Clinical trial NCT03482752
Conditions: Autoimmune Pulmonary Alveolar Proteinosis
Sponsor: Savara Inc.
Start date: 2018-04-16; Completion date: 2021-01-14
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
SAV006-03 is an open-label extension study for participants who had completed the IMPALA study.

At the baseline visit, eligible participants may continue or re-start treatment with 300 µg inhaled molgramostim (recombinant human Granulocyte-Macrophage Colony Stimulating Factor; GM-CSF) administered intermittently in cycles of seven days molgramostim, administered once daily, and seven days off treatment.

Participants will be treated with inhaled molgramostim for up to 36 months.

During the trial, whole lung lavage will be applied as rescue therapy.

Detailed description:

Arms: arm 1: Open-label treatment with molgramostim nebulizer solution (300 μg) administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment).
Interventions: intervention 1: Molgramostim
Intervention descriptions: intervention 1: 300 µg inhaled molgramostim in cycles of once daily administration for 7 days, then 7 days off treatment.

Protocol documents:
Prot_000.pdf: 
 
SAV006-03 
An open-label, non-controlled, multicentre clinical trial 
of inhaled molgramostim in autoimmune pulmonary 
proteinosis patients 
 
NCT03482752 
 
Clinical Trial Protocol 
Version 5.0 
24 August 2018 


Savara Pharmaceuticals 
Protocol SAV006-03 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
1 
 
1. 
TITLE PAGE 
MOLGRAMOSTIM NEBULISER SOLUTION 
 
CLINICAL TRIAL PROTOCOL 
SAV006-03  
 
AN OPEN-LABEL, NON-CONTROLLED, 
MULTICENTRE CLINICAL TRIAL OF INHALED 
MOLGRAMOSTIM IN AUTOIMMUNE PULMONARY 
ALVEOLAR PROTEINOSIS PATIENTS 
 
IMPALA EXTENSION TRIAL  
 
Product Name: 
Molgramostim Nebuliser Solution 
(MolgradexP®
P) 300 µg 
Indication: 
Autoimmune Pulmonary Alveolar Proteinosis  
Phase: 
III 
EudraCT No. 
Sponsor: 
2017-004078-32 
Savara ApS 
Slotsmarken 17, 2 t.v. 
2970 Hørsholm 
Denmark  
Date of Protocol: 
24-Aug-2018 
Version: 
Final version 5.0 (All countries) 


Savara Pharmaceuticals 
Protocol SAV006-03 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
2 
1. 
SYNOPSIS 
Name of Sponsor/Company: 
Savara ApS 
Name of Investigational Product: 
Molgramostim Nebuliser Solution (MolgradexP®
P) 
Name of Active Ingredient: 
Molgramostim (recombinant human GM-CSF) 
Title of Study:  
An open-label, non-controlled, multicentre clinical trial of inhaled molgramostim in autoimmune 
pulmonary alveolar proteinosis patients  
Study center(s): Centres participating in the IMPALA (MOL-PAP-002) trial 
International Coordinating Investigator: Francesco Bonella, MD, PhD (Interstitial and Rare Lung 
Disease Unit, Ruhrlandklinik University Hospital, Essen, Germany) 
Studied period (years):  
Estimated date first subject enrolled: Q1 2018 
Estimated date last subject completed: Q4 2021 
Phase of development: III 
 
Objectives:  
Primary: 
• 
To investigate safety of long term use of inhaled molgramostim.  
Secondary: 
• 
To investigate effects of long term use of inhaled molgramostim on oxygenation. 
• 
To investigate effects of long term use of inhaled molgramostim on exercise capacity. 
• 
To investigate effects of long term use of inhaled molgramostim on respiratory quality of 
life. 
• 
To investigate requirement for whole lung lavage (WLL) during long term use of inhaled 
molgramostim. 
• 
To investigate effects of long term use of inhaled molgramostim on lung function. 
• 
To investigate maintenance of effect after discontinuation of inhaled molgramostim. 
Methodology:  
Subjects with autoimmune pulmonary alveolar proteinosis (aPAP) who have completed the IMPALA 
trial will be eligible for the trial.  
At the Baseline visit, eligible subjects may continue or re-start treatment with inhaled molgramostim 
(300 µg) administered intermittently in cycles of seven days molgramostim, administered once daily, 
and seven days off treatment.  


