A Randomized, Double-blind, Placebo-controlled Clinical Trial of Once-daily Inhaled Molgramostim Nebulizer Solution in Adult Subjects With Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
Phase: PHASE3
Conditions: Autoimmune Pulmonary Alveolar Proteinosis
Sponsor: Savara Inc.



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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF TABLES .................................................................................................................. 7 
LIST OF FIGURES ................................................................................................................. 7 
1. 
PROTOCOL SUMMARY ..................................................................................... 8 
1.1. 
Synopsis................................................................................................................ 8 
1.2. 
Schema ............................................................................................................... 13 
1.3. 
Schedule of Activities (SoA)................................................................................ 14 
1.3.1. 
Double-blind Treatment Period ............................................................................ 14 
1.3.2. 
Open-label Treatment Period ............................................................................... 17 
2. 
INTRODUCTION ............................................................................................... 19 
2.1. 
Trial Rationale..................................................................................................... 19 
2.2. 
Background ......................................................................................................... 19 
2.2.1. 
Autoimmune Pulmonary Alveolar Proteinosis (aPAP) .......................................... 19 
2.2.2. 
Molgramostim Nebulizer Solution: Mode of Action.............................................. 20 
2.2.3. 
Molgramostim Nebulizer Solution: Clinical Evidence........................................... 20 
2.3. 
Benefit/Risk Assessment...................................................................................... 22 
2.3.1. 
Risk Assessment.................................................................................................. 22 
2.3.2. 
Benefit Assessment ............................................................................................. 25 
2.3.3. 
Overall Benefit/Risk Conclusion .......................................................................... 25 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................... 26 
4. 
TRIAL DESIGN ................................................................................................. 29 
4.1. 
Overall Design .................................................................................................... 29 
4.2. 
Scientific Rationale for Trial Design .................................................................... 29 
4.2.1. 
Choice of Overall Trial Design ............................................................................ 29 
4.2.2. 
Choice of Subject Population ............................................................................... 30 
4.2.3. 
Choice of Endpoints ............................................................................................ 31 
4.2.3.1. 
Primary Endpoint ................................................................................................ 31 
4.2.3.2. 
Secondary Endpoints ........................................................................................... 32 
4.3. 
Justification for Dose ........................................................................................... 36 
4.4. 
End of Trial Definition ........................................................................................ 36 
 

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5. 
TRIAL POPULATION........................................................................................ 37 
5.1. 
Inclusion Criteria ................................................................................................. 37 
5.2. 
Exclusion Criteria................................................................................................ 38 
5.3. 
Lifestyle Considerations ...................................................................................... 39 
5.4. 
Screen Failures .................................................................................................... 39 
6. 
TRIAL INTERVENTION ................................................................................... 40 
6.1. 
Investigational Medicinal Products....................................................................... 40 
6.1.1. 
Molgramostim and Placebo Dosing Regimen ....................................................... 40 
6.1.2. 
Packaging and Labelling ...................................................................................... 40 
6.2. 
Dispensing/Administration/Storage/Accountability/Destruction ............................ 41 
6.2.1. 
Dispensing .......................................................................................................... 41 
6.2.2. 
Administration .................................................................................................... 41 
6.2.3. 
Storage................................................................................................................ 42 
6.2.4. 
Accountability ..................................................................................................... 43 
6.2.5. 
Return and Destruction ........................................................................................ 43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding .................................... 43 
6.3.1. 
Double-blind Treatment Period ............................................................................ 43 
6.3.2. 
Open-label Treatment Period ............................................................................... 44 
6.4. 
Trial Intervention Compliance.............................................................................. 44 
6.5. 
Prior/concomitant Therapy................................................................................... 45 
6.5.1. 
Prior Therapy ...................................................................................................... 45 
6.5.2. 
Concomitant Therapy .......................................................................................... 45 
6.5.3. 
Rescue Treatment ................................................................................................ 46 
6.5.4. 
Oxygen Supplementation ..................................................................................... 46 
6.6. 
Dose Modification ............................................................................................... 46 
6.7. 
Intervention after the End of the Trial................................................................... 46 
7. 
DISCONTINUATION OF TRIAL INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ............................................................. 47 
7.1. 
Discontinuation of Investigational Medicinal Product ........................................... 47 
7.2. 
Withdrawal from the Trial ................................................................................... 47 
7.3. 
Lost to Follow-up ................................................................................................ 47 
8. 
TRIAL ASSESSMENTS AND PROCEDURES................................................... 49 
8.1. 
Demographics and Medical History ..................................................................... 49 
 

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8.1.1. 
Demographics ..................................................................................................... 49 
8.1.2. 
Medical History and History of aPAP................................................................... 50 
8.2. 
Efficacy Assessments .......................................................................................... 50 
8.2.1. 
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) ........................... 50 
8.2.2. 
Saint George’s Respiratory Questionnaire (SGRQ) ............................................... 51 
8.2.3. 
Exercise Capacity (EC)........................................................................................ 52 
8.2.4. 
Whole Lung Lavage (WLL)................................................................................. 54 
8.2.5. 
High Resolution Computed Tomography (HRCT) ................................................ 55 
8.2.6. 
Supplemental Oxygen Use ................................................................................... 55 
8.2.7. 
Biomarkers.......................................................................................................... 56 
8.2.8. 
Biobank .............................................................................................................. 56 
8.2.9. 
Arterial Blood Gas Assessments .......................................................................... 57 
8.2.10. 
Disease Severity Score (DSS) .............................................................................. 58 
8.2.11. 
Clinician’s Global Impression of Severity (CGIS) and Change (CGIC) ................. 58 
8.2.12. 
Patient’s Global Impression of Severity (PGIS) and Change (PGIC) ..................... 58 
8.2.13. 
Exit Interviews .................................................................................................... 59 
8.3. 
Safety Assessments ............................................................................................. 59 
8.3.1. 
Electrocardiograms .............................................................................................. 59 
8.3.2. 
Physical Examinations ......................................................................................... 60 
8.3.3. 
Vital Signs and Body Weight ............................................................................... 60 
8.3.4. 
Clinical Safety Laboratory Assessments ............................................................... 61 
8.3.5. 
Pregnancy Test .................................................................................................... 61 
8.3.6. 
Anti-GM-CSF Antibodies .................................................................................... 61 
8.3.7. 
Spirometry (FVC, FEV1 and FEV1/FVC) ............................................................. 62 
8.4. 
Adverse Events and Serious Adverse Events ........................................................ 62 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .................... 62 
8.4.2. 
Method of Recording and Assessing AEs and SAEs ............................................. 62 
8.4.3. 
Follow-up of AEs and SAEs ................................................................................ 63 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...................................................... 63 
8.4.5. 
Pregnancy ........................................................................................................... 63 
8.4.6. 
Adverse Events of Special Interest ....................................................................... 64 
8.5. 
Treatment of Overdose ........................................................................................ 64 
8.6. 
Pharmacokinetics ................................................................................................ 64 
 

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8.7. 
Pharmacodynamics .............................................................................................. 64 
8.8. 
Genetics .............................................................................................................. 65 
8.9. 
Biomarkers.......................................................................................................... 65 
8.10. 
Immunogenicity Assessments .............................................................................. 65 
8.11. 
Health Economics and Quality of Life.................................................................. 65 
8.11.1. 
EuroQoL 5 Dimensions, 5 Levels (EQ-5D-5L) ..................................................... 65 
8.11.2. 
Patient Journey .................................................................................................... 65 
8.11.3. 
Hospitalizations ................................................................................................... 65 
8.12. 
Subject Instruction and Diary ............................................................................... 66 
9. 
STATISTICAL CONSIDERATIONS .................................................................. 67 
9.1. 
Statistical Hypotheses .......................................................................................... 67 
9.2. 
Sample Size Determination .................................................................................. 67 
9.3. 
Trial Estimands ................................................................................................... 67 
9.3.1. 
Estimand for the Primary Endpoint ...................................................................... 67 
9.3.1.1. 
Treatment............................................................................................................ 67 
9.3.1.2. 
Population ........................................................................................................... 68 
9.3.1.3. 
Patient-level Endpoint ......................................................................................... 68 
9.3.1.4. 
Intercurrent Events .............................................................................................. 68 
9.3.1.5. 
Population-level Summary ................................................................................... 69 
9.3.2. 
Estimands for the Secondary Efficacy Endpoints .................................................. 69 
9.4. 
Populations for Analyses ..................................................................................... 69 
9.5. 
Statistical Analyses.............................................................................................. 70 
9.5.1. 
General Considerations ........................................................................................ 70 
9.5.2. 
Type I Error Control ............................................................................................ 70 
9.5.3. 
Demographic and Other Baseline Characteristics .................................................. 72 
9.5.4. 
Exposure to Treatment ......................................................................................... 72 
9.5.5. 
Concomitant Treatment ....................................................................................... 73 
9.5.6. 
Primary Endpoint – Absolute Change in Percent of Predicted DLCO from 
Baseline to Week 24 ............................................................................................ 73 
9.5.7. 
Secondary Endpoints ........................................................................................... 74 
9.5.7.1. 
Frequencies of (S)AEs, (S)ADRs, AESIs, Deaths and AEs Leading to 
Withdrawal ......................................................................................................... 75 
9.5.8. 
Exploratory Endpoints ......................................................................................... 75 
 

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9.5.9. 
Other Safety Analyses ......................................................................................... 75 
9.5.10. 
Other Analyses .................................................................................................... 75 
9.6. 
Interim Analyses ................................................................................................. 75 
9.7. 
Data Monitoring Committee ................................................................................ 75 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................... 76 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.................... 76 
10.1.1. 
Regulatory and Ethical Considerations ................................................................. 76 
10.1.2. 
Protocol Compliance ........................................................................................... 76 
10.1.3. 
Financial Disclosure ............................................................................................ 77 
10.1.4. 
Informed Consent Process.................................................................................... 77 
10.1.5. 
Data Protection.................................................................................................... 78 
10.1.6. 
Committees Structure .......................................................................................... 78 
10.1.7. 
Dissemination of Clinical Trial Data .................................................................... 78 
10.1.8. 
Data Quality Assurance ....................................................................................... 78 
10.1.9. 
Source Documents............................................................................................... 82 
10.1.10. 
Trial and Site Closure .......................................................................................... 82 
10.1.11. 
Publication Policy................................................................................................ 83 
10.2. 
Appendix 2: Efficacy Assessments....................................................................... 84 
10.2.1. 
Sample SGRQ ..................................................................................................... 84 
10.2.2. 
Exercise Test Summary Sheet .............................................................................. 90 
10.2.3. 
Sample Rating of Perceived Exertion (RPE) – Borg RPE Scale® ........................... 94 
10.2.4. 
Sample Borg CR Scale® (CR10) for assessment of dyspnea .................................. 95 
10.2.5. 
Sample Angina Scale ........................................................................................... 96 
10.2.6. 
Sample Oxygen eDiary ........................................................................................ 97 
10.2.7. 
Sample Patient’s Global Impression of Severity (PGIS) and Change (PGIC) 
(to be completed after the SGRQ) ........................................................................ 98 
10.2.8. 
Sample Patient’s Global Impression of Severity (PGIS) and Change (PGIC) 
(to be completed after the Exercise Test) .............................................................. 99 
10.2.9. 
Sample EQ-5D-5L............................................................................................. 100 
10.2.10. 
Sample Patient Journey...................................................................................... 103 
10.2.11. 
Clinician’s Global Impression of Severity (CGIS) and Change (CGIC) ............... 104 
10.3. 
Appendix 3: Clinical Laboratory Tests ............................................................... 105 
 

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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................................ 106 
10.4.1. 
Definition of AE................................................................................................ 106 
10.4.2. 
Definition of SAE.............................................................................................. 107 
10.4.3. 
Recording and Follow-Up of AE and/or SAE ..................................................... 108 
10.4.4. 
Reporting of SAEs............................................................................................. 109 
10.5. 
Appendix 5: Contact Information for Medical Monitor, Technical Facilities 
and Central Laboratories .................................................................................... 110 
10.6. 
Appendix 6: Signature Page ............................................................................... 111 
10.7. 
Appendix 7: Abbreviations ................................................................................ 112 
10.8. 
Appendix 8: Change log .................................................................................... 115 
11. 
REFERENCES.................................................................................................. 127 
 
 
LIST OF TABLES 
Table 1: 
Summary of Risks and Mitigation Strategies ........................................................ 23 
Table 2: 
Frequency of Symptoms in MOL-PAP-002 (% of Subjects) .................................. 33 
Table 3: 
Investigational Medicinal Products in SAV006-05................................................ 40 
Table 4: 
Disallowed Therapy............................................................................................. 45 
Table 5: 
Analysis Populations ........................................................................................... 69 
 
LIST OF FIGURES 
Figure 1: 
Change from Baseline to Week 24 in SGRQ Component Scores 
(MOL-PAP-002; MOL-OD and PBO Groups) ...................................................... 34 
Figure 2: 
Type I Error Control for Efficacy Endpoints ......................................................... 71 
Figure 3: 
Type I Error Control for Efficacy Endpoints (for Japan and South Korea) ............. 72 
Figure 4: 
Overall Data Flow ............................................................................................... 80 
 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title  
A randomized, double-blind, placebo-controlled clinical trial of once-daily inhaled 
molgramostim nebulizer solution in adult subjects with autoimmune pulmonary alveolar 
proteinosis (aPAP). 
Short Title  
Once-daily inhaled molgramostim nebulizer solution in aPAP. 
Rationale  
Data from a completed phase 2/3 trial, MOL-PAP-002, suggested that molgramostim, an inhaled 
form of the recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF), 
improves lung pathology, pathophysiology, and health status in subjects with aPAP in a dose-
frequency dependent fashion. The present confirmatory phase 3 trial will be conducted to further 
investigate the efficacy and safety of molgramostim in subjects with aPAP. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy 
 
Investigate the 
efficacy of MOL 
compared to placebo  
Primary 
• 
Change in % predicted DLCO from baseline to Week 24 
Secondary (For regulatory authorities outside of Japan and Korea) 
 
• 
Change in % predicted DLCO from baseline to Week 48 
 
• 
Change in SGRQ Total from baseline to Week 24 
 
• 
Change in SGRQ Activity from baseline to Week 24 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 24 
 
• 
Change in SGRQ Total from baseline to Week 48 
 
• 
Change in SGRQ Activity from baseline to Week 48 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 48 
 
Secondary (Specifically for Japan and South Korea) 
 
• 
Change in SGRQ Total from baseline to Week 24 
 
• 
Change in SGRQ Activity from baseline to Week 24 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 24 
 
• 
Change in A-aDO2 from baseline to Week 24 
 
 
 
 
 

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Objectives 
Endpoints 
 
Exploratory 
 
• 
Frequency of WLL in the period between baseline and Week 24, and 
between baseline and Week 48 
 
• 
Change in SGRQ Impact from baseline to Week 24 and Week 48 
 
• 
Change in SGRQ Symptoms from baseline to Week 24 and Week 48 
 
• 
Change in distance walked during treadmill test from baseline to Week 
24 and Week 48 
 
• 
Change in duration of exercise during treadmill test from baseline to 
Week 24 and Week 48 
 
• 
Change in A-aDO2 from baseline to Week 24 (included as Secondary 
endpoint for Japan and South Korea) and Week 48 
 
• 
Change in PaO2 from baseline to Week 24 and Week 48 
 
• 
Change in DSS from baseline to Week 24 and Week 48 
 
• 
Change in GGO from baseline to Week 24 
 
• 
Change in CGIS from baseline to Week 24 and Week 48 
 
• 
CGIC at Week 24 and Week 48 
 
• 
Change in PGIS from baseline to Week 24 and Week 48 
 
• 
PGIC at Week 24 and Week 48 
 
• 
Change in supplemental oxygen use from baseline to Week 24 and 
Week 48 
 
• 
Change in biomarker levels from baseline to Week 24 and Week 48 
 
• 
Change in EQ-5D-5L from baseline to Week 24 and Week 48 
 
• 
Change in dyspnea from baseline to Week 24 and Week 48 
 
• 
Number of hospitalizations in the period between baseline and Week 
24, and between baseline and Week 48 
 
Exploratory (Specifically for Japan and South Korea) 
 
• 
Change in % predicted DLCO from baseline to Week 48 
 
• 
Change in SGRQ Total from baseline to Week 48 
 
• 
Change in SGRQ Activity from baseline to Week 48 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 48 
 
 
 
 
 
 
 
 
 

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Objectives 
Endpoints 
Safety 
 
Investigate the safety 
of MOL compared to 
placebo  
Safety Endpoints 
• 
Frequencies of (S)AEs, (S)ADRs, AESIs, deaths and AEs leading to 
withdrawal from trial and/or permanent discontinuation from treatment 
in the period between baseline and Week 24, and between baseline and 
Week 48 
• 
Development of treatment-boosted anti-GM-CSF antibody titers 
during 24 weeks’ treatment and during 48 weeks’ treatment 
• 
Changes in FVC, FEV1 and FEV1/FVC from baseline to Week 24 and 
Week 48 
• 
Change in QTcF from baseline to Weeks 4 and 24  
Further 
Exploratory 
Longer-Term 
Objectives 
 
Investigate the 
efficacy of MOL 
during open-label 
treatment 
Exploratory 
• 
Frequency of WLL in the period between baseline and the end of 
open-label treatment 
• 
Changes in % predicted DLCO, SGRQ Total, Activity, Impact and 
Symptoms, CGIS, PGIS, supplemental oxygen use, biomarker levels 
and EQ-5D-5L from baseline to the end of open-label treatment 
• 
Change in GGO from baseline to Week 144 and from Week 24 to 
Week 144 
• 
CGIC and PGIC at the end of open-label treatment 
• 
Number of hospitalizations in the period between baseline and the end 
of open-label treatment 
Investigate the safety 
of MOL during 
open-label treatment 
Exploratory 
• 
Frequencies of (S)AEs, (S)ADRs, AESIs, deaths and AEs leading to 
withdrawal from trial and/or permanent discontinuation from treatment 
in the period between baseline and the end of open-label treatment 
• 
Development of treatment-boosted anti-GM-CSF antibody titers 
during double-blind and open-label treatment and 4 weeks’ post-
treatment 
• 
Changes in FVC, FEV1 and FEV1/FVC from baseline to the end of 
open-label treatment  
Abbreviations: A-aDO2=Alveolar-arterial oxygen difference; ADR=Adverse drug reaction; AE=Adverse event; 
AESI=Adverse event of special interest; CGIC=Clinician’s global impression of change; CGIS=Clinician’s global 
impression of severity; DLCO=Diffusing capacity of the lungs for carbon monoxide; DSS=Disease severity score; 
EC=Exercise capacity; FEV1=Forced expiratory volume in 1 second; FVC=Forced vital capacity; GGO=Ground 
glass opacity; GM-CSF=Granulocyte macrophage colony stimulating factor; METs=Metabolic equivalents; 
 

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MOL=Molgramostim 300 µg nebulizer solution; PaO2=Partial pressure of oxygen; PGIC=Patient’s Global 
Impression of Change; PGIS= Patient’s Global Impression of Severity; QTcF=QT interval corrected by Fridericia; 
SADR=Serious adverse drug reaction; SAE=Serious adverse event; SGRQ=Saint George’s Respiratory 
Questionnaire; WLL=Whole lung lavage. 
Overall Design 
• This is an interventional, randomized, double-blind, 2-arm, parallel, placebo-
controlled, multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP. 
• 160 subjects with aPAP will be randomized and the randomization are intended to be 
stratified by baseline diffusing capacity of the lungs for carbon monoxide (DLCO; 
>50% or ≤50% predicted) and by region (Asia and Australia, Europe including 
Turkey, or North America).  
• Autoimmune pulmonary alveolar proteinosis (aPAP) diagnosis should be confirmed 
by an anti-GM-CSF autoantibody test result, and history of PAP based on either high-
resolution computed tomography, lung biopsy, or bronchoalveolar lavage cytology.  
• The DLCO should be ≤70% predicted and the absolute change in % predicted DLCO 
should be <15% points during the screening period. The subject should have a stable 
resting oxygen saturation (SpO2) >85% without use of supplemental oxygen. 
• 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 4-week safety follow-
up period. Taking the visit windows into account, the maximum treatment duration 
will be 145 weeks and the maximum trial duration will be 156 weeks. 
• Two screening visits will be conducted at 6 and 3 weeks prior to the Baseline visit. At 
the Baseline visit, eligible subjects will be centrally randomized through an 
Interactive Response Technology system to 48-week double-blind once-daily 
treatment with either molgramostim 300 µg nebulizer solution (MOL) or placebo 
nebulizer solution (PBO). The treatment assignment will be stratified according to 
baseline % predicted DLCO and region. 
• Subjects who complete the double-blind treatment period will continue into the open-
label treatment period where they will receive open-label once-daily treatment with 
MOL. 
• During the trial, whole lung lavage will be allowed as rescue treatment in case of 
worsening of aPAP. 
Disclosure Statement 
This is a parallel group treatment trial with 2 arms that is subject- and investigator-blinded. 
Number of Subjects 
With a total of 160 subjects, the power for showing an effect on change of percent predicted 
DLCO of 5.7 points with a standard deviation of 11 points is 90%. 
The trial size will be re-evaluated by the Sponsor while remaining blinded to treatment after 
80 patients have reached the 24-week primary endpoint time. 
Intervention Groups and Duration 
 

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During the 48-week double-blind treatment period, subjects will be treated once daily with either 
MOL or PBO. All subjects who complete the double-blind treatment period will continue into 
the open-label treatment period where they will receive 96-week open-label once-daily treatment 
with MOL. 
Statistical Analysis 
The primary endpoint of change in % predicted DLCO will be analyzed with a general linear 
mixed model for repeated measurements, fitted with treatment, baseline % predicted DLCO, a 
binary indicator for DLCO stratification and a 3-level factor for region, and visit as categorical 
fixed effects, along with a treatment-by-visit interaction term. The estimated treatment effect will 
be the difference in least squares mean change in DLCO % predicted from baseline to Week 24, 
taken from the treatment-by-visit interaction term at 24 weeks. The estimated treatment effect 
will be presented with a 95% confidence interval and a P-value to test the null hypothesis that the 
effects of MOL and PBO are the same. 
Any subject with missing % predicted DLCO data will have those missing values imputed using 
a multiple imputation method using a conservative control-based rule. 
The seven secondary efficacy endpoints (change in % predicted DLCO from baseline to 
Week 48 and change in Saint George’s Respiratory Questionnaire [SGRQ] Total, SGRQ 
Activity, and exercise capacity, from baseline to Week 24 and baseline to Week 48) will be 
analyzed the same way. 
For Japan and South Korea only: There are four secondary efficacy endpoints (change in Saint 
George’s Respiratory Questionnaire [SGRQ] Total, SGRQ Activity, and exercise capacity, from 
baseline to Week 24 and change in alveolar-arterial oxygen difference (A-aDO2) from baseline 
to Week 24). All of these will be analyzed the same way. 
Two Clinical Trial Reports (CTRs) will be prepared: the first CTR will include the results from 
the double-blind period up to Week 48 and a second CTR will include the results of the open-
label period. 
 
