160 subjects with autoimmune pulmonary alveolar proteinosis (aPAP) will be randomized to receive once daily treatment with inhaled molgramostim (MOL) or placebo (PBO) for 48 weeks. Subjects completing the 48-week placebo-controlled period will receive open-label treatment with once daily inhaled molgramostim for 96 weeks.
This is an interventional, randomized, double-blind, 2-arm, parallel groups, placebo-controlled, multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP. An aPAP diagnosis should be confirmed by a Granulocyte-macrophage colony stimulating factor (GM-CSF) auto-antibody test result, and history of PAP based on either high resolution computed tomography, lung biopsy, or bronchoalveolar lavage cytology, should be available. The trial consists of a 6-week screening period, a 48-week randomized, double-blind treatment period, a 96-week open-label treatment period, and a conditional 4-week safety follow-up period. The maximum treatment duration will be 145 weeks and the maximum trial duration will be 156 weeks. During the trial, whole lung lavage will be allowed as rescue treatment in case of worsening of aPAP.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
164
Molgramostim 300 µg nebulizer solution
Matching placebo nebulizer solution
Molgramostim 300 µg nebulizer solution
Change From Baseline in Percent (%) Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Adjusted for Hemoglobin Concentration to Week 24
As a measure of pulmonary gas transfer, a standardized lung function test, DLCO, was conducted. The single-breath DLCO test was performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing. Results reported as % predicted DLCO adjusted for hemoglobin concentration (%predicted DLCOadj).
Time frame: From Baseline to Week 24
Change From Baseline in Percent (%) Predicted DLCO Adjusted for Hemoglobin Concentration (%DLCOadj) to Week 48
As a measure of pulmonary gas transfer, a standardized lung function test, DLCO, was conducted. The single-breath DLCO test was performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing. Results reported as % predicted DLCO adjusted for hemoglobin concentration (%predicted DLCOadj). Higher values indicate better respiratory gas exchange.
Time frame: From Baseline to Week 48
Change From Baseline in St. Georges Respiratory Questionnaire (SGRQ) Total Score to Week 24
The Saint Georges Respiratory Questionnaire (SGRQ) is designed to measure respiratory health impairment. The scale includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. SGRQ scored on a 0-100 scale with lower scores indicating better respiratory health.
Time frame: From Baseline to Week 24
Change From Baseline in SGRQ Activity Component Score to Week 24
The Saint Georges Respiratory Questionnaire (SGRQ) Activity scale is a subscale of the SGRQ and is designed to measure the effect of respiratory health impairment on daily activity affected by breathlessness. The questionnaire for the Activity components addresses the subject's current state. SGRQ Activity is scored on a 0-100 scale with lower scores indicating better respiratory health activity
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University Of Arkansas For Medical Services
Little Rock, Arkansas, United States
UCLA David Geffen School of Medicine
Los Angeles, California, United States
National Jewish Health
Denver, Colorado, United States
Yale University
New Haven, Connecticut, United States
University of Florida Health
Gainesville, Florida, United States
Emory University
Atlanta, Georgia, United States
Loyola University
Maywood, Illinois, United States
University of Maryland Medical Center
Baltimore, Maryland, United States
Washington University in St. Louis
St Louis, Missouri, United States
Duke University Medical Center
Durham, North Carolina, United States
...and 44 more locations
Time frame: From Baseline to Week 24
Change From Baseline in Exercise Capacity (EC), Expressed as Peak Metabolic Equivalents (METs) to Week 24
As a functional measure of exertional limitations related to dyspnea, EC was assessed by an exercise treadmill test. EC was expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved was used to calculate peak METs. Higher values indicate better functional capacity.
Time frame: From Baseline to Week 24
Change From Baseline in SGRQ Total Score to Week 48
The Saint Georges Respiratory Questionnaire (SGRQ) is designed to measure respiratory health impairment. The scale includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. SGRQ scored on a 0-100 scale with lower scores indicating better respiratory health.
Time frame: From Baseline to Week 48
Change From Baseline in SGRQ Activity From Baseline to Week 48
The Saint Georges Respiratory Questionnaire (SGRQ) Activity scale is a subscale of the SGRQ and is designed to measure the effect of respiratory health impairment on daily activity affected by breathlessness. The questionnaire for the Activity components addresses the subject's current state. SGRQ Activity is scored on a 0-100 scale with lower scores indicating better respiratory health activity
Time frame: From Baseline to Week 48
Change From Baseline in EC, Expressed as Peak METs to Week 48
As a functional measure of exertional limitations related to dyspnea, EC was assessed by an exercise treadmill test. EC was expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved was used to calculate peak METs. Higher values indicate better functional capacity.
Time frame: From Baseline to Week 48
Change From Baseline in Alveolar-arterial Oxygen Difference (A-aDO2) to Week 24 (All Subjects)
A-aDO2 was used as an additional measure of gas exchange.
Time frame: From Baseline to Week 24
Number of Subjects With Serious and Non-serious Adverse Events
Assessment of the safety of molgramostim compared to placebo
Time frame: From Baseline until End of Double-blind treatment (Week 48)
Number of Subjects With Positive Treatment-boosted Anti Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Antibody Titers During 24 Weeks' Treatment and During 48 Weeks' Treatment
Assess the effect of molgramostim or placebo on antiGM-CSF antibody titers that increased by a dilution factor of 2.(4X increase in titer compared to Baseline).
Time frame: From Baseline until End of Double-blind treatment Week-48
Changes in Forced Vital Capacity (FVC) %Predicted Normal
Forced vital capacity is the volume of air that can be expired after a deep breath. Higher volumes indicate better respiratory function. FVC is scored as % of predicted normal expired vital capacity.
Time frame: From Baseline to Weeks 24 and 48
Changes in Forced Expiratory Volume in One Second (FEV1) % Predicted Normal.
FEV1 is the volume of air expired in 1 second in liters (L). Higher values indicate better respiratory function.
Time frame: From Baseline to Weeks 24 and 48
Change in QT Interval Corrected by Fridericia (QTcF)
Assessment of the safety of MOL compared to placebo
Time frame: From Baseline to Weeks 4 and 24