Savara Pharmaceuticals 
Protocol SAV006-03 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
3 
Trial visits will be conducted at 6-monthly intervals until the end of trial. Participating subjects will 
be encouraged to contact the clinic between visits if they experience adverse events (AEs) or 
worsening of aPAP, or if they have any other concerns. 
During the trial, WLL will be applied as rescue therapy. The criterion for performing WLL is clinical 
worsening of aPAP based on symptoms, reduced exercise capacity and/or findings of hypoxaemia or 
desaturation, according to the investigator’s judgement. The reason(s) for conducting WLL will be 
documented. Subjects undergoing WLL will continue treatment with molgramostim, unless 
discontinuation is medically required, according to investigator’s discretion. 
Subjects may discontinue molgramostim due to remission of aPAP, lack of response that requires a 
different treatment modality, or AEs. Subjects becoming pregnant will be required to discontinue 
treatment with molgramostim. Subjects who discontinue molgramostim will continue in the trial and 
attend visits according to the same schedule until end of the trial. Molgramostim treatment may be 
re-started if medically required. Subjects not requiring treatment at the Baseline visit may start 
molgramostim treatment during the trial if medically required. 
Number of subjects (planned):  
Up to 90 subjects may be included. 
Diagnosis and main criteria for inclusion: 
Inclusion Criteria:  
1. Completer of the IMPALA trial. 
2. 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 where inhibition of ovulation is the primary mode of action, 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomised partner, sexual abstinence*), during and until 30 days after last dose of trial 
treatment. Females of childbearing potential must have a negative urine pregnancy test at 
Baseline, or at start of treatment if treatment is not dispensed at Baseline, and must not be 
lactating during and until 30 days after last dose of trial treatment*. 
3. 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 above. 
4. Willing and able to provide signed informed consent. 
* Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
female trial participant of child bearing potential and that the vasectomised partner has received medical assessment of 
the surgical success. 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 study 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 
 


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Exclusion criteria: 
1. Treatment with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) products 
other than molgramostim nebuliser solution within three months of Baseline. 
2. Treatment with any investigational medicinal product other than inhaled molgramostim 
within four weeks of Baseline. 
3. History of allergic reactions to GM-CSF. 
4. Connective tissue disease, inflammatory bowel disease or other autoimmune disorder 
requiring treatment associated with significant immunosuppression, e.g. more than 10 mg/day 
systemic prednisolone. 
5. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product. 
6. History of, or present, myeloproliferative disease or leukaemia. 
7. Apparent pre-existing concurrent pulmonary fibrosis. 
8. Any other serious medical condition which in the opinion of the investigator would make the 
subject unsuitable for the trial. 
Investigational product, dosage and mode of administration:  
Investigational Medicinal Product (IMP): Molgramostim nebuliser solution 
Active Substance: Molgramostim, recombinant human Granulocyte Macrophage Colony Stimulating 
Factor (rhGM-CSF) 
Pharmaceutical form: Nebuliser solution  
Route of administration: Inhalation 
Inhalation device: PARI eFlow (PARI Pharma GmbH) 
Duration of treatment:  
The total duration of the treatment is up to three years from first subject first visit. Should the product 
not have obtained marketing authorization at this date, the trial will be amended with an extension of 
one year at a time to ensure adequate treatment options for subjects in the trial who still are in need of 
treatment with inhaled molgramostim. 
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Primary Endpoints  
• 
Number of AEs, serious adverse events (SAEs), adverse drug reactions (ADRs), and AEs 
leading to treatment discontinuation during the trial.  
Secondary Endpoints: 
• 
Alveolar-arterial oxygen difference ((A-a)DO2) during the trial. 
• 
6-minute walking distance (6MWD) during the trial. 


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• 
St Georges Respiratory Questionnaire (SGRQ) total score during the trial. 
• 
Frequency of WLL during the trial. 
• 
Diffusion Capacity of the Lung for Carbon Monoxide (DLCO), Forced Expiratory 
Volume in one second (FEV1), and Forced Vital Capacity (FVC) during the trial, all 
expressed as percent predicted. 
• 
Arterial oxygen tension (PaO2) and disease severity scores (DSS) during the trial.  
• 
Need for oxygen supplement therapy during the trial. 
• 
Number of subjects not requiring treatment for aPAP and time off treatment after 
discontinuation of inhaled molgramostim 
Exploratory Endpoints: 
• 
GM-CSF levels before and 2 hours after dosing 
Methods of Assessment: 
Lung function variables – DLCO and spirometry (FEV1 and FVC) will be done in accordance with 
European Respiratory Society/American Thoracic Society (ERS/ATS) guidance using local 
equipment. For spirometry percent of predicted values will be calculated centrally using standard 
equations. 
6-minute walking test (6MWT) – will be performed in accordance with European Respiratory 
Society/American Thoracic Society (ERS/ATS) guidance. Borg CR10 scale will be used to assess 
dyspnoea before and after the test. 
Quality of Life score – SGRQ 
Laboratory analyses – Local laboratories will be used for analysis of haematology, clinical chemistry 
and pregnancy testing.  
(For Italy only: samples will be collected for pharmacokinetic (PK) analysis at Visit 1-6, pre-dose 
and 2 hours post dosing) 
Statistical methods: 
Data from the trial will be analysed descriptively. Data from the trial is planned to be combined with 
relevant data from the IMPALA trial; these combined analyses will be reported separately. 


