.
    ClinicalTrials.gov Identifier:
    NCT02702180
    Other Study ID Numbers:
    • MOL-PAP-002
    • 2015-003878-33
    First Posted:
    Mar 8, 2016
    Last Update Posted:
    Apr 15, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    Yes
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details 30 sites in 18 countries (United Kingdom, Denmark, Germany, Italy, France, Greece, Switzerland, Spain, Portugal, Slovakia, Netherlands, Turkey, Russia, Israel, Japan, South Korea, Australia, and the US) enrolled participants in the trial. First participant was enrolled on 21 March 2016 and last subject completed the study on 27 September 2019.
    Pre-assignment Detail A total of 235 participants were screened, and 138 were randomized and treated. 1 participant in the MOL-INT group and 1 participant in the PBO group withdrew between the double-blind period and the open-label period. 1 participant who withdrew from the double-blind period entered the open-label period.
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Period Title: Double-blind Treatment Period
    STARTED 46 45 47
    COMPLETED 45 44 43
    NOT COMPLETED 1 1 4
    Period Title: Double-blind Treatment Period
    STARTED 45 43 43
    COMPLETED 45 42 41
    NOT COMPLETED 0 1 2

    Baseline Characteristics

    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo Total
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Total of all reporting groups
    Overall Participants 46 45 47 138
    Age (Count of Participants)
    <=18 years
    0
    0%
    1
    2.2%
    0
    0%
    1
    0.7%
    Between 18 and 65 years
    34
    73.9%
    37
    82.2%
    41
    87.2%
    112
    81.2%
    >=65 years
    12
    26.1%
    7
    15.6%
    6
    12.8%
    25
    18.1%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    54.0
    (13.32)
    49.2
    (14.06)
    46.1
    (14.84)
    49.8
    (14.36)
    Sex: Female, Male (Count of Participants)
    Female
    18
    39.1%
    19
    42.2%
    22
    46.8%
    59
    42.8%
    Male
    28
    60.9%
    26
    57.8%
    25
    53.2%
    79
    57.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    25
    54.3%
    13
    28.9%
    11
    23.4%
    49
    35.5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    2.2%
    0
    0%
    0
    0%
    1
    0.7%
    White
    20
    43.5%
    32
    71.1%
    36
    76.6%
    88
    63.8%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    2
    4.3%
    2
    4.4%
    0
    0%
    4
    2.9%
    Japan
    20
    43.5%
    10
    22.2%
    10
    21.3%
    40
    29%
    United Kingdom
    1
    2.2%
    3
    6.7%
    1
    2.1%
    5
    3.6%
    Switzerland
    0
    0%
    0
    0%
    1
    2.1%
    1
    0.7%
    Portugal
    0
    0%
    1
    2.2%
    2
    4.3%
    3
    2.2%
    Russia
    1
    2.2%
    1
    2.2%
    6
    12.8%
    8
    5.8%
    Spain
    0
    0%
    1
    2.2%
    1
    2.1%
    2
    1.4%
    Greece
    1
    2.2%
    0
    0%
    3
    6.4%
    4
    2.9%
    Netherlands
    2
    4.3%
    3
    6.7%
    1
    2.1%
    6
    4.3%
    South Korea
    3
    6.5%
    2
    4.4%
    1
    2.1%
    6
    4.3%
    Turkey
    4
    8.7%
    4
    8.9%
    2
    4.3%
    10
    7.2%
    Denmark
    1
    2.2%
    1
    2.2%
    1
    2.1%
    3
    2.2%
    Italy
    3
    6.5%
    3
    6.7%
    7
    14.9%
    13
    9.4%
    Israel
    1
    2.2%
    5
    11.1%
    1
    2.1%
    7
    5.1%
    Slovakia
    2
    4.3%
    1
    2.2%
    1
    2.1%
    4
    2.9%
    France
    2
    4.3%
    1
    2.2%
    2
    4.3%
    5
    3.6%
    Australia
    0
    0%
    1
    2.2%
    0
    0%
    1
    0.7%
    Germany
    3
    6.5%
    6
    13.3%
    7
    14.9%
    16
    11.6%
    Smoking (Count of Participants)
    Previous
    27
    58.7%
    20
    44.4%
    20
    42.6%
    67
    48.6%
    Never
    13
    28.3%
    16
    35.6%
    16
    34%
    45
    32.6%
    Current
    6
    13%
    9
    20%
    11
    23.4%
    26
    18.8%
    Time since aPAP diagnosis (months) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [months]
    39.8
    (58.12)
    40.0
    (45.87)
    32.0
    (31.50)
    37.2
