Autoimmune Pulmonary Alveolar Proteinosis
Conditions
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.
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.
Interventions
DRUGMolgramostim
300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation
DRUGPlacebo
Placebo nebulizer solution for inhalation
PARI eFlow nebulizer system
Sponsors
Savara Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 2) 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) |
Countries
Australia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Netherlands, Portugal, Russia, Slovakia, South Korea, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Molgramostim Once Daily 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 | 46 |
| Molgramostim Intermittent 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 | 45 |
| Placebo Inhalation of placebo nebuliser solution once daily for 24 weeks
Placebo: Placebo nebulizer solution for inhalation
PARI eFlow nebulizer system: PARI eFlow nebulizer system | 47 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 0 | 0 | 1 |
| Double-blind Treatment Period | Lack of Efficacy | 0 | 0 | 1 |
| Double-blind Treatment Period | Protocol Violation | 0 | 0 | 2 |
| Double-blind Treatment Period | Withdrawal by Subject | 1 | 1 | 0 |
| Open-label Treatment Period | Withdrawal by Subject | 0 | 1 | 1 |
| Open-label Treatment Period | Withdrawn in error | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Molgramostim Intermittent | Molgramostim Once Daily |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 6 Participants | 7 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 112 Participants | 41 Participants | 37 Participants | 34 Participants |
| Age, Continuous | 49.8 years STANDARD_DEVIATION 14.36 | 46.1 years STANDARD_DEVIATION 14.84 | 49.2 years STANDARD_DEVIATION 14.06 | 54.0 years STANDARD_DEVIATION 13.32 |
| Disease severity score (DSS) DSS 1: No symptoms and PaO2 ≥70 mmHg | 12 Participants | 3 Participants | 5 Participants | 4 Participants |
| Disease severity score (DSS) DSS 2: Symptomatic and PaO2 ≥70 mmHg | 42 Participants | 16 Participants | 14 Participants | 12 Participants |
| Disease severity score (DSS) DSS 3: 60 mmHg ≤ PaO2 <70 mmHg | 44 Participants | 14 Participants | 13 Participants | 17 Participants |
| Disease severity score (DSS) DSS 4: 50 mm Hg ≤ PaO2 <60 mmHg | 24 Participants | 10 Participants | 9 Participants | 5 Participants |
| Disease severity score (DSS) DSS 5: PaO2 <50 mmHg | 16 Participants | 4 Participants | 4 Participants | 8 Participants |
| Participants with previous whole lung lavage | 84 Participants | 30 Participants | 31 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 49 Participants | 11 Participants | 13 Participants | 25 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 88 Participants | 36 Participants | 32 Participants | 20 Participants |
| Region of Enrollment Australia | 1 participants | 0 participants | 1 participants | 0 participants |
| Region of Enrollment Denmark | 3 participants | 1 participants | 1 participants | 1 participants |
| Region of Enrollment France | 5 participants | 2 participants | 1 participants | 2 participants |
| Region of Enrollment Germany | 16 participants | 7 participants | 6 participants | 3 participants |
| Region of Enrollment Greece | 4 participants | 3 participants | 0 participants | 1 participants |
| Region of Enrollment Israel | 7 participants | 1 participants | 5 participants | 1 participants |
| Region of Enrollment Italy | 13 participants | 7 participants | 3 participants | 3 participants |
| Region of Enrollment Japan | 40 participants | 10 participants | 10 participants | 20 participants |
| Region of Enrollment Netherlands | 6 participants | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Portugal | 3 participants | 2 participants | 1 participants | 0 participants |
| Region of Enrollment Russia | 8 participants | 6 participants | 1 participants | 1 participants |
| Region of Enrollment Slovakia | 4 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment South Korea | 6 participants | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Switzerland | 1 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment Turkey | 10 participants | 2 participants | 4 participants | 4 participants |
| Region of Enrollment United Kingdom | 5 participants | 1 participants | 3 participants | 1 participants |
| Region of Enrollment United States | 4 participants | 0 participants | 2 participants | 2 participants |
| Sex: Female, Male Female | 59 Participants | 22 Participants | 19 Participants | 18 Participants |
| Sex: Female, Male Male | 79 Participants | 25 Participants | 26 Participants | 28 Participants |
| Smoking Current | 26 Participants | 11 Participants | 9 Participants | 6 Participants |
| Smoking Never | 45 Participants | 16 Participants | 16 Participants | 13 Participants |
| Smoking Previous | 67 Participants | 20 Participants | 20 Participants | 27 Participants |