 

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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
 Double-blind Treatment Period 
 
Visit Name 
S1 
S2 
BL 
W4 W8 W12 W16 W20 W24 W36 W48 
Early 
withdrawala 
Unscheduled 
Visit ID 
V1  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
EW 
UN 
Visit window (days) 
± 7 
± 7 
- 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7  
± 7 
± 7 
NA 
NA 
Weeks for Visit 3 
-6 
-3 
- 
4 
8 
12 
16 
20 
24 
36 
48 
NA 
NA 
Informed consent 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(including aPAP 
history)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Resting 12-lead ECG 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
(X) 
Resting vital signs 
and body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry and 
DLCO  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Physical examination 
X 
Xc 
Xc 
X 
Xc 
X 
Xc 
Xc 
X 
X 
X 
X 
(X) 
Need for suppl. O2 
use or WLL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
ABG sample and 
resting respiration rate 
 
 
X 
 
 
X 
 
 
X 
 
X 
Xd 
(X) 
Exercise treadmill test 
 
Xd 
 
 
 
Xd 
 
 
Xd 
 
Xd 
Xd 
(X) 
Handout of eDiary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SGRQe 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
PGIS & PGIC 
 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
EQ-5D-5Le 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
(X) 
Oxygen diaryg 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
DSS 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
(X) 
HRCT 
 
Xd 
 
 
 
 
 
 
Xd 
 
 
(Xd) 
(X) 
CGIS & CGIC 
 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for 
diagnostic anti-GM-
CSF autoantibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
pregnancy test and 
contraceptive checki 
X 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 

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Visit Name 
S1 
S2 
BL 
W4 W8 W12 W16 W20 W24 W36 W48 
Early 
withdrawala 
Unscheduled 
Visit ID 
V1  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
EW 
UN 
Visit window (days) 
± 7 
± 7 
- 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7  
± 7 
± 7 
NA 
NA 
Weeks for Visit 3 
-6 
-3 
- 
4 
8 
12 
16 
20 
24 
36 
48 
NA 
NA 
Samples for 
hematology, 
biochemistry and 
urinalysis 
X 
Xk 
X 
Xl 
Xk 
Xl 
Xk 
Xk 
X 
Xl 
X 
X 
(X) 
Blood sample for 
biomarkers, anti-GM-
CSF antibodies and, 
optionally, biobankm 
 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
(X) 
Blood samples for 
GM-CSF, pre-dose 
and 2 hrs (±30 min) 
post-dose 
 
 
X 
X 
 
 
 
 
X 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility criterian 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP administration 
trainingo 
 
 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
(X) 
IMP dosing in clinic 
 
 
Xp 
X 
X 
X 
X 
X 
X 
X 
Xp 
 
 
Dispense IMP and 
ancillaries 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Return used and un-
used IMP 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Return ancillaries 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Treatment compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Subject instruction 
and diary 
X 
Xq 
Xq 
X 
X 
X 
X 
X 
Xr 
Xr 
Xr 
X 
(X) 
Exit interview 
 
 
 
 
 
 
 
 
Xs 
 
 
 
 
Abbreviations: ABG=Arterial blood gas; anti-GM-CSF=Anti-granulocyte macrophage colony stimulating factor antibodies; 
BL=Baseline visit; CGIC=Clinician’s global impression of change; CGIS=Clinician’s global impression of severity; 
DLCO=Diffusing capacity of the lungs for carbon monoxide; DSS=Disease severity score; ECG=Electrocardiogram; EQ-5D-
5L=EuroQoL 5 Dimensions, 5 Levels; FU=Follow-up; GM-CSF= Granulocyte macrophage colony stimulating factor; 
hr=Hour; HRCT=High resolution-computed tomography; IMP=Investigational medicinal product; min=Minute; NA=Not 
applicable; PGIC=Patient’s Global Impression of Change; PGIC= Patient’s global impression of change; PGIS= Patient’s 
global impression of severity; S1/S2=Screening Visit 1/2; SGRQ=Saint George’s Respiratory Questionnaire; suppl. 
O2=Supplementary oxygen; W=Week; WLL=Whole lung lavage; X=Mandatory procedure; (X)=Optional procedure to be 
performed if judged necessary by the Investigator. 
 
a. 
The Early Withdrawal visit should be conducted if a subject is withdrawn from the trial before completion of the Week 48 
visit. (See Section 1.3.2 for procedures to be conducted at the Early Withdrawal visit for the open-label treatment period.)  
b. 
An unscheduled visit can be conducted if deemed necessary by the Investigator. 
c. 
Symptom-oriented or brief physical examination as clinically indicated. 
d. 
The exercise treadmill test and the HRCT scan can be performed up to 3 weeks after Screening Visit 2, but prior to the 
Baseline visit. At all other timepoints these assessments can be performed within 7 days after the scheduled visit. These 
 

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procedures, as well as ABG sample, should occur at the Early Withdrawal Visit only if the withdrawal occurs prior to 
Week 48. 
e. 
SGRQ and EQ-5D-5L should be performed before any other trial procedures. 
f. 
Only PGIS will be assessed at Screening Visit 2 and the Baseline visit. PGIS and PGIC should be completed immediately 
after the SGRQ and exercise treadmill test. 
g. 
The oxygen diary should be completed daily, starting from 14 days prior to and until the visit (NB. Only applicable for 
subjects on supplemental oxygen). 
h. 
Only CGIS will be assessed at the Baseline visit. 
i. 
For visits with 12 weeks intervals (i.e., visits after Week 24), women of childbearing potential should also check pregnancy 
at home with monthly urine dipstick pregnancy tests. 
j. 
A urine pregnancy test must also be performed at the Baseline visit, prior to first dosing.  
k. 
Samples only include hematology at these visits. 
l. 
Samples only include hematology and biochemistry at these visits. 
m. Blood samples must be obtained before IMP dosing. 
n. 
The eligibility criteria will be assessed to the extent they are available at Screening visits 1 and 2. At the Baseline visit, all 
eligibility criteria must be assessable and complied with for the subject to be randomized. 
o. 
Re-training, marked as (X), can take place at all visits during the treatment period, if needed. 
p. 
The subject will be observed for 1 hour after the first dose. 
q. 
The Patient Journey sheet will also be handed out at Screening Visit 2 and collected at the Baseline visit.  
r. 
Urine pregnancy test kits will also be provided to females of child-bearing potential. 
s. 
Applicable for prospectively selected sites in North America and/or Europe. Can be performed up to 14 days after the 
Week 24 visit. 
 
 
 

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1.3.2. 
Open-label Treatment Period 
 
Visit Name 
W52a W60 W72 W84 W96 
W108 
W120 
W132 
W144 
W148 
Safety FUb 
Early  
withdrawalc 
Unscheduledd 
Visit ID 
V12 
V13 
V14 
V15 
V16 
V17-20 
V21 
EW 
UN 
Visit window (days) 
± 7 
± 7 
± 7 
± 7 
± 7 
± 14 
± 7 
NA 
NA 
Prior and concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Resting 12-lead ECG 
 
 
X 
 
X 
X 
 
X 
(X) 
Resting vital signs and body 
weight 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
Spirometry and DLCO  
 
X 
X 
X 
X 
X 
 
X 
(X) 
Resting respiration rate 
 
 
X 
 
X 
 
 
X 
(X) 
Physical examination 
 
Xe 
Xe 
Xe 
Xe 
Xe 
 
X 
(X) 
Need for suppl. O2 use or WLL 
 
X 
X 
X 
X 
X 
 
X 
(X) 
Return of eDiary 
 
 
 
 
 
Xf 
 
 
 
SGRQg 
 
X 
X 
X 
X 
X 
 
X 
(X) 
PGIS & PGIC 
 
X 
X 
X 
X 
X 
 
X 
(X) 
EQ-5D-5Lg 
 
 
X 
 
X 
X 
 
X 
(X) 
Oxygen diaryh 
 
X 
X 
X 
X 
X 
 
 
 
HRCT 
 
 
 
 
 
Xo 
 
 
 
CGIS & CGIC 
 
X 
X 
X 
X 
X 
 
X 
 
Blood sample for pregnancy test 
and contraceptive checki 
 
X 
X 
X 
X 
X 
 
X 
(X) 
Samples for hematology, 
biochemistry, and urinalysis 
 
XJ 
Xj 
Xj 
Xj 
Xj 
 
X 
(X) 
Blood sample for biomarkers, 
anti-GM-CSF antibodies and, 
optionally, biobankk 
 
 
X 
 
X 
X 
X b 
X 
(X) 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
IMP administration trainingl 
 
(X) 
(X) 
(X) 
(X) 
(X)m 
 
 
(X) 
IMP dosing in clinic 
 
X 
X 
X 
X 
Xm 
 
 
 
Dispense IMP and ancillaries 
 
X 
X 
X 
X 
Xm 
 
 
(X) 
Return used and un-used IMP 
 
X 
X 
X 
X 
X 
 
X 
 
Return ancillaries 
 
 
 
 
 
Xf 
 
X 
 
Treatment compliance 
 
X 
X 
X 
X 
X 
 
X 
(X) 
Subject instruction and diary 
 
Xn 
Xn 
Xn 
Xn 
Xm 
 
X 
(X) 
Abbreviations: anti-GM-CSF=Anti-granulocyte macrophage colony stimulating factor antibodies; CGIC=Clinician’s global 
impression of change; CGIS=Clinician’s global impression of severity; DLCO=Diffusing capacity of the lungs for carbon 
monoxide; DSS=Disease severity score; ECG=Electrocardiogram; EQ-5D-5L=EuroQoL 5 Dimensions, 5 Levels; FU=Follow-
 

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up; GM-CSF=Granulocyte macrophage colony stimulating factor; HRCT=High resolution-computed tomography; 
IMP=Investigational medicinal product; NA=Not applicable; PGIC=Patient’s Global Impression of Change; PGIC= Patient’s 
global impression of change; PGIS= Patient’s global impression of severity; SGRQ=Saint George’s Respiratory Questionnaire; 
suppl. O2=Supplementary oxygen; W=Week; WLL=Whole lung lavage; X=Mandatory procedure; (X)=Optional procedure to 
be performed if judged necessary by the Investigator. 
 
a. 
The Week 52 visit is a safety telephone visit. 
b. 
The Week 148 safety follow-up visit must be performed 3-5 weeks after the Week 144 visit. At the Week 148 visit, a blood 
sample for anti-GM-CSF antibodies will be obtained and any ongoing AEs at the Week 144 visit will be followed up. 
c. 
The Early Withdrawal visit should be conducted if a subject is withdrawn from the trial before completion of the Week 144 
visit. (See Section 1.3.2 for procedures to be conducted at the Early Withdrawal visit for the double-blind treatment period.) 
d. 
An Unscheduled visit can be conducted if deemed necessary by the Investigator. 
e. 
Symptom-oriented or brief physical examination as clinically indicated. 
f. 
eDiary and ancillaries are to be returned at Week 144 only. 
g. 
SGRQ and EQ-5D-5L should be performed before any other trial procedures. 
h. 
The oxygen diary should be completed daily, starting from 14 days prior to and until the visit (NB. Only applicable for 
subjects on supplemental oxygen). 
i. 
Women of childbearing potential should also check pregnancy at home with monthly urine dipstick pregnancy tests. 
j. 
Samples only include hematology and biochemistry at these visits, except at Weeks 96 and 144 when urinalysis is to be 
performed as well. 
k. 
Blood samples must be obtained before IMP dosing. 
l. 
Re-training, marked as (X), can take place at all visits during the treatment period, if needed (NB. Does not apply at Week 
144). 
m. Does not apply at Week 144. 
n. 
Urine pregnancy test kits will also be provided to females of child-bearing potential. 
o. 
Subjects will undergo another HRCT scan only at the Week 144 visit. 
 
 
 

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2. 
INTRODUCTION 
2.1. 
Trial Rationale 
Molgramostim nebulizer solution is being developed by Savara for the treatment of autoimmune 
pulmonary alveolar proteinosis (aPAP). 
Data from a completed phase 2/3 trial which was Savara’s first trial in aPAP patients, 
MOL-PAP-002, suggested that molgramostim nebulizer solution improves lung pathology, 
pathophysiology, and health status in a dose-frequency dependent fashion (Section 2.2.3). Based 
on these findings, the present phase 3 trial will be conducted to further investigate the efficacy 
and safety of molgramostim nebulizer solution in aPAP.  
2.2. 
Background 
2.2.1. 
Autoimmune Pulmonary Alveolar Proteinosis (aPAP) 
Pulmonary alveolar proteinosis (PAP) is a rare disease with an estimated prevalence in the 
United States (US) of 6.9 per 1,000,000 individuals (McCarthy et al. 2018). More than 90% of 
the reported cases of PAP are classified as autoimmune, whereas other variants (congenital and 
secondary PAP) account for less than 10% of cases. The prevalence of aPAP in Japan has been 
estimated to be 6.2 per 1,000,000 individuals (Inoue et al. 2008).   
It has been shown that pulmonary granulocyte macrophage colony stimulating factor (GM-CSF) 
is required for terminal differentiation of alveolar macrophages (Shibata et al. 2001). 
Autoimmune PAP is mediated by autoantibodies targeting GM-CSF. Lack of GM-CSF leads to 
malfunctioning macrophages resulting in an impaired surfactant catabolism causing 
accumulation of surfactant in the alveoli which has a negative impact on the gas exchange 
between lung and blood (Trapnell et al. 2009). 
PAP has a variable clinical course, ranging from spontaneous resolution to death from infections 
or progressive respiratory failure (Kumar et al. 2018). Most patients with aPAP present as adults 
in the third to fifth decade of life with exertional dyspnea of insidious onset with or without 
nonspecific respiratory symptoms (cough and/or production of white frothy sputum) or systemic 
symptoms (fatigue and/or weight loss), often lasting many months before evaluation or initial 
diagnosis. Fever and hemoptysis are less common and usually present only in the context of 
superimposed infection (Trapnell et al. 2019). In a large Japanese national PAP registry study, 
one-third of patients with aPAP were asymptomatic and were identified only through mandatory 
health screening programs (Inoue et al. 2008). 
There are currently no approved pharmacological treatments for aPAP. Whole lung lavage 
(WLL) is the only treatment option available and is only performed in a limited number of 
specialized centers . The treatment goal in aPAP is to remove excess surfactant from the alveoli, 
improve gas exchange across the alveolar arterial barrier and reduce or eliminate long-term 
parenchymal lung damage. This is attempted with WLL, which is an invasive method to 
physically remove surfactant by ‘washing’ it out with saline. Although the procedure is 
reasonably well tolerated in most patients, it is associated with some morbidity from e.g., 
 

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damage to the airways due to prolonged intubation, side-effects of general anesthesia and 
mechanical ventilation, and trauma to the alveoli from the washing procedure.  
The invasive nature of and risks associated with WLLs, a limited access to centers that can 
perform WLLs, and the variable effect of WLLs due to lack of standardization emphasizes that 
there is an unmet need for a non-invasive, safe and well-tolerated, easily accessible and effective 
treatment for aPAP patients (Khan and Agarwal 2011). 
2.2.2. 
Molgramostim Nebulizer Solution: Mode of Action 
The active substance in molgramostim nebulizer solution, molgramostim, is a non-glycosylated 
form of recombinant human GM-CSF (rhGM-CSF), which is produced in a strain of E. coli 
bearing a genetically engineered plasmid which contains a human GM-CSF gene. Molgramostim 
is formulated in a sterile nebulizer solution which is supplied in vials containing 300 µg of 
molgramostim in 1.2 mL solution and is administered by inhalation via a nebulizer (eFlow 
Nebulizer System). 
The rationale for investigating molgramostim nebulizer solution in respiratory diseases is based 
on the widely recognized ability of GM-CSF to promote differentiation and mobilization of 
different myeloid leukocyte subsets including neutrophils, tissue macrophages/dendritic cells or 
their circulating precursors. Along with other factors, GM-CSF also contributes to the 
proliferation of megakaryocytic and erythroid progenitors (Metcalf 1986; Park et al. 1986). 
Moreover, GM-CSF plays a key role in surfactant homeostasis, by maturation of alveolar 
macrophages (Hamilton 2008; Inaba et al. 1992; Bogunovic et al. 2009). It is crucially involved 
in anti-microbial pulmonary host defense (Unkel et al. 2012; Ballinger et al. 2006; Levine et al. 
1999; Steinwede et al. 2011) and ameliorates lung injury when applied systemically to influenza 
virus-infected mice (Huang et al. 2011) by increasing size and activation of the alveolar 
macrophage pool. In addition to its effects on myeloid cells, GM-CSF was found to be crucial for 
alveolar epithelial repair following hyperoxic and inflammatory lung injury (Cakarova et al. 
2009; Paine et al. 2003). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of molgramostim 
nebulizer solution is provided in the Investigator’s brochure (IB). 
2.2.3. 
Molgramostim Nebulizer Solution: Clinical Evidence 
A phase 1 clinical trial with molgramostim nebulizer solution has been conducted in 42 healthy 
volunteers (MOL-001). In this trial, molgramostim nebulizer solution was well tolerated, no 
severe adverse events (AEs) or serious AEs (SAEs) were reported, and no dose-limiting toxicity 
was observed. Inhaled molgramostim was absorbed into the systemic circulation at levels 
approximately 50-100 times lower than have been shown after systemic administration of 
rhGM-CSF and induced the expected (i.e., in subjects without anti-GM-CSF antibodies) 
pharmacodynamic effects on white blood cell populations in a dose-dependent manner, i.e., 
increases from baseline levels in monocyte, eosinophil, and neutrophil counts. There was no 
development of anti-drug antibodies. 
A randomized, double-blind, placebo-controlled, phase 2/3 trial in 138 adult subjects with aPAP 
has been conducted in 18 countries across Australia, Europe, Israel, Japan, Russia, South Korea, 
Turkey and the United States (MOL-PAP-002). Subjects received double-blind once-daily 
treatment for 24 weeks with either molgramostim 300 μg nebulizer solution continuous once-
 

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daily treatment (MOL-OD; n=46), molgramostim 300 μg nebulizer solution in intermittent 
treatment cycles (MOL-INT; 7 days on and 7 days off treatment; n=45) or placebo nebulizer 
solution (PBO; n=47). After the double-blind period, there was a 24- to 48-week follow-up 
period, during which open-label treatment with alternating cycles of molgramostim nebulizer 
solution 300 µg daily for 7 days and no treatment for 7 days was provided to all subjects. In 
addition, in a European safety extension trial (SAV006-03), subjects from selected countries 
completing MOL-PAP-002 could roll over into long-term open-label treatment with alternating 
cycles of molgramostim nebulizer solution 300 µg daily for 7 days and no treatment for 7 days. 
In MOL-PAP-002, the primary endpoint (the absolute change from baseline of the alveolar-
arterial oxygen difference [A-aDO2] after 24 weeks of treatment) improved (i.e., reduction in 
A-aDO2) in all treatment groups. The estimated treatment differences versus PBO were −4.6 and 
−2.8 mmHg (least squares mean [LSmean]), for the MOL-OD and MOL-INT groups, 
respectively. These differences were not statistically significant. After unblinding and 
prespecified analyses, results were found to contain a non-physiologic (large negative) value for 
A-aDO2 in one subject at Week 24. Re-examination of the data revealed this subject and 3 others 
(distributed across all treatment groups) had undergone blood gas analysis while breathing 
supplemental oxygen via nasal cannula, which precluded calculation of the true A-aDO2 because 
the actual fraction of inspired oxygen (FiO2) was unknown. The protocol had anticipated that 
some subjects would use supplemental oxygen during the test; to address for this confounding 
factor, the protocol required that these subjects used the same flow of supplemental oxygen at all 
testing time points and an estimated FiO2 was included in the calculations based on standard 
conversion tables. In a post-hoc analysis with the 4 subjects who used supplemental oxygen 
removed, the estimated treatment differences versus PBO were −6.4 mmHg for the MOL-OD 
group (nominal p=0.0249) and −3.4 mmHg for the MOL-INT group (p>0.05).  
As an alternative measure of gas exchange that is substantially less affected by use of 
supplemental oxygen, the diffusing capacity of the lungs for carbon monoxide (DLCO) was 
included as a secondary endpoint. The estimated differences versus PBO in LSmean change from 
baseline to Week 24 were 7.9% predicted for MOL-OD (nominal p=0.0074) and 2.9% predicted 
for MOL-INT (p>0.05). This pattern was supported by results for the post-hoc responder (>10% 
improvement in DLCO from baseline) analysis which showed odds ratios versus PBO of 3.14 
(nominal p=0.0278) and 1.39 (p>0.05) for MOL-OD and MOL-INT groups, respectively. 
Change in Saint George’s Respiratory Questionnaire (SGRQ) Total score (the SGRQ includes 
questions related to three components [Activity, Impact and Symptoms] and the Total score is 
the sum of the scores of the component scores; Section 4.2.3.2 and Section 8.2.2) was a key 
secondary endpoint. The observed mean changes in SGRQ Total scores from baseline to 
Week 24 were larger for the MOL-OD and MOL-INT groups than for the PBO group (−12.3, 
−12.0 and −4.7 points, respectively). The estimated differences vs PBO in LSmean change from 
baseline to Week 24 were −7.6 for MOL-OD (nominal p=0.0103) and −7.0 for MOL-INT 
(nominal p=0.0173). This pattern was supported by results for the post-hoc responder analysis 
(≥4 units improvement) which showed odds ratios vs PBO of 3.78 for MOL-OD (nominal 
p=0.0075) and 2.78 for MOL-INT (nominal p=0.0307). The estimated differences in change 
from baseline to Week 24 were larger for the Activity and the Impact component scores 
(nominal p<0.05) than for the Symptoms component score (p>0.05). 
 

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For the second key secondary endpoint, 6-minute walk distance (6MWD), the observed mean 
changes in 6MWD from baseline to Week 24 were largest for the MOL-OD group, followed by 
the MOL-INT group and then the PBO group (39.6, 11.3, and 6.0 meters, respectively). The 
estimated differences vs PBO in LSmean change from baseline to Week 24 were 20.6 and 
5.6 meters, respectively, for MOL-OD and MOL-INT (nominal p>0.05 for both comparisons). 
High baseline values for the 6MWD indicate a potential ceiling effect, and the variability for this 
endpoint was high despite efforts to standardize the testing across sites. 
The third key secondary endpoint, time to need of WLL, was not different between the treatment 
groups. However, the number of WLL procedures required over the 24-week double-blind period 
was numerically in favor of MOL-OD and MOL-INT (9 and 7, respectively, compared to 17 for 
the PBO group). The yearly rate of WLL prior to the trial was 0.804 for all subjects, and in the 
double-blind period, rates were 0.422, 0.336, and 0.815 for MOL-OD, MOL-INT, and PBO, 
respectively. The rate ratios vs PBO using negative binomial regression were 0.284 for the 
MOL-OD group and 0.367 for the MOL-INT group (p>0.05). During the open-label follow-up 
period, a total of 5 WLLs were required, corresponding to a rate of 0.055 per subject year. Thus, 
the reduced rate of WLL compared with baseline and PBO in the double-blind period was 
sustained and reduced further during the follow-up period. 
The subjects who had received PBO during the double-blind period showed improvements in the 
primary and key secondary endpoints in the follow-up period after switching to active treatment. 
Furthermore, the improvements observed in the active treatment groups during the double-blind 
period were maintained during the additional 24 to 48 weeks of open-label follow-up treatment. 
In general, the profiles of treatment-emergent AEs, SAEs, adverse drug reactions (ADRs), severe 
AEs, and AEs leading to discontinuation were similar across the treatment groups during the 
double-blind period, and between the double-blind and follow-up periods. Only two AEs, Chest 
pain and Cough, occurred more frequently in the MOL-OD compared to the PBO treatment 
group. 
Based on the positive findings noted above but acknowledging that the available data are not 
sufficient to demonstrate the substantial evidence of efficacy and safety required for regulatory 
approval, the present phase 3 trial will be conducted to further investigate the efficacy and safety 
of molgramostim nebulizer solution in aPAP. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
A summary of risks which may be associated with either the investigational medicinal product 
(IMP) molgramostim nebulizer solution or the trial procedures and mitigation strategies to 
address these is provided in Table 1. More detailed information about the risks associated with 
the IMP may be found in the IB. 
 

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Table 1: 
Summary of Risks and Mitigation Strategies 
Investigational Medicinal Product (molgramostim nebulizer solution) 
Risk Title: Type I hypersensitivity 
reactions (including anaphylaxis, 
urticaria, angioedema and 
bronchoconstriction) 
Risk Description: This is considered a risk due to the inherent risk of 
immunogenicity reactions to therapeutic proteins, although no 
hypersensitivity reactions were observed in clinical trials for 
molgramostim nebulizer solution. 
Risk Mitigation: First dosing will be conducted in the clinic. Subjects will 
be observed for any hypersensitivity reactions for 1 hour after the first 
dose. If a subject develops a type I hypersensitivity reaction further dosing 
should be suspended, permanently or temporarily, according to 
Investigator’s judgment. The subject should be contacted by phone 8-12 
hours after the event to check for any delayed reaction.  
Hypersensitivity reactions will be reported as AESIs with associated 
additional data collection to enable thorough evaluation in relation to 
regular monitoring activities during trial conduct. 
Subjects experiencing serious hypersensitivity reactions will be 
discontinued from the trial. 
Risk Title: Use in Pregnancy 
Risk Description: Embryo-fetal developmental toxicity studies in rabbits 
after subcutaneous dosing showed molgramostim-related embryo-fetal 
loss, and a slight increase in the incidence of major malformations at the 
highest dose level when dosed during early pregnancy. The safety factor 
based on AUC for plasma GM-CSF at NOAEL in rabbits and the 
theoretical AUC in aPAP subjects after inhalation of 300 µg dose is 19. 
The enhanced pre- and post-natal development study in cynomolgus 
monkeys following intravenous injection of molgramostim showed a 
higher frequency of abortions and early deliveries in molgramostim treated 
animals compared to control animals. A NOAEL could not be identified 
due to adverse findings at both dose levels. The AUC for plasma GM-CSF 
in cynomolgus monkeys at the lowest dose was 200-fold higher than the 
theoretical AUC in aPAP subjects after inhalation of 300 µg dose. 
Maternal health and post-natal survival and development of infants was 
unaffected by molgramostim treatment.   
No reports regarding the use of rhGM-CSF in pregnancy or lactation have 
been published. Studies in humans to determine effects of molgramostim 
nebulizer solution on fertility have not been undertaken.   
Risk Mitigation: Pregnant and breastfeeding women will not be included 
in this trial. Women of childbearing potential should use adequate 
contraception during the trial. Male subjects should agree to use condoms 
during the trial, or their female partner of child-bearing potential should 
use adequate contraception. 
During the trial check of contraceptive use and pregnancy testing will be 
performed in women of childbearing potential at each trial visit where 
molgramostim is dispensed. In addition, pregnancy testing will be 
performed at home at monthly intervals during treatment. If the patient 
becomes pregnant while receiving molgramostim nebulized solution, she 
should be apprised of the potential hazard to the fetus and treatment should 
be discontinued during pregnancy.  
 