    (46.18)
    Participants with previous whole lung lavage (Count of Participants)
    Count of Participants [Participants]
    23
    50%
    31
    68.9%
    30
    63.8%
    84
    60.9%
    Disease severity score (DSS) (Count of Participants)
    DSS 1: No symptoms and PaO2 ≥70 mmHg
    4
    8.7%
    5
    11.1%
    3
    6.4%
    12
    8.7%
    DSS 2: Symptomatic and PaO2 ≥70 mmHg
    12
    26.1%
    14
    31.1%
    16
    34%
    42
    30.4%
    DSS 3: 60 mmHg ≤ PaO2 <70 mmHg
    17
    37%
    13
    28.9%
    14
    29.8%
    44
    31.9%
    DSS 4: 50 mm Hg ≤ PaO2 <60 mmHg
    5
    10.9%
    9
    20%
    10
    21.3%
    24
    17.4%
    DSS 5: PaO2 <50 mmHg
    8
    17.4%
    4
    8.9%
    4
    8.5%
    16
    11.6%

    Outcome Measures

    1. Primary Outcome
    Title Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment
    Description Measurement of (A-a)DO2 was done by blood gas analysis. An arterial blood sample was collected in the supine position, after resting for at least 10 minutes (or longer if required to achieve stable oxygen saturation). The sample was analyzed for arterial oxygen tension (PaO2) and partial pressure of carbon dioxide (PaCO2). The calculation of (A-a)DO2 was done centrally by using a formula described in the protocol.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Full analysis set (FAS): all randomized participants, analyzed according to randomized treatment. Not all participants in the FAS had blood gas analysis done at Week 24, therefore the overall number of participants analyzed is less than the total number of randomized participants.
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 45 43 43
    Mean (Standard Deviation) [mmHg]
    28.6
    (21.95)
    29.3
    (17.96)
    32.0
    (20.90)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Molgramostim Once Daily, Placebo
    Comments Primary endpoint was evaluated using analysis of covariance with treatment, whole lung lavage within 2 months before baseline, and geographic region as factors, and baseline values as covariates. To control type I error, key secondary endpoints were analyzed using a testing hierarchy wherein once daily molgramostim and placebo was compared and if statistical significance was reached, evaluation of intermittent molgramostim and placebo would proceed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1688
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Square Means (LSmean)
    Estimated Value -4.6
    Confidence Interval (2-Sided) 95%
    -11.1 to 2.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the estimated difference between once daily molgramostim and placebo groups in LSmean change from baseline to week 24.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Molgramostim Intermittent, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3968
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Square Means (LSmean)
    Estimated Value -2.8
    Confidence Interval (2-Sided) 95%
    -9.3 to 3.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the estimated difference between intermittent molgramostim and placebo groups in LSmean change from baseline to week 24.
    2. Secondary Outcome
    Title Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment
    Description The 6MWD was assessed by the use of 6-minute walking test (6MWT). The 6MWT was performed in accordance with the 2014 ATS/ERS guideline "field walking tests in chronic respiratory disease" (Holland et al. 2014) by technicians with documented training and experience. Where possible, the test was conducted with the participant breathing ambient atmospheric air. If the participant required oxygen supplementation at rest, a titration procedure was carried out as part of the 6MWT at screening in order to determine the oxygen flow rate required for the participant to complete the test. This flow rate was to be used during subsequent tests, if possible.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    FAS. Not all participants in the FAS had 6MWT done at Week 24, therefore the overall number of participants analyzed is less than the total number of randomized participants.
