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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
139
300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation
Placebo nebulizer solution for inhalation
PARI eFlow nebulizer system
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
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
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.
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UCLA
Los Angeles, California, United States
University of Florida
Gainesville, Florida, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Royal Prince Alfred Hospital
Sydney, New South Wales, Australia
Aarhus University Hospital
Aarhus, Denmark
CHU Rennes Hospital Pontchaillou
Rennes, France
Westdeutsches Lungenzentrum am Universitätsklinikum Essen
Essen, Germany
Asklepios Fachkliniken München - Gauting
Gauting, Germany
Thoraxklinik am Universitätsklinikum Heidelberg
Heidelberg, Germany
Universitätsklinikum Schleswig-Holstein Zentralklinikum, Lübeck Medizinische Klinik III, Pneumologie
Lübeck, Germany
...and 20 more locations
Time frame: From baseline to 24 weeks
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
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
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
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
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
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