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Risk Title: Cough 
Risk Description: In MOL-PAP-002, there was a higher proportion of 
subjects reporting non-serious, mild to moderate Cough or Productive 
cough during 24 weeks’ double-blind treatment in MOL-OD (~41%) 
compared to PBO (~30%). Onset of Cough did not appear to be linked to a 
certain duration of treatment. Duration of Cough varied from one day to 
ongoing. 
Risk Mitigation: Pulmonary function test will be performed as outlined in 
the Schedule of Activities and will, along with review of adverse events, 
be part of regular safety monitoring activities during trial conduct. 
Risk Title: Chest pain 
Risk Description: In MOL-PAP-002, there was a higher proportion of 
subjects reporting non-serious, mild ’Chest pain’ cases during 24 weeks’ 
double-blind treatment with MOL-OD (22%) compared to PBO (2%). 
Review of associated Reported terms as well as relevant co-occurring AEs 
did not indicate a cardiac origin of ‘Chest pain’, although two subjects in 
the MOL-OD group had ‘Chest pain’ without any co-occurring AEs or 
SAEs of non-cardiac origin, or any pre-existing cardiovascular medical 
history. As such it cannot be ruled out that these two ‘Chest pains’ may be 
of cardiac origin and/or result from MOL-OD treatment. Onset of ‘Chest 
pain’ did not appear to be linked to a certain duration of treatment. 
Duration of ‘Chest pain’ varied from one day to ongoing. 
Risk Mitigation: All subjects should be instructed to call the site if chest 
pain develops, and based on the information provided over the phone, 
additional investigations may be conducted according to Investigator’s 
judgment. Chest pain will be reported as an AESI with associated 
additional data collection, including findings from any additional 
investigations conducted, to enable thorough evaluation in relation to 
regular safety monitoring activities during trial conduct. 
Trial Procedures 
Risk Title: Blood sampling 
Risk Description: Blood sampling is invasive and there is always a slight 
risk of bruising, infections, pain etc. 
Risk Mitigation: All blood sampling will be performed by trained staff 
and the volume of blood to be drawn at each occasion is small (10-40 mL) 
Risk Title: DLCO 
Risk Description: During the DLCO test, subjects will need to inspire 
minute amounts of carbon monoxide and tracer gases (e.g., 10% helium) 
and he/she needs to temporarily come off oxygen supply.  
Risk Mitigation: The DLCO is a well-known and frequently used test 
which will be performed on-site under supervision by qualified staff. 
Risk Title: Exercise treadmill test 
Risk Description: In subjects with preexisting heart and respiratory 
disease, e.g., angina, there may be a risk of exacerbation of these 
conditions during the test. 
The test must be performed without supplementary oxygen and this might 
induce a risk of desaturation. 
The assessment involves exercise on a treadmill which might cause a risk 
of fall. 
 

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Risk Mitigation: The test will be performed in qualified laboratories 
under supervision by qualified staff. Contraindications for the test will be 
applied according to established clinical guidelines. 
The subjects will be monitored throughout the test including 12-lead ECG, 
HR, BP, SpO2 and subjective symptoms. Termination criteria are applied 
in accordance with established clinical guidelines. 
Risk Title: HRCT 
Risk Description: Risk in connection with radiation.  
Risk Mitigation: The test is only mandated three times over the course of 
the study (i.e., over approximately 3 years), which should be consistent 
with routine HRCT frequency in this patient population. 
Other 
Risk Title: Use of placebo 
Risk Description: 50% of the subjects will be treated with placebo during 
the 48-week double-blind period. This might result in deterioration of 
aPAP. 
Risk Mitigation: Both active and placebo treatments will be added on top 
of current standard of care in form of supplemental oxygen when required 
and rescue treatment with WLL in case of worsening.  
Subjects who have been randomized to placebo and completed the first 
double-blind 48 weeks of the trial and have not permanently discontinued 
IMP due to unacceptable AE will be provided active treatment during the 
96-week open-label treatment period. 
Abbreviations: AE=Adverse event; AESI=Adverse event of special interest; aPAP= autoimmune pulmonary 
alveolar proteinosis; AUC=Area under the plasma concentration-time curve; BP=Blood pressure; 
DLCO=Diffusing capacity of the lungs for carbon monoxide; ECG=Electrocardiogram; GM-CSF=Granulocyte 
macrophage colony stimulating factor; HR=Heart rate; HRCT=High resolution-computed tomography; 
IMP=Investigational medicinal product; rhGM-CSF=Recombinant human granulocyte macrophage colony 
stimulating factor; MOL-OD=Molgramostim nebulizer solution once daily; NOAEL=No observed adverse effect 
level; PBO=Placebo; SpO2=Oxygen saturation; WLL=Whole lung lavage. 
2.3.2. 
Benefit Assessment 
Currently, no approved pharmacological treatment nor any evidence-based treatment exists for 
aPAP. Due to the pathophysiology of aPAP, this condition can lead to associated morbidity, 
including respiratory infections, pulmonary fibrosis and potentially premature death. Thus, an 
unmet need for further treatment modalities exists. Successive WLL procedures remain the 
standard of care treatment with a symptomatic rather than a targeted pathophysiological 
approach.  
Recent data from MOL-PAP-002 (Section 2.2.3) with a consistent numerical improvement on 
various endpoints, representing several elements of aPAP disease (i.e. lung pathology, 
pathophysiology, walking capacity, health status and need for rescue therapy) with no identified 
significant safety concerns indicate that molgramostim nebulizer solution may be a beneficial 
non-invasive and convenient treatment option for patients with aPAP. 
2.3.3. 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risks to subjects participating in this trial, 
the risks associated with use of molgramostim nebulizer solution or the trial procedures are 
justified by the anticipated benefits that may be afforded to subjects with aPAP in this trial. 
 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Efficacy 
 
Investigate the 
efficacy of MOL 
compared to placebo  
Primary 
• 
Change in % predicted DLCO from baseline to Week 24 
Secondary (For regulatory authorities outside of Japan and Korea) 
 
• 
Change in % predicted DLCO from baseline to Week 48 
 
• 
Change in SGRQ Total from baseline to Week 24 
 
• 
Change in SGRQ Activity from baseline to Week 24 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 24 
 
• 
Change in SGRQ Total from baseline to Week 48 
 
• 
Change in SGRQ Activity from baseline to Week 48 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 48 
 
Secondary (Specifically for Japan and South Korea) 
 
• 
Change in SGRQ Total from baseline to Week 24 
 
• 
Change in SGRQ Activity from baseline to Week 24 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 24 
 
• 
Change in A-aDO2 from baseline to Week 24 
 
Exploratory 
 
• 
Frequency of WLL in the period between baseline and Week 24, and between 
baseline and Week 48 
 
• 
Change in SGRQ Impact from baseline to Week 24 and Week 48 
 
• 
Change in SGRQ Symptoms from baseline to Week 24 and Week 48 
 
• 
Change in distance walked during treadmill test from baseline to Week 24 and 
Week 48 
 
• 
Change in duration of exercise during treadmill test from baseline to Week 24 
and Week 48 
 
• 
Change in A-aDO2 from baseline to Week 24 (included as Secondary endpoint 
for Japan and South Korea) and Week 48 
 
• 
Change in PaO2 from baseline to Week 24 and Week 48 
 
• 
Change in DSS from baseline to Week 24 and Week 48 
 
• 
Change in GGO from baseline to Week 24 
 
• 
Change in CGIS from baseline to Week 24 and Week 48 
 
• 
CGIC at Week 24 and Week 48 
 
• 
Change in PGIS from baseline to Week 24 and Week 48 
 
• 
PGIC at Week 24 and Week 48 
 

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Objectives 
Endpoints 
 
• 
Change in supplemental oxygen use from baseline to Week 24 and Week 48 
 
• 
Change in biomarker levels from baseline to Week 24 and Week 48 
 
• 
Change in EQ-5D-5L from baseline to Week 24 and Week 48 
 
• 
Change in dyspnea from baseline to Week 24 and Week 48 
 
• 
Number of hospitalizations in the period between baseline and Week 24, and 
between baseline and Week 48 
 
Exploratory (Specifically for Japan and South Korea) 
 
• 
Change in % predicted DLCO from baseline to Week 48 
 
• 
Change in SGRQ Total from baseline to Week 48 
 
• 
Change in SGRQ Activity from baseline to Week 48 
 
• 
Change in EC (expressed as peak METs) from baseline to Week 48 
Safety 
 
Investigate the safety 
of MOL compared to 
placebo  
Safety Endpoints 
• 
Frequencies of (S)AEs, (S)ADRs, AESIs, deaths and AEs leading to 
withdrawal from trial and/or permanent discontinuation from treatment in the 
period between baseline and Week 24, and between baseline and Week 48 
• 
Development of treatment-boosted anti-GM-CSF antibody titers during 
24 weeks’ treatment and during 48 weeks’ treatment 
• 
Changes in FVC, FEV1 and FEV1/FVC from baseline to Week 24 and 
Week 48 
• 
Change in QTcF from baseline to Weeks 4 and 24  
Further Exploratory 
Longer-Term 
Objectives 
 
Investigate the 
efficacy of MOL 
during open-label 
treatment 
Exploratory 
• 
Frequency of WLL in the period between baseline and the end of open-label 
treatment  
• 
Changes in % predicted DLCO, SGRQ Total, Activity, Impact and Symptoms, 
CGIS, PGIS, supplemental oxygen use, biomarker levels and EQ-5D-5L from 
baseline to the end of open-label treatment 
• 
Change in GGO from baseline to Week 144 and from Week 24 to Week 144 
• 
CGIC and PGIC at the end of open-label treatment 
• 
Number of hospitalizations in the period between baseline and the end of 
open-label treatment 
Investigate the safety 
of MOL during open 
label treatment 
Exploratory 
• 
Frequencies of (S)AEs, (S)ADRs, AESIs, deaths and AEs leading to 
withdrawal from trial and/or permanent discontinuation from treatment in the 
period between baseline and the end of open-label treatment 
 

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Objectives 
Endpoints 
• 
Development of treatment-boosted anti-GM-CSF antibody titers during 
double-blind and open-label treatment and 4 weeks’ post-treatment 
• 
Changes in FVC, FEV1 and FEV1/FVC from baseline to the end of open-label 
treatment 
 
Abbreviations: A-aDO2=Alveolar-arterial oxygen difference; ADR=Adverse drug reaction; AE=Adverse event; 
AESI=Adverse event of special interest; CGIC=Clinician’s global impression of change; CGIS=Clinician’s global 
impression of severity; DLCO=Diffusing capacity of the lungs for carbon monoxide; DSS=Disease severity score; 
EC=Exercise capacity; FEV1=Forced expiratory volume in 1 second; FVC=Forced vital capacity; GGO=Ground 
glass opacity; GM-CSF=Granulocyte macrophage colony stimulating factor; METs=Metabolic equivalents; 
MOL=Molgramostim 300 µg nebulizer solution; PaO2=Partial pressure of oxygen; PGIC=Patient’s Global 
Impression of Change; PGIS= Patient’s Global Impression of Severity; QTcF=QT interval corrected by Fridericia; 
SADR=Serious adverse drug reaction; SAE=Serious adverse event; SGRQ=Saint George’s Respiratory 
Questionnaire; WLL=Whole lung lavage. 
 

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4. 
TRIAL DESIGN 
4.1. 
Overall Design 
• This is an interventional, randomized, double-blind, 2-arm, parallel, placebo-controlled, 
multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP. 
• 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 4-week safety follow-up 
period (Section 1.2). The maximum treatment duration will be 145 weeks and the 
maximum trial duration will be 156 weeks taking the visit windows into account 
(Section 1.3). 
• Two screening visits will be conducted at 6 and 3 weeks prior to the Baseline visit. It will 
not be possible to assess all eligibility criteria at the screening visits, but subjects should 
meet the eligibility criteria for which the relevant assessment results are available at one 
visit to proceed to the next visit. 
• At the Baseline visit, it is mandatory to meet all eligibility criteria to proceed to 
randomization. Eligible subjects will be centrally assigned through an Interactive 
Response Technology (IRT) system to 48-week double-blind once-daily treatment with 
either molgramostim 300 µg nebulizer solution (MOL) or PBO. The treatment 
assignment will be stratified by region and baseline DLCO (Section 6.3). 
• Subjects who complete the double-blind 48-week treatment period and who have not 
permanently discontinued IMP will continue into the open-label treatment period where 
they will receive once-daily open-label treatment with MOL. 
• A safety follow-up visit (Week 148) will be conducted to follow-up on any AEs starting 
or ongoing at the end of open-label treatment (i.e., Week 144) and to obtain a 4-week 
post-treatment anti-GM CSF antibody sample. 
• During the trial, WLL will be allowed as rescue treatment in case of worsening aPAP. 
• Approximately 50-60 clinical sites will be involved, and each site is expected to 
randomize a minimum of 2 subjects. 
• An independent data monitoring committee (DMC) will perform a safety evaluation 
during the trial (Section 9.7)  
4.2. 
Scientific Rationale for Trial Design 
4.2.1. 
Choice of Overall Trial Design 
The randomized, double-blind, placebo-controlled, parallel-group trial design is a scientifically 
robust comparative design. 
The use of a placebo arm controls for effects of the natural course of disease. The use of a 
placebo comparator arm is justified because there is no approved treatment that could be used as 
an active comparator in the present trial. Both active and placebo treatments will be added on top 
of current standard of care, in the form of supplemental oxygen when required and rescue 
treatment with WLL, in case of worsening. Furthermore, subjects who have been randomized to 
 

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placebo and completed the first 48 weeks of the trial will be provided active treatment for the 
additional 96 weeks.   
The multi-center, international trial design allows for inclusion of subjects with aPAP from 
several regions of the world which will increase the generalizability of the results.  
4.2.2. 
Choice of Subject Population 
The subject population to be included in the current trial will be subjects with aPAP, which 
accounts for over 90% of PAP cases. Subjects with hereditary or secondary PAP will not be 
included. Hereditary PAP is often associated with a defect in the GM-CSF receptor so these 
subjects would be unlikely to benefit from rhGM-CSF treatment. In secondary PAP, treating the 
underlying cause of secondary PAP is usually sufficient to resolve the disease.  
In addition, the aPAP condition should be associated with impaired DLCO, and impairment of 
exercise capacity (EC) demonstrated in the exercise treadmill test. Furthermore, DLCO must be 
stable during the screening period. These criteria should ensure randomization of subjects with 
stable moderate to severe disease and a potential for improvement. Subjects in need of rescue 
treatment (i.e., WLL) should have this procedure conducted prior to being screened for the trial. 
It is expected that some subjects who have previously been treated with GM-CSF will be 
interested to participate in the trial. There is currently no evidence to indicate that previous 
treatment with GM-CSF would impact the response to a second treatment course. Therefore, 
subjects who were previously treated with GM-CSF (in a clinical trial, off-label, or through 
expanded access) may be randomized in the trial provided there is at least a 6-month wash-out 
prior to baseline, and they fulfill all eligibility criteria.  
Subjects with hypoxemia in need of supplemental oxygen, either continuously, intermittently, or 
when required, may use this in accordance with clinical standards. However, certain trial 
assessments must be conducted with subjects breathing room air, and therefore subjects must be 
able to temporarily come off oxygen during trial visits without significant desaturation at rest. If 
the condition worsens during the trial so that they are not able to come off oxygen, these 
assessments will not be conducted due to the risk of obtaining inaccurate data. These 
assessments include the exercise test, which will, after an at least 15-minute oxygen saturation 
(SpO2) stabilization period followed by a 5-minute monitoring period at rest, start conservatively 
at a very slow walking pace with no incline. The test will stop at specified termination criteria, 
including oxygen desaturation to 80% or lower (Section 8.2.3). Further, subjects must also be 
able to come off oxygen supply for a period of at least 15 minutes prior to conducting the DLCO 
maneuver. This interval provides an adequate margin to the specified minimum 10-minute period 
in the ATS/ERS guideline for DLCO (Graham et al. 2017). Lastly, prior to the arterial blood gas 
draw subjects must also be able to come off oxygen supply for at least 15 minutes, which was 
shown to be sufficient for 11 of 12 patients with chronic obstructive pulmonary disease (COPD) 
to stabilize after washing out supplemental oxygen (the 12th patient required 15.6 minutes) 
(Weinreich et al. 2013). Prior to all three assessments, oxygen saturation must be followed and 
should be confirmed to be stabilized prior to assessments, extending the 15-minute period if 
required. 
 

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4.2.3. 
Choice of Endpoints 
4.2.3.1. 
Primary Endpoint 
The primary endpoint is the change in % predicted DLCO from baseline to Week 24. The aim of 
this endpoint is to demonstrate treatment effect on gas exchange, using a standardized lung 
function test that has been shown to predict need for rescue treatment.  
The DLCO is a clinically valuable test of lung function and was first described more than a 
century ago (Morrell 2015). It is based on the concept that the capacity for oxygen transfer from 
the alveolar gas to the pulmonary capillary blood can be estimated by measuring the passive 
diffusion of inhaled carbon monoxide. The single-breath technique of measuring the uptake of 
carbon monoxide in the lung is the most commonly used method globally. The DLCO test is 
convenient and the 10 seconds of breath-holding required for the DLCO maneuver is easy for 
most patients to perform.  
The support for use of DLCO as a primary endpoint is based on the following findings:  
• DLCO is a standardized measure of diffusing capacity, which is widely used in the 
clinical management of patients. 
DLCO is widely used in the clinic to characterize the severity of gas exchange impairment in 
aPAP (Papiris et al. 2014; Tazawa et al. 2010; Wylam et al. 2006). As a pulmonary function test, 
DLCO is considered to better correlate with disease severity in aPAP than spirometry 
assessments (Bonella et al. 2011). It is performed in accordance with ATS/ERS guideline 
(Graham et al. 2017) , and further standardization across sites can be obtained by using the same 
equipment and implementing central overread.  
• DLCO is a measure of the same pathophysiological process that results in the relevant 
clinical outcomes in aPAP. 
The primary pathology of aPAP is a loss of pulmonary GM-CSF signaling that results in a 
defective alveolar macrophage function. This leads to the progressive accumulation of surfactant 
material in the lungs which physically impairs gas exchange across the alveolar membrane. Data 
from MOL-PAP-002 and published data (Tazawa et al. 2010) show a correlation between DLCO 
and the amount of surfactant accumulation, which supports this pathophysiological chain and, 
therefore, that DLCO is predictive of lung pathology assessed using an objective, physical sign 
of disease.  
• DLCO predicts the major clinical event in aPAP, i.e., WLL. 
Although there are no standardized, widely accepted criteria for WLL, there is general agreement 
among clinicians that lung function, computed tomography (CT) findings and subjective 
symptoms drive the decision to conduct a WLL. A published study from multiple clinical sites 
conducting WLL in adults found that 100% of sites used unspecified lung function decline 
(which would include DLCO) as an indication for WLL whereas 70% reported DLCO decline 
specifically as an indication (Campo et al. 2016).  
A national retrospective study in Korea that included 78 PAP patients showed a statistically 
significant difference (p<0.001) in DLCO between patients who required treatment with WLL 
(57.5% predicted [SD 23.3]) and those who could be managed without WLL (82.3% predicted, 
[SD 20.7]) (Hwang et al. 2017). 
 

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Likewise, subjects requiring a WLL during the double-blind period of trial MOL-PAP-002 had a 
lower baseline DLCO than subjects who did not have a WLL. Summarizing baseline data for the 
two groups (excluding a single subject in the WLL group whose baseline DLCO was an extreme 
low outlier) resulted in 37.6% predicted (SD 11.3%) for subjects requiring a WLL versus 50.8% 
predicted (SD 15.5%) for those who did not. Looking at the DLCO at the visit just prior to 
conduct of WLL, the mean DLCO was 34.6% predicted (SD 12.6%) indicating that in most cases 
the WLL decision was related to a persistently low DLCO, rather than an acute worsening 
(which is also in line with the natural history of aPAP). 
In conclusion, based on its properties as a standardized, widely used lung function test, directly 
relevant for the pathophysiology of aPAP, and predictive for the major clinical event of WLL, 
DLCO is considered suitable for use as the primary endpoint in this clinical trial for 
molgramostim nebulizer solution in aPAP. 
4.2.3.2. 
Secondary Endpoints 
The secondary endpoints SGRQ Total, SGRQ Activity, and EC, serve as clinically meaningful 
endpoints that address health status and function.  
Saint George’s Respiratory Questionnaire  
The SGRQ is a questionnaire designed to measure health impairment in patients with asthma and 
COPD. It is also valid for use in bronchiectasis, has been used successfully in patients with 
kyphoscoliosis and sarcoidosis, and there is a report on validity in cystic fibrosis (Jones 2009).  
Although SGRQ is not validated in aPAP, there are two studies in aPAP patients where SGRQ 
has been used, MOL-PAP-002 and a recently published study from China (Tian et al. 2020). 
The SGRQ 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 (effect of respiratory symptoms, their frequency and 
severity). A component score can be calculated for each component and a Total score can also be 
calculated that summarizes the impact of the disease on overall health status. 
The Activity component assesses the patients’ current state in terms of disturbance to patients’ 
daily physical activity. The two questions used to calculate the Activity component score are 
disease non-specific and measure functional aspects of shortness of breath.  
The baseline data from MOL-PAP-002 shows that a vast majority of patients are limited in their 
ability to walk up hills (94%), play sports (93%), and walk up a flight of stairs (81%). Patients 
are also commonly limited in their ability to walk around outside on level ground (46%), wash or 
dress themselves (37%), or walk around the house (28%). However, few patients report 
limitations while sitting or lying still (7%) or in taking a bath or shower (18%). 
The concepts in the two questions that are used for the Activity component score assess activities 
that cause breathlessness or are limited by breathlessness. Breathlessness is a common symptom 
of aPAP. SGRQ Activity component thus seems to be a reasonable measure of breathlessness in 
aPAP patients. 
The Impact component assesses the patients’ current state, and measures impact of cough and 
breathlessness on a physical, psychosocial and daily activity perspective. The questions used to 
calculate the Impact component score are disease non-specific.  
 