| Time since aPAP diagnosis | 37.2 months STANDARD_DEVIATION 46.18 | 32.0 months STANDARD_DEVIATION 31.5 | 40.0 months STANDARD_DEVIATION 45.87 | 39.8 months STANDARD_DEVIATION 58.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 45 | 0 / 47 | 0 / 130 |
| other Total, other adverse events | 39 / 46 | 41 / 45 | 41 / 47 | 87 / 130 |
| serious Total, serious adverse events | 8 / 46 | 5 / 45 | 8 / 47 | 16 / 130 |
Outcome results
Primary
Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Molgramostim Once Daily | Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment | 28.6 mmHg | Standard Deviation 21.95 |
| Molgramostim Intermittent | Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment | 29.3 mmHg | Standard Deviation 17.96 |
| Placebo | Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment | 32.0 mmHg | Standard Deviation 20.9 |
Comparison: 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.p-value: 0.168895% CI: [-11.1, 2]ANCOVA
p-value: 0.396895% CI: [-9.3, 3.7]ANCOVA
Secondary
Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Molgramostim Once Daily | Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment | 39.6 meters | Standard Deviation 95.89 |
| Molgramostim Intermittent | Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment | 11.3 meters | Standard Deviation 81.94 |
| Placebo | Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment | 6.0 meters | Standard Deviation 97.17 |
p-value: 0.315995% CI: [-19.8, 61]ANCOVA
p-value: 0.780995% CI: [-34.1, 45.2]ANCOVA
Secondary
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Molgramostim Once Daily | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment | -12.3 score on a scale | Standard Deviation 14.3 |
| Molgramostim Intermittent | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment | -12.0 score on a scale | Standard Deviation 15.12 |
| Placebo | Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment | -4.7 score on a scale | Standard Deviation 12.83 |
p-value: 0.010395% CI: [-13.4, -1.8]ANCOVA
p-value: 0.017395% CI: [-12.7, -1.3]ANCOVA
Secondary
Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment
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
Population: Safety analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Once Daily | Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment | 53 events |
| Molgramostim Intermittent | Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment | 27 events |
| Placebo | Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment | 33 events |
Secondary
Number of Adverse Events (AEs) During 24 Weeks of Treatment
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
Population: Safety analysis set: all randomized participants who received at least one dose of the trial drug, analyzed according to actual treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Once Daily | Number of Adverse Events (AEs) During 24 Weeks of Treatment | 215 events |
| Molgramostim Intermittent | Number of Adverse Events (AEs) During 24 Weeks of Treatment | 191 events |
| Placebo | Number of Adverse Events (AEs) During 24 Weeks of Treatment | 192 events |
Secondary
Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment
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
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molgramostim Once Daily | Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment | 2 Participants |
| Molgramostim Intermittent | Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment | 1 Participants |
| Placebo | Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment | 1 Participants |
Secondary
Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment
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
Population: Safety analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Once Daily | Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment | 13 events |
| Molgramostim Intermittent | Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment | 5 events |
| Placebo | Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment | 16 events |
Secondary
Number of Severe AEs During 24 Weeks of Treatment
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
Population: Safety analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Once Daily | Number of Severe AEs During 24 Weeks of Treatment | 28 events |
| Molgramostim Intermittent | Number of Severe AEs During 24 Weeks of Treatment | 11 events |
| Placebo | Number of Severe AEs During 24 Weeks of Treatment | 38 events |
Secondary
Number of Whole Lung Lavage During 24 Weeks of Treatment
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
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molgramostim Once Daily | Number of Whole Lung Lavage During 24 Weeks of Treatment | 9 lavages |
| Molgramostim Intermittent | Number of Whole Lung Lavage During 24 Weeks of Treatment | 7 lavages |
| Placebo | Number of Whole Lung Lavage During 24 Weeks of Treatment | 17 lavages |
p-value: 0.191895% CI: [0.043, 1.881]Negative binomial regression
p-value: 0.242195% CI: [0.068, 1.968]Negative binomial regression