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 43 43 43
    Mean (Standard Deviation) [meters]
    39.6
    (95.89)
    11.3
    (81.94)
    6.0
    (97.17)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Molgramostim Once Daily, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3159
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Square Means (LSmean)
    Estimated Value 20.6
    Confidence Interval (2-Sided) 95%
    -19.8 to 61.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the estimated difference between once daily molgramostim and placebo groups in LSmean change from baseline to week 24.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Molgramostim Intermittent, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7809
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Square Means (LSmean)
    Estimated Value 5.6
    Confidence Interval (2-Sided) 95%
    -34.1 to 45.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the estimated difference between intermittent molgramostim and placebo groups in LSmean change from baseline to week 24.
    3. Secondary Outcome
    Title Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment
    Description The SGRQ is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It consists of two parts, where Part 1 covers the participants' recollection of their symptoms over the preceding period (1 month recall used in this trial, Symptoms component) and Part 2 addresses the participants' current state in terms of disturbances to their daily physical activity (Activity component) and a wide range of disturbances of psycho-social function (Impact component). A total score as well as individual component scores were calculated. Scores (total and component) range from 0 to 100, with higher scores indicating more limitations.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    FAS. Not all participants in the FAS had SGRQ assessed at Week 24, therefore the overall number of participants analyzed is less than the total number of randomized participants.
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 45 44 43
    Mean (Standard Deviation) [score on a scale]
    -12.3
    (14.30)
    -12.0
    (15.12)
    -4.7
    (12.83)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Molgramostim Once Daily, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0103
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Square Means (LSmean)
    Estimated Value -7.6
    Confidence Interval (2-Sided) 95%
    -13.4 to -1.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the estimated difference between once daily molgramostim and placebo groups in LSmean change from baseline to week 24.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Molgramostim Intermittent, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0173
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Square Means (LSmean)
    Estimated Value -7.0
    Confidence Interval (2-Sided) 95%
    -12.7 to -1.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the estimated difference between intermittent molgramostim and placebo groups in LSmean change from baseline to week 24..
    4. Secondary Outcome
    Title Number of Whole Lung Lavage During 24 Weeks of Treatment
    Description In all versions of the protocol (no participants were recruited under version 1.0), whole lung lavage (single lung or both lungs) was applied as rescue therapy. In protocol version 2.0, the criterion for performing whole lung lavage was an increase in (A-a)DO2 by more than 10 mmHg/1.33 kilopascal compared to baseline. In protocol version 3.0 onwards, the criterion for performing whole lung lavage was clinical worsening of aPAP based on symptoms, reduced exercise capacity and/or findings of hypoxemia or desaturation according to the investigator's judgement. In protocol versions 2.0 and 3.0, participants undergoing whole lung lavage during the double-blind period were to discontinue double-blind treatment, encouraged to continue to follow the same visit schedule and, if required, receive further whole lung lavage at the investigator's discretion. In protocol version 4.0 and 5.0, participants undergoing whole lung lavage were to continue double-blind treatment.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    FAS.
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 46 45 47
    Number [lavages]
    9
    7
    17
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Molgramostim Once Daily, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1918
    Comments
    Method Negative binomial regression
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 0.284
    Confidence Interval (2-Sided) 95%
    0.043 to 1.881
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the RR between once daily molgramostim and placebo groups.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Molgramostim Intermittent, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2421
    Comments
    Method Negative binomial regression
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 0.367
    Confidence Interval (2-Sided) 95%
    0.068 to 1.968
    Parameter Dispersion Type:
    Value:
    Estimation Comments The estimated value represents the RR between intermittent molgramostim and placebo groups.
    5. Secondary Outcome
    Title Number of Adverse Events (AEs) During 24 Weeks of Treatment
    Description Treatment-emergent adverse events (AEs) were assessed on or after the first dose of trial drug to 28 days after last dose. Information about AEs was collected by the investigator by a non-leading question such as "have you experienced any new health problems or worsening of existing conditions" and by reporting events directly observed or spontaneously volunteered by participants (e.g., in the Subject Diary Card, where subjects were asked to record any AEs and answer questions regarding lung toxicity and known systemic effects). Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. All AEs were assessed by the investigator for severity (mild, moderate, severe), outcome (recovered, not recovered, recovered with sequelae, fatal, unknown) and causality (unlikely, possible, probable, not applicable) according to current regulatory standards.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set: all randomized participants who received at least one dose of the trial drug, analyzed according to actual treatment.