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The baseline data from MOL-PAP-002 show that the most frequently reported impacts were 
getting exhausted easily from cough and breathlessness (67%), not feeling exercise is safe (62%) 
and not being able to play sports (80%). 
The questions in the Symptoms component cover 4 symptoms (cough, sputum, shortness of 
breath, attacks of wheezing) and 4 additional symptom-related questions (number of severe or 
very unpleasant respiratory attacks, duration of worst respiratory attack, number of good days 
with few respiratory problems, and morning wheeze). The numbers of subjects who reported 
each of the 4 symptoms at baseline in MOL-PAP-002 are shown below (Table 2). Cough, 
sputum and/or shortness of breath (regardless of frequency) were present in a majority of 
subjects. 
Table 2: 
Frequency of Symptoms in MOL-PAP-002 (% of Subjects) 
Symptom 
Most days 
a week 
Several 
days a 
week 
A few days 
a month 
Only with 
respiratory 
infections 
Not at all 
Cough 
36 
23 
17 
7 
17 
Sputum 
32 
18 
16 
5 
29 
Shortness of breath 
42 
16 
23 
5 
14 
Wheezing attacks 
7 
7 
12 
6 
68 
Based on published data, the symptom burden in PAP is available from three cohort studies: a 
Japanese cohort study involving 223 patients (Inoue et al. 2008), a German cohort study 
involving 70 patients (Bonella et al. 2011), and an Italian cohort study involving 73 patients 
(Campo et al. 2013). Dyspnea (shortness of breath) was most commonly reported, followed by 
cough. The data from MOL-PAP-002 is consistent with the literature of shortness of breath and 
cough being the major symptoms, reported by most subjects. Based on MOL-PAP-002 the 
frequency of sputum (elicited through direct questioning) seems to be higher than previously 
reported in the literature. Wheezing attacks is not a symptom that is thought to be associated with 
aPAP, as this is not an obstructive lung disorder. It is not clear why one third of subjects reported 
this symptom. In addition, almost 50% of the subjects reported respiratory attacks, and it is not 
clear what this concept covers in the context of aPAP. 
Although not all symptoms included in the Symptoms component score are typically experienced 
by aPAP patients, the SGRQ Total score is a clinical endpoint that addresses direct patient 
benefit, i.e., overall respiratory health status including limitations in function from dyspnea. 
In MOL-PAP-002, there was numerical improvement in the SGRQ Total score as well as 
component scores of MOL-OD over PBO, and there was nominal statistical significance for the 
Total score, the Activity component score and the Impact component score (Figure 1).  
In particular, the Activity component score has high face validity in aPAP as it is focused on 
limitations in daily activities due to breathlessness. Likewise, the Impact component is not 
disease-specific and provides relevant data on the psychosocial impact of aPAP symptoms and 
activity limitations. By using the SGRQ Total score, both these components are covered, and a 
broad picture of patients’ health status is provided.  
 

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exercise testing is recognized as an important component of disease severity assessment (Khan 
and Agarwal 2011) and guiding therapeutic decisions (Borie et al. 2011). 
Given that exertional symptoms are hallmark characteristics in patients with aPAP and that 
profound limitations in EC were observed in a cohort of 7 patients with aPAP (Bautin et al. 
2005), use of exercise testing as an endpoint in clinical trials in aPAP is warranted. Previous 
research supports this approach, indicating significant improvements in EC following WLL or 
subcutaneous GM-CSF in patients with aPAP (Beccaria et al. 2004; Schoch et al. 2002; Seymour 
et al. 2001). 
The 6-minute walk test (6MWT) is an accepted method of assessing functional capacity in 
patients with pulmonary diseases (American Thoracic 2002; Holland et al. 2014). The MOL-
PAP-002 trial assessed the 6MWD, which showed a trend to improvement with MOL-OD that 
did not reach statistical significance over PBO. The potential for improvement on this test in the 
overall trial population was limited by the relatively long distances, on average around 400 m, 
that subjects walked at baseline. For reference, in healthy persons, the mean 6MWD is reported 
as 580 m in men and 500 m in women (American Thoracic 2002). It is hypothesized that within 
the target population of moderate to severe aPAP, the test is not sufficiently sensitive in 
demonstrating improvements in function, because the test methodology does not force patients to 
achieve maximum EC. Furthermore, the variability of the test is large as it does not require 
subjects to exert maximum effort and thereby is highly dependent on subject motivation. 
In the present trial, a ramp-up treadmill exercise test will be used to assess EC (Section 8.2.3). 
This is a well-accepted, reliable and valid (Fletcher et al. 2013; Arena et al. 2007; Puente-Maestu 
et al. 2016) approach to assessing baseline EC as well as changes in EC in an interventional trial. 
In fact, treadmill exercise testing overcomes several of the challenges associated with the 
assessment of EC through a timed walk test such as the 6MWT (e.g. ceiling effect, reliability, 
confounding effect of subject motivation/effort) (McLaughlin et al. 2009; Arena et al. 2007; 
Frost et al. 2005). 
The main outcome of the exercise test is EC, expressed as peak metabolic equivalents (METs) 
achieved during the final stage a subject can perform. For each stage of the test, a MET value is 
defined based on a validated equation developed from the Fitness Registry and the Importance of 
Exercise National Database (FRIEND) registry. The FRIEND equation has been confirmed to 
significantly predict the peak measured oxygen consumption (VO2; corresponding to peak MET) 
at a lower error rate compared to previously established equations (Kokkinos et al. 2017). 
Moreover, the difference between estimated and measured VO2 has been shown to be greater for 
protocols with a large increment between stages (e.g. the modified Bruce protocol) compared to 
a conservative ramp test like the one proposed for this trial (Myers et al. 1991). In this context, 
the equation to calculate METs used in the current trial in conjunction with the conservative 
ramp protocol for exercise testing optimizes the accuracy in assessing EC in the current trial. 
As previously noted, peak METs is a well-established and widely used measure of EC. In fact, 
the American Heart Association, which proposed EC be viewed as a vital sign (Ross et al. 2016), 
recognizes peak METs as an accepted expression of EC with high clinical value. The benefit of 
using peak METs as the key efficacy variable of the test is that it accounts for the increase in 
effort associated with the ramp-up of the test, where the effort required to complete the same 
distance in meters or duration in minutes will continuously increase. Thus, the METs required to 
achieve a fixed distance will increase over the course of the test. This makes it more 
 

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discriminatory for improvements in EC at the high end of the test. Furthermore, age- and sex- 
adjusted reference data are available in the literature (Kaminsky, Arena, and Myers 2015). 
Finally, there are well established published data on METs required to perform numerous daily 
activities and thus the achieved MET can be directly translated to the patient’s capability to 
perform a specific activity (Ainsworth et al. 2011; Ainsworth et al. 2000; Jette, Sidney, and 
Blumchen 1990). However, distance walked and exercise duration will be included as 
exploratory endpoints. 
In summary, a controlled exercise test that requires patients to reach their maximum EC by 
means of standardized increases in speed and grade on a treadmill is expected to be a good 
measure of function in this target population for the present trial.  
Japan and South Korea only: Alveolar-arterial oxygen difference 
For Japan and South Korea, A-aDO2 will be used as an additional secondary endpoint as a 
measure of gas exchange. The absolute change from baseline of the A-aDO2 after 24 weeks of 
treatment was the primary endpoint in MOL-PAP-002, and may therefore serve as a bridge from 
the results obtained in MOL-PAP-002 to the results obtained in the present trial. 
4.3. 
Justification for Dose 
In the present trial, treatment with molgramostim nebulizer solution 300 µg administered once 
daily in a double-blind fashion will be investigated against matching placebo for 48 weeks, and 
in an open-label fashion for a subsequent period of 96 weeks.  
The recently completed MOL-PAP-002 trial confirmed that molgramostim nebulizer solution 
administered once daily over 24 weeks (i.e., MOL-OD) consistently showed a numerical 
improvement over the intermittent dosing arm with alternating weeks on and off treatment (i.e., 
MOL-INT). The MOL-OD regimen was nominally statistically significant over PBO for many of 
the secondary and exploratory endpoints in contrast to the MOL-INT regimen. The MOL-OD 
regimen is therefore proposed for further evaluation in the present clinical trial, considering that 
no important risks were identified with either of the investigated dose regimens.  
As molgramostim nebulizer solution is intended for chronic treatment of patients with aPAP, a 
double-blind treatment period of 48 weeks is scheduled in the present trial to obtain efficacy and 
safety data during an extended period of time. 
The subsequent 96-week period where all subjects will be given open-label treatment using the 
same dosing regimen will provide a possibility for active treatment to subjects who have been 
randomized to placebo during the first 48 weeks of the trial. 
4.4. 
End of Trial Definition 
A subject is considered to have completed the trial if he/she has completed the double-blind and 
the open-label treatment periods.   
The end of the trial is defined as the date of the last visit on-site of the last subject in the trial. 
 

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5. 
TRIAL POPULATION 
Subjects fulfilling all inclusion and none of the exclusion criteria can be randomized in the trial.  
Prospective approval of protocol deviations to inclusion or exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Age 
1. Subject must be ≥18 years of age, at the time of signing the informed consent. Specific 
for Japan; Subject must be ≥20 years of age, at the time of signing the informed consent. 
Type of Subject and Disease Characteristics 
2. A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.  
3. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) 
cytology, or a high-resolution computed tomogram (HRCT) of the chest. 
4. DLCO 70% predicted or lower at the first screening and baseline visits. 
5. Change in % predicted DLCO of <15% points during the screening period.   
6. Willing and able to come off supplemental oxygen use prior to and during the treadmill 
exercise test, the DLCO assessment, and the arterial blood gas sampling. 
7. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the 
screening visits. 
Sex 
8. Male or female 
9. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a. Male subjects: Males agreeing to use condoms during and until 30 days after last dose 
of trial treatment, or males having a female partner who is using adequate 
contraception as described below. 
b. Female subjects: 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, 
vasectomized partner, sexual abstinence***), during and until 30 days after last dose 
of trial treatment. Females of childbearing potential must have a negative serum 
pregnancy test at the screening visits, and a negative urine pregnancy test at Baseline 
visit (Visit 3) and must not be lactating.  
* Post-menopausal is defined as no menses for at least 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not 
 

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using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
** A female is considered of childbearing potential following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
***Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the trial treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject.  
Informed Consent 
10. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
11. 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. 
5.2. 
Exclusion Criteria  
Medical Conditions 
1. Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant 
production. 
Prior/Concomitant Therapy 
2. WLL performed within 3 months prior to baseline. 
3. Requirement for WLL at screening or baseline. 
4. GM-CSF treatment within 6 months prior to baseline. 
5. Treatment with rituximab within 6 months prior to baseline. 
6. Treatment with plasmapheresis within 6 weeks prior to baseline. 
Prior/Concurrent Clinical Trial Experience 
7. Treatment with any investigational medicinal product within 5 half-lives or 3 months 
(whichever is longer) prior to baseline. 
8. Previously randomized in this trial. 
Other Exclusions 
9. History of allergic reactions to GM-CSF or any of the excipients in the nebulizer 
solution. 
10. Inflammatory or autoimmune disease of a severity that necessitates significant (e.g., more 
than 10 mg/day systemic prednisolone) immunosuppression.  
11. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product. 
 

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12. History of, or present, myeloproliferative disease or leukemia. 
13. Apparent pre-existing concurrent pulmonary fibrosis, or diagnosis of interstitial lung 
disease other than aPAP. 
14. Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise or 
confound assessment of the primary endpoint: including presence of pulmonary edema, 
or diagnosis of chronic obstructive pulmonary disease (COPD), pulmonary vasculitis, or 
pulmonary hypertension.  
15. Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the 
efficacy evaluation in the trial. 
16. Physical disability or other condition that precludes safe and adequate exercise testing. 
17. Any other serious medical condition which in the opinion of the Investigator would make 
the subject unsuitable for the trial. 
18. Pregnant, planning to become pregnant during the trial, or breastfeeding woman. For 
France only: including as further defined by French Health Code L-1121-5. 
19. For France only: Any subject considered to be “vulnerable” on account of, e.g., mental 
or physical disability, socio-economic situation, or subjects deprived of their liberty, 
including as further defined by French Health Code articles L1121-6, L1121-8, and 
L1121-8-1. 
5.3. 
Lifestyle Considerations 
Smoking is not allowed on the day of DLCO testing, prior to the test. 
5.4. 
Screen Failures 
Screen failures are defined as subjects who sign the ICF but are not subsequently randomized. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious AE (SAE). 
In general, rescreening of subjects who do not meet the criteria for participation in this trial 
(screen failures) is not permitted. However, due to the rarity and natural course of aPAP, subjects 
may be rescreened in certain cases. Rescreening can only occur once and only after discussion 
with the Medical Monitor. The rescreened subjects should be assigned a new screening number 
and will need to perform all assessments again according to the SoA (Section 1.3). There will be 
a question in the electronic case report form (eCRF) to clarify whether the subject has been 
screened before. 
 
 

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6. 
TRIAL INTERVENTION 
Trial intervention is defined as any IMP or medical device(s) intended to be administered to a 
trial subject according to the trial protocol. 
6.1. 
Investigational Medicinal Products 
6.1.1. 
Molgramostim and Placebo Dosing Regimen 
Subjects will be randomized in a 1:1 ratio to MOL:PBO. 
During the 48-week double-blind treatment period, subjects will be self-administering either 
MOL or PBO as a daily inhalation. All subjects who complete the double-blind 48-week 
treatment period and who have not permanently discontinued IMP will continue into the open-
label treatment period where they will receive once-daily open-label treatment with MOL. 
6.1.2. 
Packaging and Labelling 
IMPs will be supplied in kits. Each individual kit will contain the necessary supplies to treat a 
subject for 1 week. Each time a new kit is used, a tear-off label should be placed in a Subject 
Instruction and Diary (Section 8.12) and the date of the first dose taken should be noted. 
Packaging and labelling of the IMPs and the device used for administration (eFlow Nebulizer 
System) will be performed under the responsibility of the Sponsor in accordance with Good 
Manufacturing Practice and national regulatory requirements. Details about the packaging of the 
IMPs and the device is provided in Table 3. 
Table 3: 
Investigational Medicinal Products in SAV006-05 
Investigational Medicinal 
Product Name 
Molgramostim 300 µg nebulizer 
solution (MOL) 
Placebo nebulizer solution (PBO) 
Note: placebo nebulizer solution 
is matched to MOL in appearance, 
color and weight except for the 
active substance. 
Active Substance 
Molgramostim, recombinant 
human Granulocyte Macrophage 
Colony Stimulating Factor (rhGM-
CSF)  
Not applicable 
Dose Formulation 
Nebulizer solution 
Nebulizer solution 
Unit Dose Strengths 
250 µg/mL 
0 µg/mL 
Dosage Levels 
300 µg in 1.2 mL, daily 
0 µg in 1.2 mL, daily 
Device system used for 
administration 
The eFlow Nebulizer System 
including controller, complete 
nebulizer handset and aerosol 
heads (single subject, reusable 
electronic nebulizer) and easycare 
(cleaning aid for aerosol heads) 
will be made available to all 
subjects. 
The eFlow Nebulizer System 
including controller, complete 
nebulizer handset and aerosol 
heads (single subject, reusable 
electronic nebulizer) and easycare 
(cleaning aid for aerosol heads) 
will be made available to all 
subjects. 
 

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Route of Administration 
Inhalation of MOL using eFlow 
Nebulizer System.  
Inhalation of PBO using eFlow 
Nebulizer System. 
Sourcing 
Provided centrally by the Sponsor Provided centrally by the Sponsor 
Packaging and Labeling 
(IMPs) 
MOL: 
Provided in a kit containing 7 
vials. Each kit will be labelled 
with a trial-specific label as 
required per local regulations and 
will be printed in local language. 
 
Device: 
The main components (controller 
and handset) of the eFlow 
Nebulizer System will be labelled 
with a trial-specific label and will 
be printed in local language. 
The easycare cleaning aid will be 
enclosed in the box with the 
controller). 0.9% saline (isotonic 
sodium chloride solution) needed 
for cleaning will be supplied. 
PBO: 
Provided in a kit containing 7 
vials. Each kit will be labelled 
with a trial-specific label as 
required per local regulations and 
will be printed in local language. 
 
Device: 
The main components (controller 
and handset) of the eFlow 
Nebulizer System will be labelled 
with a trial-specific label and will 
be printed in local language. 
The easycare cleaning aid will be 
enclosed in the box with the 
controller). 0.9% saline (isotonic 
sodium chloride solution) needed 
for cleaning will be supplied. 
6.2. 
Dispensing/Administration/Storage/Accountability/Destruction 
6.2.1. 
Dispensing 
IMPs and ancillaries (e.g., nebulizer handsets) be dispensed at the trial visits summarized in SoA 
(Section 1.3). The IMP will only be dispensed to subjects who meet the eligibility criteria and are 
randomized to a treatment group in the trial.  
On each dispensing occasion, an adequate number of kits and ancillaries will be dispensed to 
allow for the dosing regimen of once daily inhalation across the visit intervals (the intervals 
between each dispensing occasion are either 4 weeks or 12 weeks). A spare kit will be supplied 
to cover additional doses needed should visit scheduling require the ±7-day visit window. 
Additional kits can be assigned to subjects as required.   
The IMP and device will be labelled with a unique identifier for dispensing and drug/device 
accountability.   
IMP labels will comply with local regulations and will be printed in local language. 
6.2.2. 
Administration 
The eFlow Nebulizer System will be used to administer the IMP. This device has been 
specifically designed for use with molgramostim nebulizer solution. In the US, the device is 
designated as “Investigational” which is reflected on all labeling and accompanying 
documentation. This device is CE certified according to MDD 93/42/EEC. 
 

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The eFlow Nebulizer Handset includes a fine particle aerosol generator (perforated vibrating 
membrane) defined by a 30L mesh and an aerosol chamber that can produce aerosols with high 
density of MOL or PBO, precisely defined droplet size and a high proportion of respirable 
droplets. The eFlow nebulizer handset will be replaced approximately every 4 weeks during the 
treatment period.  
All subjects, investigators and trial nurses will be trained in IMP administration and medical 
device maintenance and assembling procedures. Training of the subject will take place at the 
Baseline visit prior to administration of the subject’s first dose of IMP. The subject will 
administer the first dose of IMP at the Baseline visit (Visit 3) under the supervision of trial 
personnel. Training will ensure that critical tasks for the safe and efficacious delivery of the IMP 
using the eFlow Nebulizer System can be correctly completed. The subject’s ability to perform a 
list of pre-specified critical tasks will be assessed and recorded on a worksheet that will be 
uploaded to the eCRF. A repeat assessment will be done at Week 4 (Visit 4). If re-training is 
needed at subsequent visits, the assessment will be repeated. The subject will be observed for 
any type I hypersensitivity reactions for 1 hour after the first dose. 
Information on how to prepare the IMPs for administration will be provided in the ‘eFlow 
Instruction for Use’ and in the Subject Instruction and Diary. 
During the treatment period, subjects will be instructed to always administer the trial treatment at 
approximately the same time of day. However, on days of trial visits, subjects will be asked not 
to take their trial treatment prior to the clinic visits. At each visit to the site, dosing will take 
place in the clinic, under supervision of trial staff and after all blood samples have been taken 
except the post-dose GM-CSF sample at selected visits. The time of dosing at site will be 
recorded. The subject should be instructed to take the last dose the day before the 48-week and 
144-week visits. 
In the event of a complaint related to the drug product or device, the subject should be instructed 
to immediately call the site. The site will complete a complaint form with all relevant details of 
the incident, including time, date, a description of the complaint and whether dosing was 
affected; refer to the Investigator Drug Manual, also known as the IMP Handling Manual or 
Pharmacy Manual, for the complaint form and instructions for completing and submitting the 
complaint form. For device-related cases, the eFlow Nebulizer System and/or nebulizer handset 
will be replaced, and the treatment should continue.  
6.2.3. 
Storage 
The IMPs should be stored at the trial site or at the site pharmacy as required by local regulations 
and laws for the participating sites. The Investigator will ensure that the IMPs will be stored in 
appropriate conditions in a secure location with controlled access. The storage compartment 
must be monitored, and the temperature documented. The IMPs must be stored at 2-8°C 
(35.6-46.4°F), must not be frozen or shaken and must be protected from sunlight and other light 
sources during storage. Any deviations in storage temperature must be reported to the Sponsor 
without delay as instructed in the Investigator Drug Manual. In case of a temperature deviation 
or damaged kit upon receipt or during storage at trial site, the affected IMPs must not be used 
until acceptance from the Sponsor. The Sponsor will decide if the affected IMPs may be released 
back into inventory, returned to the supply vendor, or destroyed locally. The affected IMPs 
 

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should be kept segregated in quarantine if evaluation results in the decision that the IMPs cannot 
be used.  
Site staff should immediately document the kit status in IRT and contact their clinical research 
associate (CRA) for further guidance.  
Storage of IMP and ancillaries at subjects’ homes should be according to clinical labels and the 
Subject Instruction and Diary. 
6.2.4. 
Accountability 
The responsibility for the IMP and device is transferred from the Sponsor to the Investigator 
from the time of IMP and device receipt at the trial site to the time of destruction or return. 
The Investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and eFlow Nebulizer Systems. The Investigator or delegated person should 
determine IMP kits and nebulizer handset accountability and complete the accountability logs. 
The IMP must be accounted for throughout the duration of the trial. Accountability of IMP is 
performed on a vial level and comments must be made in case of discrepancies. IMP 
accountability will be reviewed by the CRA during monitoring visits and at the completion of the 
trial.  
Copies of all Drug Receipt Confirmations, Returned Clinical Supplies Reconciliation Forms and 
Drug Accountability Logs will be retained in the trial file. These forms are subject to regulatory 
inspection at any time. 
6.2.5. 
Return and Destruction 
Subjects are instructed to return all used/partly used and unused medication including empty 
packaging material at their next clinic visit and at the end of treatment visit. Compliance will be 
assessed at each visit by direct questioning and counting returned vials. This will be recorded in 
the source data (i.e., subject drug accountability form).   
Unused and un-dispensed IMPs must be returned to the supply vendor on an ongoing basis or 
sent for local destruction after agreement with the Sponsor, but only after drug accountability has 
been completed and verified by the CRA. IMP return will be described further in the Investigator 
Drug Manual.  
IMPs to be returned to the supply vendor can be stored at room temperature and must be stored 
separately from non-allocated IMPs. Returned IMPs should not be re-dispensed to the subjects. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Double-blind Treatment Period 
All eligible subjects will be centrally randomized to IMP using an IRT system in the double-
blind treatment period. The IRT system will ensure random allocation of eligible subjects to the 
MOL and PBO treatment groups.  
The treatment randomization is intended to be stratified by baseline DLCO and by region. Thus, 
subjects will be randomized to treatment arms in a 1:1 ratio according to whether they have a 
DLCO of >50% predicted or ≤50% predicted. Furthermore, subjects will be regionally stratified 
 

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based on whether they are living in Asia and Australia, Europe including Turkey, or North 
America.  
All subjects will inhale IMP once daily during the double-blind treatment period. Blinding will 
be ensured using a matching placebo. 
A statistician otherwise not involved in the trial will prepare a computer-generated 
randomization list. The randomization list and treatment allocation list will not be available to 
any person involved in the conduct and evaluation of the trial until the trial database is declared 
clean and locked.   
The IRT system will be integrated with the Electronic Data Capture (EDC) system and the log in 
information and instructions for the system will be provided to each site. 
The packaging and labelling of the IMPs for the double-blind treatment period will contain no 
evidence of their identity and it is not considered possible to differentiate between the IMPs 
solely by sensory evaluation. 
The IRT system will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a subject’s 
intervention assignment is warranted. Subject safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to unblinding a subject’s 
intervention assignment unless this could delay emergency treatment of the subject. If a subject’s 
intervention assignment is unblinded, the Sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. 
If code break is considered necessary for other safety concerns, for example due to signals of 
alerting ADRs and regulatory reporting of suspected unexpected serious adverse reactions 
(SUSARs), unblinding can be performed by the Sponsor without compromising blinded 
members of the trial team, and the reason for unblinding should be documented.  
6.3.2. 
Open-label Treatment Period 
All subjects who complete the double-blind 48-week treatment period and have not permanently 
discontinued IMP will continue into the open-label treatment period where they will receive 
once-daily open-label treatment with MOL.   
6.4. 
Trial Intervention Compliance 
Subjects’ self-administration of IMP at home and treatment compliance will be assessed at each 
visit, including timing of dose (e.g., morning or evening). Compliance will be assessed by 
checking unused and used vials during the site visits and data will be entered in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in 
the eCRF. 
A record of the number of IMP vials dispensed to and taken by each subject must be maintained 
and reconciled with IMP and compliance records. Intervention start and stop dates, including 
dates for intervention delays, and compliance below 80% between the visits will also be recorded 
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If a subject is found to be non-compliant, the Investigator should remind the subject of the 
importance of following the treatment instructions and the degree of and nature of non-
compliance will be specified.   
If a dose of IMP is missed, the subject should not adjust their dosing schedule to accommodate 
the missed administration. The subject should therefore not reschedule dosing to achieve the 
dosing regimen or add the missed dose to the next administration. 
6.5. 
Prior/concomitant Therapy 
6.5.1. 
Prior Therapy 
Relevant prior therapy should be reported in the subject’s medical record and the eCRF. 
Relevant prior therapy includes but is not necessarily limited to all previous WLL procedures, 
plasmapheresis procedures, GM-CSF, rituximab, statins and pioglitazone treatment (life-long 
recall period). Use of supplemental oxygen or any other treatment for aPAP should be reported 
for a period of 6 months prior to Screening Visit 1. All other prior therapy should be reported if 
considered relevant by the Investigator. 
6.5.2. 
Concomitant Therapy 
The use of concomitant medicines or other treatment regimen during the trial should be kept at a 
minimum and as stable as possible. 
During the trial, subjects must abstain from the therapies described in Table 4. 
Table 4: 
Disallowed Therapy 
Therapy 
Any GM-CSF other than the IMP 
Rituximab 
Plasmapheresis 
Any investigational medicinal product (this also 
includes approved products when administered as 
experimental therapy for aPAP) 
The disallowance of these therapies should start at the time of signing informed consent. 
Subjects who want to start disallowed therapy for aPAP must withdraw from the trial and will 
not be able to re-enter, e.g., in the open-label period.  
Any therapy that the subject is receiving at the time of screening or receives during the trial must 
be recorded in the eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose, dose unit and frequency 
• Administration route 
 

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6.5.3. 
Rescue Treatment 
During the trial, WLL is allowed as rescue treatment for worsening aPAP.  
Subjects in need of WLL prior to the trial should have the procedure performed at least 3 months 
before Baseline, and therefore screening activities cannot be started until approximately 6 weeks 
after the WLL. Subjects who require a WLL during screening or at baseline are not eligible. 
Such subjects may be rescreened once, after consultation with the Sponsor and respecting the 
window for pre-trial WLL so that fulfilment of the inclusion criteria can be established after the 
WLL. 
The primary reason for conducting WLL should be provided in the eCRF. Date of the WLL and 
type of WLL (right or left lung), amount of saline used, and time used for performing the WLL 
will be documented. For sites applying therapeutic segmental or lobar lavages, such lavages will 
also be recorded. 
Before and after WLL, an assessment of DLCO, and other relevant assessments according to the 
Investigator’s discretion, should be obtained. This could be done at the regular trial visits, 
provided that they occur within 4 weeks prior to and after the procedure, respectively. Otherwise, 
an unscheduled visit should be conducted. If two unilateral WLLs are conducted in a preplanned 
sequence less than 4 weeks apart, the DLCO assessments should be done within 4 weeks before 
the first WLL and after the second WLL, respectively. 
6.5.4. 
Oxygen Supplementation 
Oxygen supplementation may be considered necessary for subject safety and well-being and may 
be given according to clinical standards at the discretion of the Investigator. Indications for 
oxygen supplementation will be recorded in the eCRF by the Investigator or designee and 
subjects will self-report actual oxygen use during the trial. 
However, certain trial assessments (i.e., the exercise treadmill test, DLCO test and arterial blood 
gas assessment) must be conducted with subjects breathing room air, and therefore they must be 
able to temporarily come off oxygen during trial visits without significant desaturation at rest 
(see Section 4.2.2).  
If a subject is unable to come off supplemental oxygen prior to any of these trial assessments, the 
assessment will not be performed. The reason for omitting an assessment should be documented 
in the eCRF. The subject will continue in the trial and conduct all other assessments according to 
the protocol. 
6.6. 
Dose Modification 
The dose of the IMPs must not be modified in the trial. 
6.7. 
Intervention after the End of the Trial 
After completion of the trial, the Investigator will advise trial subjects on access to appropriate 
and available treatment options. 
 

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7. 
DISCONTINUATION OF TRIAL INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Investigational Medicinal Product 
In rare instances, it may be necessary for a subject to discontinue IMP, if deemed necessary by 
the Investigator. 
Potential reasons for discontinuation of IMP are:  
• Lack of efficacy/worsening of disease 
• Unacceptable AE (Section 8.4.3) 
• Pregnancy (Section 8.4.5) 
If IMP is discontinued, the subject will remain in the trial and will be encouraged to continue to 
follow the same visit schedule, i.e., they will continue through the 48-week double-blind period 
and then they may continue into the open-label period.  
The reason and date the subject is discontinued from IMP will be documented in the eCRF. 
7.2. 
Withdrawal from the Trial 
A subject may withdraw from the trial at any time at his/her own request or may be withdrawn at 
any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons. Withdrawal from the trial will not affect or prejudice the subject’s further care or 
treatment. 
At the time of withdrawal from the trial, if possible, an early withdrawal visit should be 
conducted, as shown in the SoA (Section 1.3). See the SoA for data to be collected at the time of 
trial withdrawal and follow-up and for any further evaluations that need to be completed. The 
reason and date the subject is withdrawn from the trial will be documented in the eCRF.  
Subjects who withdraw before randomization will be considered screen failures. 
If a subject withdraws from the trial, the data collected on the subject to the point of withdrawal 
(including data and samples collected during the early withdrawal visit, if conducted) remain part 
of the trial database and will not be removed.   
If a subject withdraws from the trial and withdraws consent for analysis of samples taken but not 
yet analyzed, the Investigator or designee must document this in the site trial records and 
expedite notification to the Sponsor. The Sponsor will notify the relevant laboratories and 
request destruction of any stored biological material in accordance with the subject’s wishes. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 
The following actions must be taken if a subject fails to return to the clinic for a required trial 
visit: 
 

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• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the trial. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the trial.  
Discontinuation of specific sites or of the trial as a whole is described in Section 10.1. 
 

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8. 
TRIAL ASSESSMENTS AND PROCEDURES 
Trial procedures and their timing are summarized in the SoA (Section 1.3). The informed 
consent process must be completed prior to any other assessment or procedure.  
At each visit, where applicable, the order of assessments should preferably follow the order in 
the SoA. However, the following sequences must be adhered to: 
• Assessments in the eDiary (SGRQ, immediately followed by the corresponding 
SGRQ-related PGIS and, where applicable, PGIC; and EQ-5D-5L) should be done 
before any other assessments. 
• For the pulmonary function tests, spirometry assessment should be performed prior to 
the DLCO assessments.  
• Arterial blood gas sampling and other laboratory sampling must be done prior to IMP 
dosing at site.  
• At visits, where the exercise treadmill test is conducted, it may be done on a separate 
day than the other assessments. If the exercise treadmill test is done on the same day, 
it should be done after pulmonary function tests and arterial blood sampling. The 
corresponding exercise-related PGIS and, where applicable, PGIC, should be done 
immediately after the exercise treadmill test.  
• AE assessment should be done after IMP dosing at site. 
Protocol waivers or exemptions are not allowed. 
Safety concerns may lead to discontinuation of IMP if deemed necessary by the investigator. 
Adherence to the trial design requirements, including those specified in the SoA, is essential and 
required for trial conduct. 
At the Baseline visit, all screening evaluations must be completed and reviewed to confirm that 
potential subjects meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for screen 
failure, as applicable. 
8.1. 
Demographics and Medical History 
8.1.1. 
Demographics 
The following demographics of each subject will be collected at Screening Visit 1: 
• Year of birth 
• Weight (kg) in indoor clothes without shoes 
• Height (cm) without shoes 
• Sex 
• Race (White/Asian/Black/American Indian or Alaska Native/Native Hawaiian or 
Other Pacific Islander)  
 

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• Smoking (Previous/Current/Never; Start year/Average number of packs per day for 
previous and current smokers, and additionally Stop year for previous smokers) 
• Occupational dust exposure (Previous/Current and Type/Start year and, if applicable, 
Stop year, of exposure) 
8.1.2. 
Medical History and History of aPAP 
Relevant medical history of each subject, including all current diseases, and relevant prior 
diseases, including recent respiratory infections, will be recorded at Screening Visit 1. 
In addition, the following aPAP history information will be collected at Screening Visit 1 in a 
separate eCRF module: 
• Date of PAP diagnosis plus information regarding evidence of PAP (HRCT, biopsy 
or BAL cytology according to inclusion criterion no 3) 
• Date of first positive anti-GM-CSF antibody test 
• Information about previous WLL and plasmapheresis procedures, GM-CSF treatment 
and use of supplemental oxygen 
8.2. 
Efficacy Assessments 
8.2.1. 
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) 
As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be 
conducted at the timepoints shown in the SoA (Section 1.3). See also Section 4.2.3.1 for further 
information regarding DLCO. 
The single-breath DLCO test will be performed in accordance with ATS/ERS guidelines for 
DLCO testing (Graham et al. 2017), and further standardization across sites will be obtained by 
using standardized equipment (EasyOne Pro®, ndd Medical Technologies) and implementing 
central overread by a team of external, independent respiratory experts. A manual will be 
provided to all trial sites that will describe the procedure for DLCO testing in more detail. 
In order to avoid impact on the DLCO by an acute respiratory infection, subjects experiencing 
such infection should be asked to contact the site and the visit should be postponed, if possible, 
within the visit window. If a subject attends the visit anyway with an acute respiratory infection, 
this should be noted in the eCRF, either as concurrent disease (if detected or diagnosed prior to 
signing of ICF at Screening Visit 1) or as an AE (all other timepoints). 
Subjects must be asked to refrain from smoking on the day of the test. If the subject is a regular 
smoker, the date and time of the last cigarette smoked prior to the DLCO must be recorded.  
All subjects should be seated for at least 15 minutes prior to the DLCO testing. Subjects on 
supplemental oxygen should discontinue their oxygen supply at the start of this 15-minute 
resting period. During this period, oxygen saturation is monitored and recorded every 5 minutes 
and must be stable prior to initiating the DLCO maneuver. Oxygen saturation stability is defined 
as a change of ≤2 % points over 5 minutes. If the stability criterion is not met after 15 minutes, 
the resting period should be prolonged with 5 minutes at a time, until stability is confirmed. 
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stabilization procedure prior to the next maneuver. If a subject does not tolerate discontinuation 
of oxygen until stabilization, the DLCO assessment will not be conducted. The reason for 
missing data must be recorded.   
The predicted DLCO value will be calculated by the centrally provided equipment according to 
the Global Lung Function Initiative prediction equation (Stanojevic et al. 2017). 
The measured DLCO value will be adjusted for the hemoglobin (Hb) value obtained from the 
central laboratory, expressed in g/dL, using the following formula:  
• Males: Predicted DLCO adjusted for Hb = Predicted DLCO / (1.7Hb/(10.22+Hb))  
• Females: Predicted DLCO adjusted for Hb = Predicted DLCO / (1.7Hb/(9.38+Hb))    
For each subject, an adjusted value of % predicted DLCO will be derived based on the adjusted 
absolute value.   
The Hb value from the same day as the DLCO test will be entered into the DLCO device when 
available from the central laboratory to be used for adjustment. For decision on inclusion / 
exclusion at baseline, the Hb value obtained at Screening Visit 2 will be used for real time 
adjustment of % predicted DLCO results at the Baseline visit. For analysis of the trial data, the % 
predicted DLCO results at baseline will be adjusted for Hb based on the Hb value obtained at the 
Baseline visit. 
At least two acceptable and repeatable maneuvers according to ATS/ERS criteria are required. 
Up to five maneuvers may be conducted, if needed, during a session. For the final DLCO result 
the average of the two best efforts, as determined by the overreader, will be used. Central 
overread will be conducted real time (within 1 hour) at baseline, Week 24 and Week 48. Only 
results from the overread may be used for determining eligibility criteria for the trial. 
8.2.2. 
Saint George’s Respiratory Questionnaire (SGRQ) 
As a measure of respiratory health impairment, including limitations in activity due to 
breathlessness and psychosocial impact of respiratory problems, SGRQ will be used at the 
timepoints shown in the SoA (Section 1.3). 
The SGRQ (Section 10.2.1) 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. 
See also Section 4.2.3.2 for further information regarding SGRQ. 
Subject must complete the SGRQ on their own in the eDiary, before any other trial procedures 
are performed, but someone from the trial staff should be available to give advice if required. 
As an additional global measure of health, the subjects will be asked to grade their current health 
on a 5-point scale (very poor, poor, fair, good, or very good). This question is included within the 
SGRQ questionnaire; however, the question is not included in the calculation of the SGRQ 
scores.  
 

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After completion of the SGRQ, the PGIS and PGIC (at post-baseline visits) will be completed 
(see Section 8.2.12). 
8.2.3. 
Exercise Capacity (EC) 
As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an 
exercise treadmill test at the timepoints shown in the SoA (Section 1.3). See also Section 4.2.3.2 
for further information regarding EC assessment and the treadmill test. EC will be expressed in 
peak METs (1 MET=3.5 mL O2/kg/min). 
A conservative ramp-up treadmill protocol, employing minimal adjustments in speed and grade 
from one stage to the next, will be used. The highest treadmill speed and grade achieved will be 
used to calculate peak METs. The treadmill test will be conducted at local exercise testing 
laboratories by qualified staff experienced in the conduct of clinical exercise testing. 
Standardization across the exercise testing laboratories will be obtained by generating a trial-
specific Exercise Test Manual that follows established guidelines (Myers et al. 2009; Myers et al. 
2014) and by implementing central overread by an external, independent expert (exercise test 
core laboratory). The overreader will review all data collected in the test, require clarification of 
questionable data, and make the final confirmation that the exercise test is valid (i.e., maximal 
EC achieved) according to the pre-specified criteria. 
Subject instructions on the needed preparations before the test will be provided to the subject in 
the Subject Instruction and Diary (e.g., meal composition and timing before the exercise test, 
what type of clothes to wear, etc.) (Section 8.12). When the subject arrives to the exercise testing 
laboratory, she/he will receive detailed information on: 
• How the exercise test will be conducted, with emphasis on the use of a conservative 
ramp-up protocol (i.e., treadmill starts very slowly at no gradient). 
• Monitoring (i.e., heart rate, electrocardiogram [ECG], blood pressure, subjective 
symptoms, pulse oximetry). 
• Criteria for test termination.  
Subjects will be given time to ask questions prior to initiating the exercise test. Detailed 
instructions for subject preparation prior to and upon arrival to the exercise testing laboratory 
will be provided in the Exercise Test Manual. 
Supplemental oxygen is not allowed during the 3 phases of the exercise test (i.e., pre-exercise, 
exercise and recovery phases; see below). Subjects using supplemental oxygen should stop 
oxygen flow while seated and SpO2 should be monitored.  
All subjects should wait for at least 15 minutes and until a stable oxygen saturation of >85% for 
5 minutes has been achieved, whichever is longest, before the pre-exercise phase is initiated. 
Oxygen saturation stability is defined as a change of ≤2% points over 5 minutes. If the stability 
criterion is not met after 15 minutes the resting period should be prolonged with 5 minutes at a 
time, until stability is confirmed. 
The test should not be initiated if the subject has an SpO2 ≤85% at rest, or if desaturation to 
≤85% occurs after supplemental oxygen is discontinued. 
The exercise test consists of 3 phases:  
 

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• Pre-exercise phase monitoring (i.e., heart rate, ECG, blood pressure, pulse oximetry, 
and symptoms) with collection of data at rest. Duration 5 minutes. 
• Exercise phase with controlled ramp-up exercise, increasing speed and gradient on 
the treadmill every 30 seconds. The initial stage is at 1 mph with no incline. For each 
stage, the speed is increased by 0.1 mph and the gradient by 0.5%. The full protocol 
comprises 31 stages (total duration of exercise phase is 15 minutes and 30 seconds) 
(Section 10.2.2). Subjects will be encouraged to exercise until they achieve maximal 
effort. The subject may request to stop the test at any time. The exercise test will be 
terminated prior to maximal effort if absolute termination criteria (e.g., drop in 
systolic blood pressure, ventricular arrythmia, and ST segment depression) develop.  
• Recovery phase: If the test is not terminated prematurely, the first two minutes of 
recovery will consist of walking at 1 mph and 0% gradient followed by passive 
recovery for 4 minutes. If no abnormal signs/symptoms develop, total duration of the 
monitored (i.e., heart rate, ECG, blood pressure, pulse oximetry and symptoms) 
recovery phase is 6 minutes. Monitoring may continue past 6 minutes if abnormal 
signs/symptoms persist. 
Safety criteria for exercise test termination according to the American Heart Association 
guidelines (e.g. drop in systolic blood pressure, ventricular arrythmia, and ST segment 
depression) (Fletcher et al. 2013) will be described in the Exercise Test Manual. The test will be 
terminated on subject’s request in case of intolerable symptoms, e.g., dyspnea, leg fatigue, or 
angina. An additional criterion of desaturation to SpO2 ≤80% will be applied (Ross 2003). A 
termination criterion for heart rate will not be applied given that the standard equations to 
calculate maximal heart rate according to age are inaccurate on the individual level (Arena, 
Myers, and Kaminsky 2016).  
The following data will be collected during the test at the timepoints specified in Section 10.2.2:   
• Current use of betablocker (name / dose) 
• Heart rate  
• Blood pressure (systolic / diastolic) 
• Rating of Perceived Exertion (RPE) (Borg RPE Scale®, scale from 6-20; 
Section 10.2.3) 
• Dyspnea (Borg CR Scale® [CR10], scale from 0-absolute maximum; Section 10.2.4) 
• Angina (Angina scale from +1 to +4, or no angina; Section 10.2.5)  
• Oxygen saturation (%) 
• Time of stopping the test (last stage, seconds completed at last stage) and reason for 
stopping 
• Any symptoms or abnormalities observed during or after the test 
ECG should be monitored in all phases of the test and an ECG summary sheet should be 
uploaded to the eCRF. Printed 12-lead ECGs at rest and every minute of exercise and monitored 
recovery should be stored at the exercise testing laboratory. ECG abnormalities present at rest or 
 

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developed during the exercise test or recovery should be documented on the ECG summary 
sheet. If the exercise test was terminated due to ECG abnormalities, this should be documented 
on the ECG summary sheet.  
Heart rate, blood pressure, SpO2 and subjective symptom data as well as the ECG summary sheet 
will be reviewed by an expert central overreader to ensure that all data points are within expected 
physiological range. Values falling outside the expected physiologic range will be discussed with 
the exercise testing laboratory and considered invalid upon agreement with the facility. 
Based on the collected data, the following parameters will be calculated: 
• Whether sufficient effort during exercise testing was achieved or not (according to 
criteria below) – to be confirmed by the central overreader. 
• Peak MET (using an established equation based on the speed and grade of the last 
stage the subject was able to complete for at least 15 seconds). The following 
validated equation to calculate peak METs will be used: 
Peak METs = (speed X (0.17 + fractional grade X 0.79) +3.5)/3.5. Note: Speed in 
meters/minute (Kokkinos et al. 2017). 
• Distance walked. 
• Duration of exercise. 
The scores from the Borg CR Scale® will be used to investigate changes in dyspnea during the 
trial.  
The criterion for achieving maximal EC is one or more of the following:  
• Termination of the exercise test due to desaturation to SpO2 ≤80% 
• For subjects not prescribed a betablocker, termination due to any criteria other than 
desaturation together with attainment of a maximal exercise heart rate ≥80% of the 
age-adjusted predicted maximum (220 – Age) (Fletcher et al. 2013). 
• For subjects prescribed a betablocker, termination due to any criteria other than 
desaturation together with attainment of a maximal exercise heart rate ≥65% of the 
age-adjusted predicted maximum (220 – Age) (Hung et al. 2016). 
After completion of the exercise test, the PGIS and PGIC (at post-baseline visits) will be 
completed (see Section 8.2.12). 
Any abnormalities observed during the exercise test will be reported to the Investigator who will 
assess the abnormality as ‘clinically significant’ or ‘not clinically significant’. All clinically 
significant abnormalities must be recorded as AEs. 
8.2.4. 
Whole Lung Lavage (WLL) 
The need for rescue therapy will be assessed by the frequency of WLL. At each visit, 
information on whether WLL is required will be evaluated by the Investigator and will be 
recorded in the eCRF. 
The reason(s) for WLL performed will be documented in the eCRF. In addition, the following 
information will be entered: date and type of WLL (right and/or left lung), amount of saline used, 
 

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and time used for performing the WLL. Segmental or lobar lavages will also be recorded on the 
WLL eCRF page, if used as therapy of aPAP according to local practice. 
8.2.5. 
High Resolution Computed Tomography (HRCT) 
As a measure of surfactant accumulation, ground glass opacity (GGO) will be assessed. For this 
purpose, an HRCT scan will be collected at the timepoints shown in the SoA (Section 1.3) and 
uploaded into a central database for evaluation of GGO. In order not to unnecessarily increase 
radiation exposure, chest X-rays are not mandated during the trial. 
The fundamental pathological defect in aPAP is surfactant accumulation over time, which can be 
indirectly assessed by HRCT scan of the chest. Chest CT scans in aPAP shows characteristic 
findings of GGO with intralobular lines and interlobular septal thickening, often in polygonal 
shapes (Trapnell and McCarthy 2019; Lee et al. 1997). A semi-quantitative assessment of GGO 
was introduced by Akira et al (Akira et al. 2000) and subsequently adapted for use in PAP by 
Tazawa et al (Tazawa et al. 2010). 
The extent of GGO will be scored in 3 zones (upper, middle and lower parts) on a scale from 
0-5: 
0 – No GGO 
1 - <5% GGO  
2 – 5-24% GGO 
3 – 25-49% GGO  
4 – 50- 74% GGO  
5 - ≥75% GGO  
The GGO scores will be assessed by two independent readers with expertise in radiological 
diagnosis of PAP. The readers will be blinded to subjects’ treatment assignment and sequence of 
the assessed scans (not applicable for the Week 144 HRCT). The total GGO score is calculated 
by summing up zonal GGO scores (i.e., total GGO score ranges from 0-15). The average total 
GGO score of the two readers will be used in the statistical analysis.  
Furthermore, based on the local radiologic assessment, the HRCT scans will be classified by the 
Investigator as normal, having a non-clinically significant abnormality, or having a clinically 
significant abnormality. All clinically significant abnormalities will be recorded as AEs except 
conditions known or diagnosed prior to the trial and observed at Screening Visit 2, which will be 
recorded as medical history. 
The scans may further be evaluated using the automated parenchymal Pattern Analysis using the 
Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) software 
(McCarthy et al. 2019). Densitometry assessments of the scans may also be performed. These 
assessments may be reported separately from the clinical trial report. 
8.2.6. 
Supplemental Oxygen Use  
As a clinically meaningful variable, the use of supplemental oxygen during the trial will be 
assessed at the timepoints shown in the SoA (Section 1.3). 
 

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Subjects on supplemental oxygen will be asked to complete a daily oxygen diary in the eDiary. 
Subjects start completing the eDiary 14 days prior to a visit (Section 10.2.6). If a visit date is 
rescheduled, the actual number of days of data collection may be less or more than 14 days. The 
eDiary will capture information on oxygen flow at rest, during sleep, and during exertion, and 
hours of oxygen use during exertion.  
The data from the eDiary will be combined into an oxygen index approximating the average use 
in liters per minute, assuming that oxygen use during rest equates to 24 hours per day, oxygen 
use during sleep to 8 hours per day, and oxygen use during exertion to the reported number of 
hours. 
At each visit, the Investigator will further evaluate the current need for supplemental oxygen and 
enter the following information in the eCRF: 
• Oxygen use during exertion, sleep and rest  
• Flow rates  
The need for supplemental oxygen will be evaluated by the Investigator and the criteria for using 
oxygen should be entered in the eCRF:  
• Resting partial pressure of oxygen (PaO2) ≤55 mmHg (7.3 kPa) 
• Resting PaO2 ≤60 mmHg (8 kPa) and hematocrit (Hct) ≥55% 
• Other 
8.2.7. 
Biomarkers  
Blood samples for assessment of the following aPAP-related biomarkers will be taken at the 
timepoints shown in the SoA (Section 1.3): 
• Krebs von den Lungen-6 (KL-6) 
• Cytokeratin 19 fragments (CYFRA 21-1) 
• Carcinoembryonic antigen (CEA)  
• Lactate dehydrogenase (LDH) 
• Hb and Hct  
Analysis of these biomarkers will be performed by a central laboratory using validated methods. 
LDH will be analyzed from the standard biochemistry safety laboratory sample, and Hb and Hct 
from the standard hematology safety laboratory sample. 
8.2.8. 
Biobank  
Blood samples for storage in a biobank will be taken at the timepoints shown in the SoA 
(Section 1.3). Samples will only be taken from subjects who have signed a separate biobank 
consent. The biobank sample may be used for further exploratory analyses on biomarker variants 
or other variables thought to play a role in aPAP, or for further analyses of variables that may 
impact safety or efficacy of the IMP. 
 