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 46 45 47
    Number [events]
    215
    191
    192
    6. Secondary Outcome
    Title Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment
    Description SAEs are defined as any untoward medicinal occurrence or effect that at any dose: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Is a congenital anomaly or birth defect May jeopardise the subject or may require intervention to prevent one or more of the other outcomes listed above (Important Medical Events)
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 46 45 47
    Number [events]
    13
    5
    16
    7. Secondary Outcome
    Title Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment
    Description All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as ADRs. The expression reasonable causal relationship means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility i.e. the relationship cannot be ruled out.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 46 45 47
    Number [events]
    53
    27
    33
    8. Secondary Outcome
    Title Number of Severe AEs During 24 Weeks of Treatment
    Description All AEs were assessed by the investigator for severity (mild, moderate, severe) according to current regulatory standards: Mild: The AE is easily tolerated and does not interfere with daily activity. Moderate: The AE interferes with daily activity, but the subject is still able to function. Medical intervention may be considered. Severe: The AE is incapacitating and requires medical intervention.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 46 45 47
    Number [events]
    28
    11
    38
    9. Secondary Outcome
    Title Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment
    Description Participants could be discontinued from treatment and assessments at any time, if deemed necessary by the investigator. Potential reasons for discontinuation of treatment included e.g. unacceptable AE.
    Time Frame From baseline to 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Molgramostim Once Daily Molgramostim Intermittent Placebo
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system
    Measure Participants 46 45 47
    Count of Participants [Participants]
    2
    4.3%
    1
    2.2%
    1
    2.1%

    Adverse Events

    Time Frame Treatment-emergent adverse events (AEs) were assessed on or after the first dose of trial drug to 28 days after last dose.
    Adverse Event Reporting Description Information about AEs was collected by the investigator by a non-leading question such as "have you experienced any new health problems or worsening of existing conditions" and by reporting events directly observed or spontaneously volunteered by participants. Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns.
    Arm/Group Title Double-blind Molgramostim Once Daily Double-blind Molgramostim Intermittent Double-blind Placebo Open-label Molgramostim Intermittent
    Arm/Group Description Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of placebo nebuliser solution once daily for 24 weeks Placebo: Placebo nebulizer solution for inhalation PARI eFlow nebulizer system: PARI eFlow nebulizer system Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period Molgramostim: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation
    All Cause Mortality
    Double-blind Molgramostim Once Daily Double-blind Molgramostim Intermittent Double-blind Placebo Open-label Molgramostim Intermittent
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/46 (0%) 0/45 (0%) 0/47 (0%) 0/130 (0%)
    Serious Adverse Events
    Double-blind Molgramostim Once Daily Double-blind Molgramostim Intermittent Double-blind Placebo Open-label Molgramostim Intermittent
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/46 (17.4%) 5/45 (11.1%) 8/47 (17%) 16/130 (12.3%)
    Eye disorders
    Cataract 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Hepatobiliary disorders
    Cholelithiasis 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Infections and infestations
    Pneumonia bacterial 1/46 (2.2%) 1 1/45 (2.2%) 1 0/47 (0%) 0 1/130 (0.8%) 1