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8.2.9. 
Arterial Blood Gas Assessments 
The following variables will be assessed from an arterial blood gas sample collected on room air 
at the timepoints shown in the SoA (Section 1.3):  
• PaO2 (mmHg/kPa) – arterial partial pressure of oxygen 
• PaCO2 (mmHg/kPa) – arterial partial pressure of carbon dioxide 
In addition, the resting respiration rate (breaths per minute) will also be assessed in connection 
with the arterial blood gas sampling. 
All subjects should rest in a supine position for at least 15 minutes prior to the arterial blood gas 
sampling. Subjects on supplemental oxygen should discontinue their oxygen supply at the start 
of this 15-minute resting period. During this period, oxygen saturation is monitored and recorded 
every 5 minutes and must be stable prior to initiating the arterial blood gas sampling. Oxygen 
saturation stability is defined as a change of ≤2 % points over 5 minutes. If the stability criterion 
is not met after 15 minutes, the resting period should be prolonged with 5 minutes at a time, until 
stability is confirmed. If a subject does not tolerate discontinuation of oxygen until stabilization, 
the arterial blood gas sampling will not be conducted. The reason for missing data must be 
recorded. 
Syringes with vented tip caps should be used. The sample must be visually inspected 
immediately after sampling and bubbles should be expelled immediately after sampling and 
before mixing by gently tapping the syringe while holding the syringe with the tip pointed 
upwards and pressing the piston until all visible air has been expelled from the syringe. After 
that, the cap must be placed on the tip immediately. The blood should be analyzed immediately; 
no later than 15 minutes after sampling.  
PaO2 will be used for allocating subjects into Disease Severity Score (DSS) categories 
(Section 8.2.10). 
The Investigator must evaluate the PaO2 result before the subject leaves the clinic and compare 
this to the oxygen saturation value obtained during the procedure. At the Baseline visit and 
Visit 9 (Week 24), the test must be repeated if a suspected preanalytical error has occurred. Pre-
analytical errors may include:  
• Sample contamination with venous blood  
• Air-bubble in the syringe 
• Clotted sample 
 

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In addition, at Week 12, Week 24 and Week 48 subjects reporting worsening or improvement in 
PGIC will be asked if the change was important to them or not.  
8.2.13. 
Exit Interviews 
An exit interview will be performed at Week 24 to qualify the subjects’ perception of the 
meaningfulness of observed changes from baseline and to understand the burden of treatment. 
An exit interview protocol and guide will be developed. The interview will be performed as a 
phone interview by a trained interviewer with subjects at prospectively selected sites in North 
America and/or Europe. The exit interviews will be recorded and transcribed. The results from 
the exit interviews will be reported separately. 
Interviewers will be trained on AE handling. Potential AEs identified during the exit interviews 
will be forwarded to the site and the investigator should evaluate if an AE form should be 
completed in the eCRF.  
8.3. 
Safety Assessments 
The safety objectives of the trial will be assessed by using the following variables: 
• Frequencies of (S)AEs, (S)ADRs, adverse events of special interest (AESIs), deaths 
and AEs leading to withdrawal from trial and/or permanent discontinuation from 
treatment. These variables are dealt with in Section 8.4 and Section 8.11.3. 
• Development of treatment-boosted anti-GM-CSF antibody titers  
• Spirometry (Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second 
(FEV1) and FEV1/FVC)  
• Change in QT interval corrected by Fridericia (QTcF)  
Although not included as formal safety endpoints of the trial, subject safety will also be assessed 
by physical examinations, ECG, vital signs, body weight and clinical safety laboratory 
assessments. In addition, pregnancy screen and check of contraceptive use will be performed. 
In the event of a COVID-19 outbreak impacting patients participating in the trial, the Sponsor 
will work with any impacted sites on appropriate mitigation procedures. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Electrocardiograms 
Three (3) unique, resting, 12-lead ECG assessments will be obtained using centrally provided 
ECG equipment at the time points shown in the SoA (Section 1.3.1). After Week 48 (and upon 
implementation of protocol version 10.0), a single resting, 12-lead ECG assessment will be 
obtained at the time points shown in the SoA (Section 1.3.2). 
ECGs collected at baseline, Week 4 and Week 24 will be overread by a central ECG laboratory 
using a limited number of readers overseen by a cardiologist. R-R, PR, QRS, and QT intervals 
will be determined on 3 consecutive beats in Lead II, or an alternative lead if Lead II is not 
acceptable for measurement. Mean RR, PR, QRS, QT, QTcB, QTcF and heart rate will be 
calculated. The cardiologist will conduct standard interpretation of the ECGs as normal/abnormal 
 

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and type of abnormality. The ECG procedures will be described in an ECG manual. Cardiologist 
reports will be reviewed, signed and dated by the Investigator or his/her designee. 
All ECGs collected will be interpreted and signed and dated by the Investigator or his/her 
designee. Any abnormalities will be recorded in the eCRF and assessed as ‘clinically significant’ 
or ‘not clinically significant’. In case of discrepancy between the cardiologist and the 
Investigator assessment, the Sponsor should be contacted to facilitate resolution. Abnormalities 
classified as ‘clinically significant’ will be recorded as AEs except those observed at Screening 
Visit 1 which will be recorded as medical history. 
8.3.2. 
Physical Examinations 
All subjects will undergo physical examinations at the timepoints shown in the SoA 
(Section 1.3). 
Full physical examinations will include at a minimum: 
• A review of the subject’s general appearance 
• Head, eyes, ears, nose, and throat  
• Neck 
• Heart and lungs 
• Abdomen 
• Extremities 
• Skin 
• General neurological system.  
Any abnormalities will be recorded in the eCRF and assessed as ‘clinically significant’ or ‘not 
clinically significant’. Abnormalities classified as ‘clinically significant’ will be recorded as AEs 
except those observed at Screening Visit 1 which will be recorded as medical history. 
Symptom-oriented or brief physical examinations, as clinically indicated, will be performed at 
the timepoints shown in the SoA (Section 1.3). New abnormal clinically significant physical 
examination findings which were not present during the Screening Visit 1 should be recorded as 
AEs and followed during subsequent visits.  
8.3.3. 
Vital Signs and Body Weight 
The following parameters will be assessed at the timepoints shown in the SoA (Section 1.3). 
• Resting systolic and diastolic blood pressure (mmHg), after 5 minutes sitting  
• Resting heart rate (beats per minute), after 5 minutes sitting  
• Body temperature (°C) 
• Body weight (kg) in indoor clothes without shoes 
The observed values will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal findings 
will be assessed as ‘clinically significant’ or ‘not clinically significant’. All clinically significant 
 

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abnormalities will be recorded as AEs except those observed at Screening Visit 1 which will be 
recorded as medical history. 
8.3.4. 
Clinical Safety Laboratory Assessments 
See Section 10.3 for a list of clinical laboratory tests (hematology, biochemistry, and urinalysis) 
to be performed and to the SoA (Section 1.3) for the timing and frequency of the assessments.  
Sampling methods and procedures will be in accordance with local routine care and samples will 
be analyzed by a central laboratory. A trial-specific Laboratory Manual for sampling, handling, 
storage and shipment of samples will be provided to the site personnel. The manual will be 
provided to the site before start of the trial.  
The reported results will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal results 
will be assessed by the Investigator as ‘clinically significant’ or ‘not clinically significant’. All 
clinically significant abnormalities will be recorded as AEs except those observed at Screening 
Visit 1 which will be recorded as medical history. 
8.3.5. 
Pregnancy Test 
Serum pregnancy tests will be performed for women of childbearing potential at all visits during 
the double-blind and open-label treatment periods except for the Week 52 telephone visit. In 
addition, a urine pregnancy test will be performed before dosing at the Baseline visit (Visit 3) to 
immediately confirm that the subject is not pregnant. A contraceptive check of both male and 
female subjects will also be performed at all visits.  
For visits with 12-week intervals (i.e., visits after Week 24), women of childbearing potential 
should also check pregnancy at home with monthly urine dipstick pregnancy tests. Date of the 
dipstick test should be recorded in the Subject instructions and diary (Section 8.12). Results of 
the pregnancy tests (on-site and at home tests) will be entered in the eCRF. 
8.3.6. 
Anti-GM-CSF Antibodies   
Blood sampling for assessment of diagnostic anti-GM-CSF autoantibodies will be performed at 
Screening Visit 1. In addition, blood sampling for assessment of treatment-boosted anti-GM-CSF 
antibodies will be performed at time points shown in the SoA (Section 1.3).  
Analyses for diagnostic anti-GM-CSF antibodies will be performed at three regional central 
laboratories (in the US, Europe, and Japan). The cut-off values for diagnostic levels of anti-GM-
CSF autoantibodies will be according to clinical standards at the regional central laboratories.  
The titer of anti-GM-CSF antibodies over the course of treatment until 4 weeks after end of 
treatment will be analyzed at a central specialized laboratory. 
Anti-excipients antibodies (including immunoglobulin types) and the neutralizing capacity of 
anti-GM-CSF antibodies measured by cell-based methods may also be analyzed according to a 
separate bioanalysis plan. 
 

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8.3.7. 
Spirometry (FVC, FEV1 and FEV1/FVC) 
Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) will be assessed 
at the time points shown in the SoA (Section 1.3). Spirometry will be conducted prior to the 
DLCO, using the same equipment. 
FEV1 and FVC will be performed in accordance with ATS/ERS guidelines for spirometry testing 
(Miller et al. 2005). At least three acceptable and repeatable maneuvers according to ATS/ERS 
criteria are required. Up to eight maneuvers may be conducted, if needed, during a session. The 
largest FEV1 and FVC will be used in the analyses. Standardization across sites will be obtained 
by using the same equipment and implementing central overread by a team of external, 
independent respiratory experts. Predicted values will be calculated by the centrally provided 
equipment according to the Global Lung Function Initiative prediction equations (Quanjer et al. 
2012). A manual will be provided to all trial sites that will describe the spirometry test in more 
detail. 
A drop of ≥10% predicted in either FEV1 or FVC between two visits should be evaluated for 
clinical significance by the Investigator. All clinically significant changes should be recorded as 
AEs.  
8.4. 
Adverse Events and Serious Adverse Events 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. 
AEs and SAEs will be collected from the signing of the ICF until the Week 148 visit at the time 
points specified in the SoA (Section 1.3). 
Medical occurrences that begin before signing the ICF will be recorded as medical history. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.4.4. The Investigator will 
submit any updated SAE data to the Sponsor or designee within 24 hours of it being available. 
Investigators are not obligated to actively report new AEs or SAEs for subjects who have 
completed or are withdrawn from the trial. However, if the Investigator learns of any SAE, 
including a death, at any time after a subject has completed or been withdrawn from the trial, and 
he/she considers the event to be reasonably related to the IMP or trial participation, the 
Investigator must promptly notify the Sponsor. 
8.4.2. 
Method of Recording and Assessing AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.4.4. 
 

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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow up at 
subsequent visits/contacts on all AEs until either resolution or until judged by the Investigator to 
be stable/needing no further follow-up. Further information on follow-up procedures is provided 
in Section 10.4.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of an IMP 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IMP under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), 
and investigators. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it in the Investigator trial master file (TMF) and will notify the IRB/IEC, if appropriate according 
to local requirements. 
SAEs qualifying as SUSARs are subject to a 7-day reporting timeframe for life-threatening and 
fatal SUSARs and a 15-day reporting timeframe for all other SUSARs. Investigator safety 
reports will be prepared by the Sponsor for SUSARs according to local regulatory requirements 
and Sponsor policy and forwarded to investigators, as necessary. 
In the European Union (EU), SUSARs will be registered in EudraVigilance as applicable. Once a 
year, a development safety update report (DSUR) will be submitted to competent authorities and 
IECs via the Clinical Trial Information System (CTIS). 
 
8.4.5. 
Pregnancy 
Female subjects will be instructed to notify the Investigator immediately if they become pregnant 
during the trial. Male subjects will be instructed to notify the Investigator immediately if their 
female partner becomes pregnant. Pregnant subjects will have their IMP discontinued. Male and 
female subjects will also be instructed to report pregnancies discovered after the last visit, if they 
believe that conception occurred during their participation in the trial.  
A pregnancy as such is not an AE, unless there is a possibility that the IMP has interfered with 
the efficiency of any contraceptive measures. However, the Investigator should report 
pregnancies according to the procedures and timelines described for reporting of SAEs, 
Section 10.4.4. The pregnancy report form should be used instead of the SAE form. 
 

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The pregnant subject or partner will be followed until the end of the pregnancy. Any 
complication during the pregnancy should preferably be reported as an AE. The outcome of the 
pregnancy must be reported on the pregnancy report form. Any spontaneous abortion, stillbirth, 
birth defect/congenital anomaly, death, or other serious infant condition must be reported and 
followed up as an SAE. 
8.4.6. 
Adverse Events of Special Interest  
The following AEs have been identified as AESIs with need for additional data collection, which 
may include additional investigations when required, to further characterize and understand 
them: 
• Hypersensitivity reaction 
Subjects will be observed for any hypersensitivity reactions for 1 hour after the first 
dose. If a subject develops a type I hypersensitivity reaction further dosing should be 
suspended, permanently or temporarily, according to Investigator’s judgment. The 
subject should be contacted by phone 8-12 hours after the event to check for any 
delayed reaction. Subjects experiencing serious hypersensitivity reactions will be 
discontinued from the trial. 
• Chest pain 
All subjects should be instructed to call the site if chest pain develops, and based on 
the information provided over the phone, additional investigations, e.g., ECG and 
chest X-ray, may be conducted according to Investigator’s judgment. 
The events may be serious or non-serious and must follow the standards for AE/SAE reporting 
as described above. In addition, a specific form for each type of event must be filled out within 
the time frame as for other AE/SAEs as specified in Section 8.4.1. 
In case the Sponsor identifies potentially missed AESIs through predefined review of available 
data, the Investigator will be asked to reconsider if this is an AESI. 
8.5. 
Treatment of Overdose 
Molgramostim nebulizer solution in doses of 600 µg once daily for 6 days have been 
administered via inhalation to healthy volunteers without any safety concerns. In the present 
trial, in the event of an overdose, as judged by the Investigator, the event should be reported as 
an AE and supportive treatment or discontinuation of the IMP may be applied as judged by the 
Investigator. 
8.6. 
Pharmacokinetics 
Pharmacokinetic samples will be collected at the timepoints shown in the SoA and the time of 
sampling will be recorded. 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this trial. 
 

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8.8. 
Genetics 
Genetics are not evaluated in this trial. 
8.9. 
Biomarkers 
See Section 8.2.7. 
8.10. 
Immunogenicity Assessments 
See Section 8.3.6. 
8.11. 
Health Economics and Quality of Life 
8.11.1. 
EuroQoL 5 Dimensions, 5 Levels (EQ-5D-5L) 
Subjects will complete the EQ-5D-5L questionnaire in the eDiary, after the SGRQ, before other 
trial assessments, at the time points shown in the SoA (Section 1.3). 
The EQ-5D-5L is a generic, multidimensional, health-related, quality-of-life instrument and 
comprises a Visual Analogue Scale (VAS) and a short descriptive system questionnaire. The 
VAS provides an alternative way to elicit a subject’s rating of his/her own overall current health. 
The questionnaire provides a simple descriptive profile of a respondent’s health state.  
The VAS records the subject’s overall current health on a vertical VAS where the endpoints are 
labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. The VAS 
provides a quantitative measure of the subject’s perception of his/her overall health. 
The descriptive system allows subjects to rate their health in 5 domains: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression using a 5-level scale indicating: 1. No 
problem, 2. Slight problem, 3. Moderate problem, 4. Severe problem or 5. Unable to/extreme 
problems (Section 10.2.9). The perceived problem levels for each domain are combined into a 5-
digit health state that is converted to an index value which reflects how good or bad a health state 
is according to the preferences of the general population, with higher scores indicating better 
quality of life.  
8.11.2. 
Patient Journey 
As a description of burden of disease in terms of relevant patient experiences from first 
symptoms and diagnosis up to the time of the trial, a sheet to capture such information 
(Section 10.2.10) will be handed out to the subject at Screening Visit 2 and returned completed at 
the Baseline visit. The site will upload a pdf copy of the completed sheet to the eCRF. The 
results from the Patient Journey assessments are intended for use in e.g., health economic 
evaluations and will not be included in the clinical database. 
8.11.3. 
Hospitalizations 
If a subject is hospitalized during the trial, the following information will be collected in the 
eCRF: 
• Admission diagnosis 
 

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• Admission date 
• Admission facility/ward (e.g., intensive care unit, emergency room, pulmonary 
department, other specified) 
• Any invasive aPAP-related treatment during admission (e.g., WLL, ventilator, other 
specified) 
• Discharge status (e.g., recovered, in recovery, unchanged, deteriorating) 
• Discharged to e.g., nursing home, home, other hospitalizations 
• Discharge date 
Ambulatory hospitalizations will not be collected in the eCRF. 
8.12. 
Subject Instruction and Diary 
At the time points shown in the SoA (Section 1.3), subjects will receive a Subject Instruction and 
Diary. The subject should hand-back the Subject Instruction and Diary at the following visit. The 
Subject Instruction and Diary will include information about assessments at the next visit and 
details about the handling of the IMP. The subject will be asked to complete information about 
dates for starting on new IMP kits, cleaning of the nebulizer, change of nebulizer handsets, dates 
for taking pregnancy test (if applicable) and any potential AEs experienced by the subject 
between the visits.  
 
 

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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be finalized prior to database lock and subsequent 
unblinding of trial treatment codes and it will include a more technical and detailed description of 
the statistical analyses described in this section. The following sections are a summary of the 
planned statistical analyses of the most important endpoints including primary and secondary 
endpoints. 
9.1. 
Statistical Hypotheses 
The primary null hypothesis is that there is no difference between MOL and PBO in the mean 
change from baseline to 24 weeks in % predicted DLCO. 
The alternative hypothesis is that there is a difference between MOL and PBO in the mean 
change from baseline to 24 weeks in % predicted DLCO. 
9.2. 
Sample Size Determination 
Based on data from MOL-PAP-002, the sample size was estimated for the primary endpoint 
assuming a treatment effect for change from baseline to Week 24 in DLCO of 5.7 percentage 
points, a standard deviation (SD) of 11 percentage points and a significance level of 5%. With a 
total of 160 randomized subjects, assigned at a 1:1 ratio to double-blind treatment per treatment 
group, the power for showing an effect on DLCO is 90%. 
In addition, a blinded sample size re-assessment will be conducted by the Sponsor (or delegate) 
after 80 subjects have completed the Week 24 visit. Using the estimate of variance and an 
assumed effect size of 5.7 percentage points, a sample size calculation will be performed to 
determine if the sample size should be increased. The calculations will be based on having 90% 
power for the primary endpoint.   
A short report will be prepared to document the sample size re-assessment process and results. 
The sample size re-assessment report will be included in the trial documentation. 
The Sponsor will remain blinded to the treatment allocations throughout the process of sample 
size re-estimation. 
9.3. 
Trial Estimands 
The following sections describe the attributes of the estimands that will be used for evaluation of 
the primary endpoint and similar principles that will be applied for the secondary efficacy 
endpoints. 
9.3.1. 
Estimand for the Primary Endpoint 
9.3.1.1. 
Treatment 
The treatment is molgramostim nebulizer solution administered by inhalation once daily over a 
period of 24 weeks, which will be compared to placebo inhalation. Both interventions will be 
applied on top of standard of care that includes supplemental oxygen when required and rescue 
treatment with WLL in case of worsening, but not off-label treatments like GM-CSF or 
rituximab.   
 

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9.3.1.2. 
Population 
The primary analysis will be performed in all randomized subjects, who represent a population 
of adult patients with a confirmed diagnosis of aPAP as defined by the trial population 
inclusion/exclusion criteria. 
9.3.1.3. 
Patient-level Endpoint 
For each patient, efficacy will be measured using the primary endpoint of absolute change in % 
predicted DLCO from baseline to Week 24. The calculation requires an acceptable and 
repeatable maneuver at baseline and Week 24, including the required discontinuation of 
supplemental oxygen for 15 minutes prior to the assessments. 
9.3.1.4. 
Intercurrent Events 
Anticipated intercurrent events include rescue therapy (i.e., WLL), supplemental oxygen, off-
label treatments, treatment discontinuation, treatment non-compliance, and trial withdrawal: 
• For subjects who require supplemental oxygen or a WLL for worsening of aPAP as 
specified in the clinical trial protocol, outcomes observed during and after the period of 
this additional treatment are included as they are consistent with the treatment condition 
under evaluation. Therefore, the treatment policy strategy is planned with respect to these 
types of events. 
Similarly, if any subjects use prohibited off-label treatments (such as other GM-CSF 
products or rituximab), outcomes observed during and after the period of this additional 
treatment are included as such off-label use in clinical practice can be a consequence of 
the treatment policy.  
• For subjects who are non-compliant with the trial intervention, all data will be used, 
irrespective of compliance. Therefore, the treatment policy strategy is used with 
respected to this type of event. 
• Subjects who discontinue trial therapy for any reason prior to Week 24 will be 
encouraged to remain in the trial and complete all scheduled assessments and, as a 
minimum, the Week 24 visit. Data collected before and after treatment discontinuation 
will be used for the primary analysis. Therefore, the treatment policy strategy is used with 
respect to this type of event. 
• Whilst withdrawal from the trial is not, in itself, an intercurrent event, for subjects who 
withdraw from the trial or are lost to follow-up prior to Week 24, their Week 24 data will 
be imputed using control-based multiple imputation. (Note that this could include, for 
example, patients who have a WLL and who may subsequently withdraw from the trial 
prior to Week 24, or those who discontinue therapy and who may subsequently withdraw 
from the trial prior to Week 24). The rationale for this imputation is based on the 
assumption that trial withdrawal may be related to lack of efficacy, desire to initiate off-
label treatment, or adverse events, and therefore it is assumed that patients who drop out 
of the trial will not show a Week 24 benefit. 
• For subjects who worsen to the extent that DLCO cannot be adequately conducted 
according to ATS/ERS guidelines at Week 24, although expected to be a very rare event, 
 

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their Week 24 data will be imputed using control-based multiple imputation. This is 
based on the assumption that this degree of worsening indicates that the subject did not 
have treatment benefit at Week 24.  
9.3.1.5. 
Population-level Summary 
On the population level, the difference in Lsmean change in DLCO % predicted from baseline to 
Week 24 will be used to compare the treatment groups.  
9.3.2. 
Estimands for the Secondary Efficacy Endpoints 
For secondary efficacy endpoints, similar principles will be applied as for the primary efficacy 
endpoints with further details included in the SAP, which will be finalized before unblinding. For 
example, replacing Week 24 by Week 48 (where applicable). 
As for DLCO, for subjects who worsen to the extent that the exercise test cannot be initiated with 
the subject breathing room air due to worsening of aPAP, their Week 24 data will be imputed 
using control-based multiple imputation. This is based on the assumption that this degree of 
worsening indicates that the subject did not have treatment benefit at Week 24. Corresponding 
imputation will be done for DLCO and for the exercise test at Week 48 (further details in the 
SAP). 
Only applicable for Japan and South Korea: 
• Intercurrent Events: For subjects who worsen to the extent that blood gas sampling 
cannot be conducted with the subject breathing room air, although expected to be a very 
rare event, their Week 24 data will be imputed using control-based multiple imputation. 
This is based on the assumption that this degree of worsening indicates that the subject 
did not have treatment benefit at Week 24. 
 
9.4. 
Populations for Analyses 
The analysis populations are defined in Table 5. Although efficacy summaries will be performed 
on both the Full Analysis Set (FAS) and the Per-protocol Set (PPS), the FAS will be considered 
the primary analysis population. Safety summaries will be performed on the safety analysis set 
(SAS). 
Table 5: 
Analysis Populations 
Population 
Description 
Screened  
All subjects who sign the informed consent form. 
Full analysis set (FAS) 
All subjects randomized. Subjects will be analyzed according to the 
randomized treatment. 
Per-protocol set (PPS) 
All randomized subjects who have completed 24 weeks’ double-blind 
treatment (Visit 9) and are deemed to have no important protocol 
deviations that could interfere with the objectives of this trial. 
Important deviations of eligibility criteria and other deviations from the 
protocol will be assessed. Important deviations from the protocol may 
 

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Population 
Description 
lead to exclusion of a subject or data points from the PPS. All such 
decisions will be made and documented before the final trial database 
is unblinded. 
Safety analysis set (SAS) 
All subjects randomized and who take at least 1 dose of IMP. Subjects 
will be analyzed according to the IMP they actually received. 
9.5. 
Statistical Analyses 
9.5.1. 
General Considerations 
The trial will be unblinded and the primary analysis will be conducted after all subjects have 
completed the 48-week double-blind period. In addition, a blinded sample size re-assessment 
will be conducted after 80 subjects have completed the Week 24 visit to evaluate whether the 
sample size needs to be increased (see Section 9.2).  
Before the trial is unblinded for primary analysis, a blind review of the data will be completed. 
At that time, adjustments to the planned analyses may be identified based on, for example, the 
extent and timing of missing data. Confirmation of eligibility for analysis populations (see 
Section 9.4) will be confirmed at this time. 
Analyses of data from the first 48 weeks of treatment will be described in the SAP. The data 
from the open-label period will be presented descriptively.  
Baseline measurements are defined as the last measurement taken before randomization, taken 
either at the screening visits or the Baseline visit. 
9.5.2. 
Type I Error Control 
For regulatory authorities outside of Japan or South Korea: 
There is one primary efficacy parameter and seven secondary efficacy endpoints which are 
intended to support conclusions based on the primary parameter. A type I error control procedure 
that uses a combination of sequential testing and alpha-splitting will be used for analysis of these 
endpoints to maintain the overall type I error rate at 5%. The procedure is shown schematically 
in Figure 2 and described beneath the schematic. 
 