    Diverticulitis 0/46 (0%) 0 1/45 (2.2%) 1 0/47 (0%) 0 0/130 (0%) 0
    Lower respiratory tract infection 0/46 (0%) 0 0/45 (0%) 0 1/47 (2.1%) 1 0/130 (0%) 0
    Pneumonia 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 2/130 (1.5%) 2
    Respiratory tract infection 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Oesophageal candidiasis 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Oral candidiasis 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Influenza 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Bronchitis 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Urinary tract infection 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Lung infection 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Nasopharyngitis 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Investigations
    Weight decreased 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Squamous cell carcinoma of the tongue 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Nervous system disorders
    Aphasia 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Epilepsy 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Psychiatric disorders
    Gambling disorder 0/46 (0%) 0 0/45 (0%) 0 1/47 (2.1%) 1 0/130 (0%) 0
    Reproductive system and breast disorders
    Prostatitis 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 1/130 (0.8%) 1
    Respiratory, thoracic and mediastinal disorders
    Alveolar proteinosis 3/46 (6.5%) 4 3/45 (6.7%) 3 6/47 (12.8%) 12 6/130 (4.6%) 7
    Asthma 0/46 (0%) 0 0/45 (0%) 0 1/47 (2.1%) 1 0/130 (0%) 0
    Cough 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Dyspnoea 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Laryngeal oedema 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Respiratory failure 1/46 (2.2%) 1 0/45 (0%) 0 0/47 (0%) 0 0/130 (0%) 0
    Surgical and medical procedures
    Drug detoxification 0/46 (0%) 0 0/45 (0%) 0 1/47 (2.1%) 1 0/130 (0%) 0
    Other (Not Including Serious) Adverse Events
    Double-blind Molgramostim Once Daily Double-blind Molgramostim Intermittent Double-blind Placebo Open-label Molgramostim Intermittent
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 39/46 (84.8%) 41/45 (91.1%) 41/47 (87.2%) 87/130 (66.9%)
    Gastrointestinal disorders
    Diarrhoea 0/46 (0%) 0 6/45 (13.3%) 6 3/47 (6.4%) 3 3/130 (2.3%) 3
    General disorders
    Chest pain 10/46 (21.7%) 11 2/45 (4.4%) 2 1/47 (2.1%) 2 3/130 (2.3%) 3
    Pyrexia 2/46 (4.3%) 2 3/45 (6.7%) 3 3/47 (6.4%) 4 4/130 (3.1%) 6
    Infections and infestations
    Nasopharyngitis 7/46 (15.2%) 10 10/45 (22.2%) 12 6/47 (12.8%) 6 24/130 (18.5%) 33
    Respiratory tract infection 2/46 (4.3%) 2 2/45 (4.4%) 2 2/47 (4.3%) 2 4/130 (3.1%) 4
    Upper respiratory tract infection 0/46 (0%) 0 3/45 (6.7%) 3 3/47 (6.4%) 3 5/130 (3.8%) 6
    Investigations
    Weight increased 3/46 (6.5%) 4 5/45 (11.1%) 6 0/47 (0%) 0 3/130 (2.3%) 3
    Musculoskeletal and connective tissue disorders
    Back pain 2/46 (4.3%) 5 3/45 (6.7%) 4 1/47 (2.1%) 1 4/130 (3.1%) 4
    Arthralgia 2/46 (4.3%) 2 0/45 (0%) 0 4/47 (8.5%) 4 0/130 (0%) 0
    Nervous system disorders
    Headache 6/46 (13%) 9 7/45 (15.6%) 9 7/47 (14.9%) 16 3/130 (2.3%) 6
    Dizziness 2/46 (4.3%) 2 2/45 (4.4%) 2 2/47 (4.3%) 4 3/130 (2.3%) 4
    Respiratory, thoracic and mediastinal disorders
    Cough 15/46 (32.6%) 22 12/45 (26.7%) 18 11/47 (23.4%) 12 11/130 (8.5%) 14
    Dyspnoea 5/46 (10.9%) 8 7/45 (15.6%) 7 4/47 (8.5%) 5 4/130 (3.1%) 8
    Alveolar proteinosis 3/46 (6.5%) 4 5/45 (11.1%) 5 8/47 (17%) 18 7/130 (5.4%) 10
    Productive cough 4/46 (8.7%) 5 3/45 (6.7%) 3 3/47 (6.4%) 3 3/130 (2.3%) 3
    Skin and subcutaneous tissue disorders
    Rash 0/46 (0%) 0 0/45 (0%) 0 0/47 (0%) 0 6/130 (4.6%) 6

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dhaval Desai, VP Head of Clinical Development
    Organization Savara Inc
    Phone +1 302-442-2309
    Email dhaval.desai@savarapharma.com
    Responsible Party:
    Savara Inc.
    ClinicalTrials.gov Identifier:
    NCT02702180
    Other Study ID Numbers:
    • MOL-PAP-002
    • 2015-003878-33
    First Posted:
    Mar 8, 2016
    Last Update Posted:
    Apr 15, 2022
    Last Verified:
    Feb 1, 2022