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9.5.5. 
Concomitant Treatment 
Concomitant medication and concomitant therapy will be summarized as number of subjects 
being treated with each type of medication/therapy classified according to Anatomical 
Therapeutic Chemical (ATC) level 3 and WHO Drug Dictionary preferred term. The Safety 
Analysis Set (SAS) will be used for this presentation. 
9.5.6. 
Primary Endpoint – Absolute Change in Percent of Predicted DLCO from 
Baseline to Week 24 
A general linear mixed model for repeated measurements will be used to analyze the primary 
endpoint and will be fitted with treatment, baseline DLCO % predicted, a binary indicator for 
DLCO stratification and a 3-level factor for region, and visit as categorical fixed effects, along 
with a treatment-by-visit interaction term. The estimated treatment effect will be the difference in 
Lsmean change in DLCO % predicted from baseline to Week 24, taken from the treatment-by-
visit interaction term at 24 weeks. Although data is also collected after the Week 24 visit, only 
data up to Week 24 will be used in the statistical model used for the primary endpoint at 
Week 24 (i.e., up to Visit 9). The estimated treatment effect will be presented with a 95% 
confidence interval (CI) and a P-value to test the null hypothesis that the effects of 
molgramostim and placebo at Week 24 are the same.  
The analysis model is: 
𝑌𝑌𝑖𝑖𝑖𝑖𝑖𝑖= 𝛽𝛽0 ∙𝑦𝑦𝑖𝑖𝑖𝑖0 + 𝑇𝑇𝑖𝑖+ 𝑅𝑅𝑙𝑙+ 𝑆𝑆𝑚𝑚+ 𝑉𝑉𝑘𝑘+ 𝑇𝑇𝑇𝑇𝑖𝑖𝑖𝑖+ 𝑠𝑠𝑖𝑖𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 
where 
Yijk 
 is the % predicted DLCO value for the jth subject of treatment group i at visit k (where 
k=4,…,9) 
yij0 is the baseline % predicted DLCO value for the jth subject of treatment group i 
β0 is the unknown fixed slope for the baseline DLCO % predicted 
Ti is the unknown fixed effect of treatment i 
Rl is the unknown fixed effect of regional stratification factors l (0 or 1 or 2) 
Sm is the unknown fixed effect of DLCO severity stratification factor m (0 or 1) 
Vk is the unknown fixed effect of visit k 
TVik is the unknown fixed interaction effect between treatment i and visit k 
sij is the subject effect associated with the jth subject of treatment i 
eijk is the error (residual) associated with the jth subject of treatment i at visit k 
sij and eijk are assumed to be independent from each other and follow a multivariate 
normal distribution. The covariance matrix for e will be the unstructured variance-
covariance matrix, since it assumes pair-wise correlations are not constrained by the data. 
The estimated treatment effect is taken from the TVik interaction term at Visit 9 (i.e., 24 weeks). 
 

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Any subject with missing % predicted DLCO data will have those missing values imputed using 
a multiple imputation method, using a conservative control-based rule: 
• The missing values are filled in n times to generate n complete data sets (using SAS 
PROC MI). 
This is done by fitting n linear regression models using placebo-only subjects with observed 
values for the endpoint and further covariates (baseline covariates and measurements of % 
predicted DLCO at earlier visits; full details of the covariates to be used will be included in the 
SAP). 
Based on the fitted regression model, a new regression model is simulated from the Bayesian 
posterior predictive distribution of the regression parameters and is used to impute the missing 
values: 
• The n complete datasets are analyzed by using the model described above. 
• The results from the n analyses are combined for statistical inference using Rubin’s 
rules (using SAS PROC MIANALYZE). 
Multiple imputation aims to allow for the uncertainty about the missing data by creating several 
different plausible imputed data sets and appropriately combining results obtained from each of 
them. The method assumes that missing values are a result of patients stopping taking their 
medication and so following a trajectory akin to patients randomized to placebo. 
Sensitivity analyses, including tipping point analyses and responder analyses (5-, 7-, and 
10-point change in DLCO % predicted) will be described in the SAP. In addition, the SAP will 
describe sensitivity analyses and estimands that address both COVID-19 pandemic-related and 
unrelated issues. 
9.5.7. 
Secondary Endpoints 
Absolute change in % predicted DLCO from baseline to Week 48 will be analyzed using a 
similar model as for DLCO at Week 24 but with the Week 48 timepoint used for inference (using 
data from Visits 4 to 11).  
Change from baseline to Week 24 and baseline to Week 48 in SGRQ Total and SGRQ Activity 
will be analyzed using a similar model as for DLCO at Week 24 and Week 48 respectively 
except using baseline SGRQ Total or SGRQ Activity as the covariate (yij0) instead of baseline 
DLCO. 
Change from baseline to Week 24 and baseline to Week 48 in EC (expressed as peak METs) will 
be analyzed using a similar model as for DLCO at Week 24 and Week 48 respectively except 
using baseline (measured at Screening Visit 2) peak METs as the covariate (yij0) instead of 
baseline DLCO.  
Only applicable for Japan and South Korea: Change from baseline to Week 24 in A-aDO2 will 
be analyzed using a similar model as for DLCO at Week 24 except using baseline A-aDO2 as the 
covariate (yij0) instead of baseline DLCO. 
For Week 24 endpoints, imputation for missing values for all secondary endpoints will follow 
the same procedure as for the primary endpoint. For Week 48 endpoints, imputation will follow 
the same principles as for the primary endpoint but will use data up to Week 48 (visits 4 to 11). 
 

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Sensitivity analyses, including tipping point analyses, methods for establishing responder 
thresholds (for SGRQ Total, SGRQ Activity and EC) and corresponding responder analyses will 
be described in the SAP. 
9.5.7.1. 
Frequencies of (S)AEs, (S)ADRs, AESIs, Deaths and AEs Leading to 
Withdrawal 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
tabulated by system organ class (SOC) and by preferred term (PT). 
The total number of subjects with at least one AE, the total number of AEs, and AE event rate 
will be presented. The number of subjects and the number of AEs will be tabulated by SOC and 
by PT. AEs will also be tabulated by severity and by relationship. 
All SAEs and AEs leading to withdrawal from trial and/or permanent discontinuation from 
treatment will be fully described in individual subject narratives. 
9.5.8. 
Exploratory Endpoints 
The statistical analyses of the exploratory endpoints will be described in the SAP. 
9.5.9. 
Other Safety Analyses 
The statistical analyses of other safety endpoints will be described in the SAP. 
9.5.10. 
Other Analyses  
The statistical analyses of the health economic and quality of life endpoints will be described in 
the SAP. 
Exit interviews will be analyzed according to a separate SAP. 
9.6. 
Interim Analyses  
No Interim Analyses are planned and thus no early stopping for efficacy is intended.  
9.7. 
Data Monitoring Committee 
A DMC will be established to perform a safety evaluation during the trial. A DMC Charter will 
define the primary responsibilities of the DMC, its membership, the purpose and timing of its 
meetings, and its procedures including those for restricted access to unblinded data. 
Safety evaluation on blinded data will also be performed by the Sponsor via regular safety 
surveillance. 
 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
− The rights of the subject to physical and mental integrity, to privacy and to the 
protection of the data concerning them are safeguarded according to local 
regulations 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the trial is initiated. In 
the EU, these documents must be submitted to the competent authorities and ethics 
committees via CTIS. The approval of the trial in the EU will also be provided via 
CTIS.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the trial design, except for changes necessary to 
eliminate an immediate hazard to trial subjects.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the trial at the site and adherence to 
pertinent requirements of title 21 of the US Code of Federal Regulations (CFR), 
ICH guidelines, the IRB/IEC, European Directive 2001/20/EC or European 
regulation 536/2014 for clinical studies (as applicable), and all other applicable 
local regulations 
10.1.2. 
Protocol Compliance 
• Serious breaches of the Clinical Trial Regulation no. 536/2014 (EU 2014) or this 
protocol will be reported to the EU CTIS within seven calendar days (7) after the 
Sponsor has been made aware of the breach. Serious breaches mean breaches likely to 
 

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affect to a significant degree the safety and rights of the subject or the reliability or 
robustness of the data generated in the clinical trial. Suspected serious breaches 
should be reported in a timely manner. Savara should be notified of suspected serious 
breaches within 1 business day of discovery. 
10.1.3. 
Financial Disclosure 
• Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. Investigators are responsible for providing information on financial 
interests during the course of the trial and for 1 year after completion of the trial. 
10.1.4. 
Informed Consent Process 
• The Investigator or his/her delegate will explain the nature of the trial to the subject 
or his/her legally authorized representative and answer all questions regarding the 
trial.  
• Subjects must be informed that their participation is voluntary. Prior to participation 
in the trial, subjects will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR part 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act and/or the General Data Protection 
Regulation requirements, where applicable, and the IRB/IEC or trial site.  
• The medical record must include a statement that written informed consent was 
obtained before the subject was screened and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the 
ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial.  
• A copy of the ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 
• A subject who is rescreened is not required to sign another ICF if the rescreening 
occurs within 8 weeks from the previous ICF signature date. 
• The ICF will contain a separate section that addresses the collection and use of 
additional biobank samples for optional exploratory research. The Investigator or 
authorized designee will explain to each subject the objectives of the exploratory 
research. Subjects will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a subject’s agreement to allow 
collection and use of biobank samples for exploratory research. Subjects who decline 
to participate in this optional research will not provide this separate signature. 
 

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10.1.5. 
Data Protection 
• The Sponsor will ensure confidentiality of the participants by appropriate technical 
and organizational safety measures. 
• Subjects will be assigned a unique identifier by the Sponsor. The Sponsor will only 
receive pseudonymized trial data; information related to the subject’s identity is kept 
at the trial site and is not accessible to the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred.  
• The subject must be informed that his/her personal trial-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject who will be required to give consent for their data to 
be used as described in the informed consent.  
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• All data will be handled in accordance with the EU’s current Data Protection Law 
Enforcement Directive, The General Data Protection Regulation and the local data 
protection regulations. For this trial, the Sponsor and Investigational Site are the data 
controller of all data processed during the trial and CROs and other sub-contractors 
used are data processors. In the EU, the contracts between the Sponsor, CRO and 
other sub-contractors used, and trial sites specify responsibilities of the parties related 
to data protection, including handling of data subjects’ rights and data security 
breaches as well as respective communication and cooperation of the parties. 
10.1.6. 
Committees Structure 
•  An independent data monitoring committee (DMC) will perform a safety evaluation 
during the trial. A separate charter for this committee will be prepared. 
10.1.7. 
Dissemination of Clinical Trial Data 
• The trial results will be posted on www.clinicaltrials.gov and the CTIS Portal in the 
EUaccording to current regulations.  
• Two Clinical Trial Reports (CTRs) will be prepared; both will follow the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3): the first 
CTR will include the results from the double-blind period and a second CTR will 
include the results of the open-label period.   
10.1.8. 
Data Quality Assurance 
• Subject data will be collected by means of EDC. The overall dataflow is described in 
Figure 4.  
 

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• DLCO, spirometry, imaging, ECG, laboratory data and biomarkers will be collected 
electronically in separate databases and will be transferred electronically to the 
Sponsor or designee.   
• Data collected in databases other than the eCRF will be reconciled with relevant 
eCRF data. 
• SAE reports will be entered in the eCRF system and/or SAE Report Form and will be 
transferred to the pharmacovigilance database.  
• Pregnancy reports will be handled via paper forms. 
• A reconciliation between the eCRF and the pharmacovigilance database will be 
performed. 
• Subject data should be entered into the eCRF as soon as possible after the visit in 
accordance with the time requirements described in the Clinical Trial Agreement with 
the site.  
• Seemingly non-physiological values will be discussed with the Investigator to 
evaluate if the values are correct or likely to be erroneous. Data from patient reported 
outcomes, including eDiary data, will not be queried. Handling of data used for the 
analyses will be described before unblinding the trial. 
• The Investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF. 
 
 

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eCRF database but are uploaded to a separate database. Data will be available for the 
site personnel right after data entry.   
• eDiary data will be available immediately after data entry and available for monitors 
and site personnel, including the Investigator, with read access only. The Investigator 
(or designee) is expected to review eDiary data and remind and re-train the subject if 
appropriate to ensure data completeness.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.  
• The Investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• In exceptional circumstances, such as a local outbreak of COVID-19, the Sponsor 
will determine the extent and nature of any remote source data verification that is 
needed for the trial in the specific situation and will carefully weigh it against the 
extra burden for the site staff and facilities. The Investigator will at all times 
determine whether the situation at their clinical site allows any of the guideline 
recommended options for remote source data verification (e.g., sharing of 
pseudonymized copies, controlled remote access to electronic records, or video 
review of records with site staff support) without compromising patient care or 
subject integrity.  
• Monitoring details describing strategy (e.g., risk-based initiatives), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, and on-site monitoring) are provided in the 
Monitoring Plan  
• The Sponsor or designee is responsible for the data management of this trial including 
quality checking of the data.  
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organization personnel). 
• Trial monitors will perform ongoing source data review/verification in accordance 
with a monitoring manual to confirm that data entered into the eCRF by authorized 
site personnel is accurate, complete, and verifiable from source documents; that the 
safety and rights of subjects are being protected; and that the trial is being conducted 
in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this trial 
must be retained by the Investigator for 25 years after trial completion unless local 
regulations or institutional policies require a longer retention period. However, the 
medical files of trial subjects shall be archived in accordance with national law. No 
records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor.  
 

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• The Sponsor is responsible for archiving the content of the clinical TMF for at least 
25 years after completion of the trial (i.e., last subject last visit). 
• For archiving purposes, each investigator will be supplied with a copy of the data 
collected for all subjects (including screen failures) at the trial site. This is done after 
completion of the trial and before site access to the eCRF and eDiary databases are 
revoked. Audit trail and query information will be included. eCRFs, ePROs, eDiaries 
must be available for inspection by authorized representatives from Savara, from 
regulatory authorities and/or IEC/IRBs. 
• Exit interviews will be collected over the phone and transcripts will be prepared. The 
transcripts will be archived together with the trial data.  
10.1.9. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
site. 
• Source data should as a rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected 
as a routine part of the clinical practice at the site may be entered on a worksheet. 
Clinical assessments/safety evaluations must be signed by medically qualified 
(Sub)investigators. 
• Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents. The Investigator may need to request previous 
medical records or transfer records. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in a source document 
agreement at each trial site. There must only be one source defined at any time for 
any data element.  
• Randomization is performed in the IRT system, which is integrated with the eCRF 
database. No other source data will be entered directly in the eCRF.  
• Source data will be captured directly for selected assessments e.g., DLCO, 
spirometry, eDiary, ECG and laboratory assessments. These assessments are captured 
electronically and will be stored in databases separately from the eCRF.   
10.1.10. 
Trial and Site Closure 
• The Sponsor reserves the right and sole discretion to close the trial site or terminate 
the trial at any time for any reason. Trial sites will be closed upon trial completion. A 
trial site is considered closed when all required documents and trial supplies have 
been collected and a trial-site closure visit has been performed. 
• The Investigator may initiate trial-site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
 

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• Reasons for the early closure of a trial site by the Sponsor or Investigator may include 
but are not limited to: 
− Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s or designee’s procedures, or 
GCP guidelines 
− Inadequate recruitment of subjects by the Investigator 
− Discontinuation of further IMP development 
• If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and contract research 
organization used in the trial of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up. 
10.1.11. 
Publication Policy 
• Savara is committed to data transparency by disclosing information from its research 
programs through presentations at scientific congresses and publication in peer-
reviewed journals. Savara adheres to the International Committee of Medical Journal 
Editors (ICMJE) recommendations regarding authorship. 
• Draft manuscripts for joint publication will be prepared in collaboration between 
Savara, the coordinating Investigator and other Investigators, as appropriate 
depending on their contribution to the trial. 
• Investigators participating in this multi-center trial may publish data subsets from 
their individual institution, but only after publication of the primary manuscript. A 
written permission to publish must be obtained from the Sponsor in advance. As some 
of the information regarding the IMP and development activities at the Sponsor may 
be of a strictly confidential nature, the Sponsor must be given a 30-day period to 
review and approve any publication manuscript prior to their submission to journals, 
meetings or conferences. Such a manuscript should always reference the primary 
publication of the entire trial. 
 

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10.2.5. 
Sample Angina Scale 
 
  
     1+  
Onset of discomfort 
 
2+  
Moderate, bothersome 
 
3+  
Moderately severe 
 
4+  
Severe, most pain ever experienced 
 
 
 
 

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10.2.6. 
Sample Oxygen eDiary 
Subjects on supplemental oxygen will complete a daily electronic diary about their oxygen use 
for 14 days prior to the relevant visits. 
1 
Have you used supplemental oxygen during the last 24 hours? 
Yes 
No  
  
If no to question 1, skip the rest of the questionnaire. 
 
 
 
2 
Did you use oxygen at rest? 
Yes 
No  
  
If no to question 2, go to question 4 
 
3 
What oxygen flow was used most often at rest? 
____ 
L/min 
 
4 
Did you use oxygen during sleep? 
Yes 
No   
 
If no to question 4, go to question 6 
 
5 
What oxygen flow was used most often during sleep? 
____ 
L/min 
 
6 
Did you use oxygen during exertion? 
Yes 
No   
 
If no to question 6, skip the rest of the questionnaire 
 
7 
What oxygen flow was used most often during exertion? 
____ 
L/min 
 
8 
For how many hours did you exert and use supplemental oxygen? 
____ 
Hrs. 
 
 
 
 
 

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10.2.7. 
Sample Patient’s Global Impression of Severity (PGIS) and Change (PGIC) (to 
be completed after the SGRQ) 
 
Please choose the response below that best describes the severity of your breathing problems. 
□ None 
□ Mild 
□ Moderate 
□ Severe 
□ Very severe 
 
Please choose the response below that best describes the overall change in your breathing 
problems since you started taking the study medication. 
□ Much better 
□ A little better 
□ No change 
□ A little worse 
□ Much worse 
 
Was this change in your breathing problems important for you? 
□ Yes 
□ No 
 
Please choose the response below that best describes how much your breathing problems limit 
your daily physical activity level. 
□ Not at all 
□ Slightly 
□ Moderately 
□ Strongly  
□ Very strongly 
 
Please choose the response below that best describes the overall change in your daily physical 
activity level since you started taking the study medication. 
□ Much better 
□ A little better 
□ No change 
□ A little worse 
□ Much worse 
 
Was this change in your daily physical activity level important for you? 
□ Yes 
□ No 
 
 
 
 

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10.2.8. 
Sample Patient’s Global Impression of Severity (PGIS) and Change (PGIC) (to 
be completed after the Exercise Test) 
 
Please choose the response below that best describes how much your breathing problems limit 
your ability to exercise. 
 
□ Not at all 
□ Slightly 
□ Moderately 
□ Strongly  
□ Very strongly 
 
 
Please choose the response below that best describes the overall change in your ability to 
exercise since you started taking the study medication. 
 
□ Much better 
□ A little better 
□ No change 
□ A little worse 
□ Much worse 
 
Was this change in your ability to exercise important for you? 
 
□ Yes 
□ No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.3. 
Appendix 3: Clinical Laboratory Tests 
 
Laboratory 
Assessments 
Parameters 
Blood 
hematology 
• Hemoglobin 
• Red blood cell count and red blood cell distribution width 
• Hematocrit  
• Mean cell volume, mean cell hemoglobin, mean cell hemoglobin 
concentration 
• Platelet count 
• White blood cell count, and white cell differential absolute count: 
Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils.  
Serum 
biochemistry 
• Aspartate aminotransferase 
• Alanine aminotransferase 
• Gamma glutamyl transpeptidase 
• Alkaline phosphatase 
• Bilirubin 
• Urea, S-creatinine, estimated glomerular filtration rate 
• Potassium, sodium, calcium, chloride, phosphate 
• Total protein, albumin 
• Lactate dehydrogenase 
• Glucose (non-fasting) 
Urinalysis 
• Glucose 
• Nitrite 
• Protein 
• Hematuria 
• Microalbuminuria 
 
 

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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.4.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical trial subject, temporally associated 
with the use of IMP or other trial procedures, whether or not considered related to the IMP or 
the trial procedures. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of IMP or other trial procedures.  
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology or biochemistry) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgment 
of the Investigator). 
• 
Worsening of the disease/disorder being studied. 
• 
Worsening of a pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
• 
New conditions detected or diagnosed after signing the ICF even though it may have been 
present before the start of the trial. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae. 
• 
Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfil the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any abnormal laboratory findings or other abnormal safety assessments which are associated 
with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 

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Events NOT Meeting the AE Definition  
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the trial that do not worsen. 
10.4.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
• 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Important medical event 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
 

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10.4.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then enter all relevant AE and SAE information in the eCRF and/or 
SAE Report Form (additional instructions on the reporting of SAEs will be provided 
separately). 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
the Sponsor in lieu of completion of the AE/SAE CRF page or SAE Report Form. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all subject identifiers, with the exception of the subject number, will be 
redacted on the copies of the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
trial and assign it to one of the following categories (the most severe category should be recorded, 
if the intensity changes):  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. 
• 
An AE that is assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. 
Assessment of Seriousness 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined criteria as described 
in the definition of an SAE (Section 10.4.2), NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between IMP and each occurrence of 
each AE/SAE. 
• 
Causality will be assessed as either “related”, “possibly related”, “unlikely related” or “not 
related”. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
 

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Assessment of Causality 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IMP administration will be 
considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always assess causality for every event before the initial transmission of SAE data. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. In case causality 
assessment of an AE changed over the duration of the trial, the last causality assessment will 
prevail. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor or 
delegate to elucidate the outcome and causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
New or updated information will be recorded in originally completed in eCRF or entered in 
the follow-up SAE Report Form. 
• 
The Investigator will submit any updated SAE data to the Sponsor or designee within 
24 hours of receipt of the follow-up information. 
10.4.4. 
Reporting of SAEs 
SAE Reporting to the Sponsor 
• 
The primary mechanism for reporting an SAE will be via entry to the electronic data 
collection tool.  
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool in order to report the event within 24 hours.  
• 
The site will enter the SAE data into the electronic system as soon as it becomes available.  
• 
After the trial is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.  
• 
If a site receives a report of a new SAE from a trial subject or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form. 
• 
Contacts for SAE reporting will be provided to the sites and can be found in the Investigator 
TMF. 
 

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10.7. 
Appendix 7: Abbreviations 
• 6MWD 
6-minute walk distance 
• 6MWT 
6-minute walk test 
• A-aDO2  
Alveolar-arterial oxygen difference 
• ADR  
Adverse drug reaction 
• AE 
 
Adverse event 
• AESI  
Adverse event of special interest 
• Anti-GM-CSF Antibodies to granulocyte macrophage colony stimulating factor 
• aPAP  
Autoimmune pulmonary alveolar proteinosis 
• ATS 
 
American Thoracic Society 
• BAL  
Bronchoalveolar lavage 
• CEA  
Carcinoembryonic antigen 
• CGIC  
Clinician’s Global Impression of Change 
• CGIS  
Clinician’s Global Impression of Severity 
• CFR 
 
Code of Federal Regulations 
• CI 
 
Confidence interval 
• COPD  
Chronic obstructive pulmonary disease 
• CRA  
Clinical research associate 
• CT 
 
Computed tomography 
• CTIS  
Clinical Trial Information System 
• CTR 
 
Clinical Trial Report 
• CYFRA 21-1 Cytokeratin 19 fragment 
• DLCO  
Diffusing capacity of the lungs for carbon monoxide 
• DMC  
Data monitoring committee 
• DSS 
 
Disease severity score 
• EC 
 
Exercise capacity 
• ECG  
Electrocardiogram 
• eCRF  
Electronic case report form 
• EDC  
Electronic Data Capture  
• EQ-5D-5L 
EuroQoL 5 Dimensions, 5 Levels 
• ERS 
 
European Respiratory Society 
 

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• FAS 
 
Full analysis set 
• FEV1  
Forced expiratory volume in one second 
• FDA  
Food and Drug Administration 
• FiO2 
 
Fraction of inspired oxygen 
• FRIEND 
Fitness Registry and the Importance of Exercise National Database 
• FVC 
 
Forced vital capacity 
• GGO  
Ground glass opacity 
• GM-CSF 
Granulocyte macrophage colony stimulating factor 
• Hb 
 
Hemoglobin 
• Hct 
 
Hematocrit 
• HRCT  
High resolution computed tomography 
• IB 
 
Investigator’s Brochure 
• ICF 
 
Informed Consent Form 
• ICH 
The International Council for Harmonisation of Technical Requirements 
 
for Pharmaceuticals for Human Use 
• IEC 
Independent Ethics Committee 
• IMP 
Investigational medicinal product 
• IRB 
Institutional Review Board 
• IRT 
 
Interactive Response Technology 
• KL-6  
Krebs von den Lungen-6 
• LDH  
Lactate dehydrogenase 
• Lsmean 
Least squares mean 
• MedDRA 
Medical Dictionary for Regulatory Activities 
• MET  
Metabolic equivalent 
• MOL  
Molgramostim 300 µg nebulizer solution 
• MOL-INT 
Molgramostim 300 µg nebulizer solution intermittent treatment 
• MOL-OD 
Molgramostim 300 µg nebulizer solution once-daily treatment 
• PaO2  
Arterial partial pressure of oxygen 
• PAP 
 
Pulmonary alveolar proteinosis 
• PBO 
 
Placebo (treatment group) 
• PGIC  
Patient’s Global Impression of Change 
 

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• PGIS  
Patient’s Global Impression of Severity 
• PPS 
 
Per-protocol set 
• PT 
 
Preferred term 
• QTcF  
QT interval corrected by Fridericia 
• rhGM-CSF 
Recombinant human granulocyte macrophage colony stimulating factor 
• RPE 
 
Rating of Perceived Effort 
• SAE 
 
Serious adverse event 
• SAP 
 
Statistical analysis plan 
• SAS 
 
Safety analysis set 
• SD 
 
Standard deviation 
• SGRQ  
Saint George’s Respiratory Questionnaire 
• SoA 
 
Schedule of Activities 
• SOC 
 
System organ class 
• SpO2  
Oxygen saturation 
• SUSAR 
Suspected unexpected serious adverse reaction 
• TMF  
Trial master file 
• US 
 
United States 
• VAS  
Visual Analogue Scale 
• VC 
 
Vital capacity 
• VO2 
 
Maximum oxygen consumption 
• WHO  
World Health Organization 
• WLL  
Whole lung lavage 
 
 
 
 
 
 
 

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10.8. 
Appendix 8: Change log 
 
Protocol 
Version 
Date 
Changes 
Rationale 
1.0 
22 June 2020 
Not applicable (original protocol) 
 
2.0 
17 August 2020 
Amendment 1  
Change 1 (only applicable for Japan) 
Promotion of the exploratory efficacy 
endpoint ’Change in A-aDO2 from 
baseline to Week 24’ to a secondary 
endpoint. 
This change caused updates to the 
following sections: 
• 
Section 1.1, Synopsis 
• 
Section 3, OBJECTIVES AND 
ENDPOINTS 
• 
Section 4.2.3.2, Secondary 
Endpoints 
• 
Section 9.3.2., Estimands for the 
Secondary Efficacy Endpoints 
• 
Section 9.5.1, General 
Considerations 
• 
Section 9.5.6, Secondary Endpoints 
Change 2 (applicable for all countries) 
Addition of an exclusion criterion 
(‘Known active infection [viral, 
bacterial, fungal. Or mycobacterial] that 
may affect the efficacy evaluation in the 
trial‘). 
This change caused updates to the 
following section: 
• 
Section 5.2, Exclusion Criteria 
The protocol was amended on 17 
August 2020 due to two requests by 
the Pharmaceutical and Medical 
Devices Agency  (PMDA), Japan,  
during pre-trial consultation. 
Amendment 1 is considered 
substantial. 
 
 
3.0 
08 September 
2020 
Amendment 2 
Adding more frequent full physical 
examination, and symptom-oriented or 
The protocol was amended on 08 
September 2020 due to requests from 
European Regulatory Authorities 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
brief physical examination at interim 
visits.  
This change caused updates to the 
following sections:  
1.3 Schedule of Activities 
8.3.2. Physical Examination 
Adding a definition of postmenopausal 
and women of child-bearing potential. 
This change caused updates to the 
following sections:  
Section 5.1. Inclusion Criteria 
Adding an exclusion criterion for women 
who are pregnant, planning to become 
pregnant during the trial, or 
breastfeeding.  
This change caused updates to the 
following sections:  
Section 2.3.1 Risk Assessment 
Section 5.2, Exclusion Criteria 
Adding a definition of postmenopausal 
and women of child-bearing potential. 
This change caused updates to the 
following section:  
Section 5.1. Inclusion Criteria 
Adding a definition of postmenopausal 
and women of child-bearing potential. 
Clarifying that subjects who cannot 
conduct an assessment because their 
condition worsened so that they cannot 
discontinue supplemental oxygen will 
stay in the trial and conduct all other 
assessments according to the protocol 
This change caused updates to the 
following section:  
Section 6.5.4 Oxygen Supplementation 
during a Voluntary Harmonization 
Procedure. 
Amendment 2 is considered 
substantial. 
 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
Clarifying that in case of safety concerns 
the subject may discontinue the IMP if 
deemed necessary by the investigator. 
This change caused updates to the 
following section:  
Section 8 Trial Assessments and 
Procedures 
Specifying the timeframes for reporting 
of SUSARs (7 versus 15 days)  
This change caused updates to the 
following section:  
8.4.4. 
Regulatory Reporting 
Requirements for SAEs 
 
4.0 
Revised 
25 March 2021 
Amendment 3 
 
The changes specified in the ‘Rationale’ 
column caused updates to the following 
protocol sections: 
1.1. 
Synopsis 
1.2.  
Schema 
1.3. 
Schedule of Activities (SoA) 
 
10. Objectives and endpoints 
 
4.1 
Overall design 
4.2.1. 
Choice of Overall Trial Design  
4.2.3.2. Secondary Endpoints 
4.4. 
End of Trial Definition 
 
5.2. 
Exclusion Criteria 
 
6.2.2. 
Administration 
6.2.3. 
Storage 
6.3.1. 
Double-blind Treatment Period 
6.5.3. 
Rescue Treatment 
 
8.2.1. 
Diffusing Capacity of the Lungs 
for Carbon Monoxide (DLCO) 
To address recommendations from 
the FDA, the protocol was amended 
to:   
• 
Add PK sampling pre-dose 
and 2 hours post-dose at 
baseline, Week 4, Week 24 
and Week 48. 
• 
Convert Week 98 telephone 
follow-up visit to a Week 100 
on-site visit to collect samples 
for anti-GM-CSF antibody 
analysis. 
• 
Change scope of biobank 
sample to cover analyses to 
support efficacy or safety. 
• 
Revise the secondary endpoint 
hierarchy to include 48-week 
endpoints for all countries 
except Japan and South Korea. 
• 
Replace the interim analysis 
with a blinded sample size re-
assessment and an unblinded 
safety review. 
To address requirements of the South 
Korean competent authority, the 
protocol was amended to:  
• 
Upgrade (A-a)DO2 to a 
secondary endpoint for South 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
8.2.3. 
Exercise Capacity (EC) 
8.2.4. 
Whole Lung Lavage (WLL) 
8.2.8. 
Biobank 
8.2.13. Exit Interviews 
8.3.5. 
Pregnancy Test 
8.3.6. 
Anti-GM-CSF Antibodies 
8.4.1. 
Time Period and Frequency for 
Collecting AE and SAE Information 
 
8.6. 
Pharmacokinetics 
 
9. 
Statistical Considerations 
9.2. 
Sample Size Determination 
9.3. 
Trial Estimands 
9.3.2. 
Estimands for the Secondary 
Efficacy Endpoints (all subsections) 
9.5. 
Statistical Analyses (all 
subsections) 
9.6. 
Interim Analyses 
9.7. 
Data Monitoring Committee 
 
10.1.5. Committees Structure 
10.1.7. Data Quality Assurance 
10.2.2. Exercise Test Summary Sheet   
 
10.4. 
Appendix 4: Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, and 
Reporting 
 
10.5. 
Appendix 5: Contact 
Information for Medical Monitor, 
Technical Facilities and Central 
Laboratories   
10.6. 
Appendix 6: Signature Page 
Korea (as already done for 
Japan). 
• 
Revise two exclusion criteria 
to mention specific pulmonary 
conditions that may confound 
analysis of the primary 
endpoint. 
To address requirements of the 
French IEC, the protocol was 
amended to: 
• 
Add an exclusion criterion for 
vulnerable subjects. 
To address requirements of the 
German IEC, the protocol was 
amended to: 
• 
Elaborate on remote access to 
patient information if needed 
during the COVID-19 
pandemic. 
To improve feasibility and oversight 
of the exercise treadmill test (ETT), 
the protocol was amended to: 
• 
Update the description of the 
ETT and the exercise 
summary sheet. 
To provide additional data on 
performance of critical tasks and 
improve compliance, the protocol 
was amended to: 
• 
Add mandatory repeat 
nebulizer training assessment 
at Week 4. 
To reflect changes in trial operational 
set-up, the protocol was amended to: 
• 
Update the list of CROs and 
align procedures accordingly. 
In addition:  
• 
Minor changes to data 
collection were added. 
• 
Minor edits were made 
throughout for clarity and 
consistency. 
Amendment 3 is considered 
substantial. 
5.0 
June 28, 2021 
1.3 Schedule of Activities 
 
 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
• 
Prior and concomitant therapy added 
to unscheduled visits 
• 
Vitals and body weight added to all 
visits 
• 
Exercise Treadmill Test added to 
early withdrawal 
• 
Oxygen diary card added to all visits 
• 
Baseline Exercise Treadmill Test 
and HRCT performed up to 3-week 
after Screening Visit 2, but prior to 
baseline visit.  At other time points, 
allow 7 days flexibility. 
• 
Blood sampling for GM-CSF gives a 
window of 30 minutes 
• 
Return ancillaries added to last visit 
and early withdrawal 
 
 
2.2 Background, 2.2.1 aPAP 
• 
Deleted words that state the whole 
lung lavage are done under general 
anesthesia, can be done in intensive 
care units, and washes out fluid from 
alveoli 
 
2.2.2 Benefit Assessment 
• 
Removed the work “curative’ from 
the statement that no evidence-based 
treatment exists for aPAP 
 
5.1 Inclusion Criteria 
• 
The requirement of DLCO to be 
70% or lower at the Screening visit 
and Baseline visit clarified by 
adding the qualifier “first” to the 
Screening visit 
 
 
• 
These are relevant information to 
obtain at all visits 
• 
Vitals and body weights are 
relevant information to obtain 
• 
Collect this information on 
patients withdrawing from the 
study early 
• 
Collect and record this 
information 
• 
Exercise Treadmill Test and 
HRCT are time consuming and 
may be done at different 
facilities.  The change allows for 
in scheduling and would not 
impact trial design. 
• 
No window was previously 
specified 
• 
Not specified previously  
 
 
• 
Such details are redundant and 
not necessary to make the point 
that whole lung lavage is an 
invasive and difficult procedure 
 
 
• 
The word “curative” may imply 
that other forms of medical 
treatment may exist for aPAP, 
which is not the case 
 
 
• 
There are two Screening visits in 
the study, at -6 weeks (first 
screening visit) and – 3 weeks 
(second screening visit).  Adding 
the word “first” clarifies that 
DLCO 70% or lower is 
necessary for the first screening 
visit.  The second screening visit 
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Protocol 
Version 
Date 
Changes 
Rationale 
 
 
 
• 
Remove the requirement that 
patients enrolled in the study have 
functional impairment in the 
treadmill exercise test (defined as 
peak METS of 8 or lower) 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2 Exclusion criteria 
20. For France only: including as 
further defined by French 
Health Code articles L1121-6, 
L1121-8, and L1121-8-1. 
 
6.2.2 Administration (of IMP) 
• 
The word “approximately” inserted 
to the statement that the nebulizer 
handset will be replaced every 4 
weeks, and to the statement that 
subjects will administer the trial 
treatment at the same time of the 
day. 
to exclude patients with a 
variability of 15% or higher. 
 
• 
The exercise test will be 
performed, and the peak METS 
will be used as the baseline 
value, but not be used as an 
eligibility requirement.  While it 
is reasonable to enroll patients 
who are functionally impaired, 
there is no previous data what 
that impairment number would 
be in METS in patients with 
aPAP.  The value of 8 was 
chosen arbitrarily partly using 
information of oxygen saturation 
of aPAP patients.  Enrolling 
patients at any METS would not 
materially change the study, 
because on treatment patients 
can still show improvement form 
a baseline METS number to a 
higher number.  Changing a 
criterion on a secondary endpoint 
is also not materially critical.  
This change would not impact 
the conduct of the study and the 
planned data analysis.  The 
change wasdecided before any 
patient was randomized. 
 
 
Address the requirement for France 
specific language aligned to the 
global protocol 
 
 
 
• 
The change of nebulizer handset 
periodicity, and the timing of 
trial treatment administration is 
qualified by the word 
“approximately” to clarify that 
some reasonable variability 
around these time points can be 
accepted.   
 

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Protocol 
Version 
Date 
Changes 
Rationale 
 
5.3.1 Double-Blind Treatment Period 
• 
Added words “are intended to” and 
“approximately” to stratification 
based on DLCO threshold and 
region 
• 
Added Australia to the region of 
Asia. 
 
 
 
6.5.2 Concomitant Therapy 
• 
A sentence added to state that the 
disallowed therapies start at the time 
of signing informed consent. 
 
6.5.3 Rescue Treatment 
• 
Wording changed around whole 
lung lavage procedure to make the 
sentence read better  
 
8.2.6 Supplemental Oxygen Use 
• 
Duplicate use of the word PaO2 
removed 
 
9.2 Sample Size Determination 
• 
A word “delegate” added as an 
alternate to Sponsor to specificity 
who will conduct blinded sample 
size re-assessment after 80 subjects 
have completed the Week 24 visit. 
 
 
 
9.7 Data Monitoring Committee 
 
• 
Stratification numbers are 
intended and not absolute 
because it is not possible to 
predict screen failure rates and 
dropout rates.  Wording added to 
clarify these points. 
• 
Australia added as a new country 
and Australia will be added as a 
country to the region Asia for 
stratification.   
 
 
• 
Clarifying langue added to make 
it clear the disallowed therapy 
monitoring starts at the time of 
signing informed consen 
 
 
• 
Minor change in writing style 
 
 
 
• 
Minor change in writing style 
 
 
• 
Adding the word “delegate” 
clarifies that the blinded sample 
size re-assessment will be 
conducted either by the Sponsor 
or a delegate, such as Parexel as 
the CRO for the trial. 
 
 
 
 
 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
• 
Specific reference to “The 
Development Safety Team” 
removed to the statemnt that safety 
evaluation will also be performed by 
the Sponsor. 
 
 
Overall Design (page 11) 
• 
Corresponding changes made to the 
Overall Design to capture changes 
that are also captured in the Overall 
Design Section. 
• 
Safety of the study subjects will 
be reviewed by the Data 
Monitoring Committee and also 
by the Sponsor of the trial.  
Specific reference to a specific 
Development Safety Team is not 
necessary and removed. 
 
 
• 
Relevant sections are on subject 
stratification based on DLCO % 
predicted and on region 
• 
And adding Australia as a new 
country and to the region of 
Asia. 
• 
Clarification on aPAP diagnosis 
criteria to ensure consistency 
with 5.1 inclusion criteria 
 
6.0 
August 5, 2021 
1.3 Schedule of Activities 
• 
Removal of ‘X’ for ‘Resting vital 
signs and body weight’ and ‘Oxygen 
diary’ at Week 52, Visit 125.7 
Exclusion Criteria 
5.7 Exclusion Criteria 
• 
Removal of reference to French 
Health Codes in Exclusion Criterion 
18 
• 
Removal of Exclusion Criterion 19 
‘X’ was inadvertently added to these 
assessments due to typographical 
error (Visit 12 is conducted via 
telephone) 
 
 
Address request during Virtual 
Harmonization Process (VHP) review 
to remove these references, and to 
ensure identical protocol wording in 
all global regions outside of France. 
7.0 
October 6, 2022 5.4 Screen Failures 
• 
Removal of sentence that limited re-
screening of subjects to situations 
where a required screening 
assessment fails due to a non-aPAP 
related, temporary problem 
• 
Clarification that re-screening of a 
particular subject should be 
discussed with the Medical Monitor 
 
Patients whose aPAP may have 
become more severe since initially 
screen failing could be considered 
appropriate for re-screening (such as 
if screen fail reason was DLCO 
>70% predicted). 
The study Medical Monitor is the 
appropriate person with whom to 
discuss potential re-screenings. 
 
 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
8.0 
January 25, 2023 1.1 Synopsis – Overall Design 
• 
2nd bullet – See section 6.3.1 
below 
• 
4th bullet – Removal of 
reference to demonstrating 
functional impairment in 
exercise treadmill test 
6.3.1 Double-blind Treatment Period 
• 
Removal of sentence that 
stipulated a randomization cap 
by stratum based on DLCO 
9.2 Sample Size Determination 
• 
Removal of reference to a cap 
on recruitment 
 
 
10.5 Contact Information 
• 
Update to name of global 
medical monitor 
• 
Change of vendor name from 
ERT to Clario 
Reference to functional impairment 
in section 1.1 should have been 
deleted in version 5.0, where this 
requirement was removed (see p. 
119 above). It was not removed at 
that time due to an editorial 
oversight. 
The remaining changes were made 
based on enrollment trends to date, 
and the fact that any cap on 
enrollment (whether by stratum or 
overall) will have no meaningful 
impact on the analysis of the data.  
Patients with DLCO <50% are fewer 
(currently 40% of enrolled subjects) 
and retention of the DLCO stratum-
based enrollment cap would 
substantially delay completion of the 
trial.   
 
The global medical monitor for the 
study is Dr. Anthony Bohnert. 
ERT has changed its name to Clario. 
9.0 
March 20, 2023 1.3 Schedule of Assessments 
• 
Removal of ABG at Weeks 72 
and 96 (Visits 14 and 16) 
• 
Addition of 48 weeks to the 
open-label treatment period 
(new Visits 17-20) 
• 
Change of safety follow-up 
from Visit 17 (Week 100) to 
Visit 21 (Week 148) 
1.3 Schedule of Assessments and 
throughout the document 
• 
Change all reference to 
duration of open-label 
treatment period from 48 weeks 
to 96 weeks 
10.2.2 Exercise Treadmill Test 
Summary Sheet 
• 
Replacement of version 1.0 
with version 2.0 
 
 
ABG and respiration rate are not of 
significant clinical or scientific 
interest during the open-label 
treatment period, and reduces burden 
on the subject. 
Open-label treatment with 
molgramostim was increased by 48 
weeks to obtain additional long-term 
safety and to assess the durability of 
effect. 
 
 
 
Exercise Treadmill Test Summary 
Sheet was up-versioned in July 2022. 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
9.1 
November 21, 
2023 
1.3.2 Open-label Treatment Period 
• 
Addition of ‘X’ at Week 148 
(Visit 21) for “Resting vital 
signs and body weight” 
• 
Addition of footnote ‘b’ next to 
the ‘X’ at Week 148 (Visit 21) 
for “Blood sample for 
biomarkers, anti-GM-CSF 
antibodies and, optionally, 
biobank” 
5.2 Exclusion Criteria 
• 
Text added to Criterion no. 18, 
which is applicable to sites in 
France only 
• 
Criterion no. 19 added, which 
is applicable to sites in France 
only 
8.3.1 Electrocardiograms 
• 
Clarification of wording to 
state that three unique ECG 
assessments are to be 
performed at the indicated 
visits 
10.8 Appendix 8: Change log 
• 
Deletion of wording “and 
resting respiration rate,” which 
was erroneously included in the 
change log for version 9.0 
 
The omission of this ‘X’ in version 
9.0 was inadvertent; the Case Report 
Forms prompt for the collection of 
these data at all visits. 
Simply a clarification to align with 
version 8.0, where this footnote 
appears both at the top of the Week 
148 (“Safety FU”) column and next 
to the ‘X.’ 
 
 
These additions allow for a single 
global protocol (previously there was 
a separate version specific to 
France). 
 
 
 
The instructions as previously 
worded could have been 
misconstrued as requiring only a 
single ECG assessment to be 
uploaded three times. 
 
 
Resting respiration rate is assessed at 
Weeks 72 and 96, as noted in the 
Schedule of Activities (Section 1.3), 
and the Case Report Forms prompt 
for the collection of these data at all 
visits. 
10.0 
October 9, 2024 Title page 
• 
Addition of EU Clinical Trial 
number 
 
To comply with requirements in the 
Clinical Trial Regulation in the EU. 
 
 
Synopsis – Objectives and Endpoints 
and 3 Objectives and Endpoints 
• 
Addition of “Change in GGO 
from baseline to Week 144 and 
from Week 24 to Week 144” as 
long-term exploratory endpoint 
 
 
To evaluate the data obtained from 
the extra HRCT scan. 
 
 
 
1.3.2 Schedule of Assessments  
 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
• 
Addition of an HRCT scan to 
the Week 144 visit (Visit 20). 
• 
Change from mandatory to 
optional assessment at 
unscheduled visits for ‘prior 
and concomitant therapy’, 
‘resting vital signs and body 
weight’, and ‘adverse events’  
• 
Clarification that the safety 
follow-up visit (Week 148) 
must be performed 3-5 weeks 
after the Week 144 visit. 
To obtain additional information 
regarding long-term impact of 
molgramostim on HRCT appearance 
in aPAP 
To clarify that all assessments at 
unscheduled visits are performed at 
the discretion of the investigator 
 
The safety follow-up assessments 
should be performed approximately 
4 weeks after the last dose of IMP. 
 
 
2.3.1 Risk Assessment 
• 
The number of mandated 
HRCT was updated from 2 to 
3. 
 
See rationale for additional HRCT 
scan above. 
 
 
6.2.2 Administration 
• 
Updates of text regarding how 
to report technical complaints 
related to the drug product or 
device.  
 
To align information in the 
Investigator Drug Manual with the 
protocol. 
 
 
 
8.2.5 High Resolution Computed 
Tomography (HRCT) 
• 
Added statement that the 
independent GGO readers will 
not be blinded to subjects’ 
treatment assignment and 
sequence of the assessed scans 
at new Week 144 HRCT scan. 
 
 
Clarification of the procedure. 
 
 
 
8.3.1 Electrocardiograms 
• 
Clarification that after Week 48 
(and at the time of 
implementation of protocol 
version 10.0), only a single 12-
lead ECG assessment will be 
obtained. 
 
To clarify that 3 unique ECG 
assessments are only needed during 
the double-blind 48-week period. 
 
 
8.4.4 Regulatory Reporting 
Requirements for AEs and SAEs 
• 
Updates of text regarding 
reporting requirements in the 
EU for SUSARs. 
 
 
To comply with requirements in the 
Clinical Trial Regulation in the EU. 
 

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Protocol 
Version 
Date 
Changes 
Rationale 
 
 
10.1 Appendix 1: Regulatory, Ethical, 
and Trial Oversight Considerations 
• 
Updates of text regarding 
regulatory and ethical 
considerations, protocol 
compliance, data protection, 
and data quality assurance.  
 
 
To comply with requirements in the 
Clinical Trial Regulation in the EU. 
 
 
 
Whole document 
• 
Minor edits, clarifications, and 
updates have been made 
throughout the document. 
 
To enhance clarity and correct non-
substantial errors. 
 

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REVISION HISTORY
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Category: Protocol
Title: SAV006-05 Clinical Trial Protocol V10.0 Global
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