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Table 1: 
Study Flow Chart 
Visit  
Visit 1  
Visit 2 
Visit 3  
Visit 4  
Visit 5  
Visit 6 
Visit 7 
FU TC 
Unscheduled  
Baseline a 
Month 6 
Month 12  
Month 18 
Month 24 
Month 30 
Month 36 
2 wks after 
trial 
completion 
Time  
0 
Week 26  
Week 52  
Week 78  
Week 104  Week 130 
Week 156 
Visit Window  
N/A 
± 4wks 
± 4 wks 
± 4 wks  
± 4 wks 
± 4 wks 
± 4 wks 
+ 1 wk 
 
Informed consent  
X  
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
 
X 
WLL information b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test and 
contraceptive check c 
X 
X 
X 
X 
X 
X 
X 
 
(X)d 
Physical Exam 
(X) 
 
X 
 
X 
 
X 
 
(X) d 
Vital signs 
(X) 
X 
X 
X 
X 
X 
X 
 
(X) d 
ECG 
(X) 
X 
X 
X 
X 
X 
X 
 
(X) d 
Blood gas analysis e 
(X)T  
X  
X 
X 
X 
X 
X 
 
(X) d 
Lung function tests f 
(X)T  
X 
X 
X 
X 
X 
X 
 
(X) d 
6MWT g 
(X)T  
X 
X 
X 
X 
X 
X 
 
(X) d 
Quality of Life (SGRQ) 
(X)T  
X 
X 
X 
X 
X 
X 
 
 
DSS 
(X)T  
X 
X 
X 
X 
X 
X 
 
(X) d 
Overall Clinical 
Assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
CT Scan 
(X) d 
(X) d 
(X) d 
(X) d 
(X) d 
(X) d 
(X) d 
 
(X) d 


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Protocol SAV006-03 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
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Visit  
Visit 1  
Visit 2 
Visit 3  
Visit 4  
Visit 5  
Visit 6 
Visit 7 
FU TC 
Unscheduled  
Baseline a 
Month 6 
Month 12  
Month 18 
Month 24 
Month 30 
Month 36 
2 wks after 
trial 
completion 
Time  
0 
Week 26  
Week 52  
Week 78  
Week 104  Week 130 
Week 156 
Visit Window  
N/A 
± 4wks 
± 4 wks 
± 4 wks  
± 4 wks 
± 4 wks 
± 4 wks 
+ 1 wk 
 
Laboratory Safety 
Analyses h  
(X)  
X 
X 
X 
X 
X 
X 
 
(X)  d 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samples (Italy only) 
i 
X 
X 
X 
X 
X 
X 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Dispense trial drug j 
X 
X 
X 
X 
X 
X 
 
 
(X) d 
Subject Diary Card k 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance 
 
X 
X 
X 
X 
X 
X 
 
(X) d 
Study continuation or 
termination l 
 
X 
X 
X 
X 
X 
X 
 
(X) d 
 
Notes: See next page.  
 
 
 
 
 
 
 
 


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FU = follow-up, TC = telephone call, WLL = whole lung lavage 
a
 Baseline (Visit 1) may coincide with the final visit of the IMPALA (MOL PAP 002) trial; if so, assessments performed at Visit 11 (for subjects enrolled under 
protocol MOL PAP 002 version 4.0 or later), or Visit 13 (subjects enrolled under a protocol version prior to version 4.0) may serve as the baseline assessments 
for this protocol. If more than 3 months have elapsed since completion of the IMPALA study to Baseline (Visit 1) the assessments must be repeated. 
 b
 Requirement for WLL and if required, indication for procedure will be recorded. If WLL is performed date of WLL and type of WLL (unilateral, bilateral) will 
be recorded. 
 c
 Serum pregnancy test at Baseline (Visit 1) and at all subsequent visits during treatment with inhaled molgramostim (pregnancy tests for subjects not receiving 
trial drug are not mandatory). A urine pregnancy test will also be performed at dosing at Baseline (Visit 1) to immediately confirm that the subject is not 
pregnant and meets the inclusion criterion for treatment. If treatment is not dispensed at Baseline (Visit 1) the urine pregnancy test will instead be performed at 
the first visit treatment is dispensed. Subjects will be requested to do monthly urine testing at home during treatment. 
d
 Only applicable if assessment is done according to clinical practice or medical need, e.g. in case of a clinical deterioration. If done, results will be recorded 
 e
O  Capillary sampling for blood gas analysis may be used instead of an arterial blood gas sample at sites that routinely use this method. 
 f
 DLCO, FEV1, and FVC (absolute values and % of predicted values). 
 g
 6MWT includes assessment of SpO2 and Borg CR10 score for dyspnoea before, during (SpO2) and after (Borg) the test. If the subjects used supplemental O2 
during the procedure in IMPALA, the same O2 flow will be used at the subsequent tests in this trial, if possible. 
 h
 Haematology and clinical chemistry 
 i
 For Italy only: Patients will have their visits scheduled for an on-treatment week within the allowed window of +/- 4 weeks. The first sample must be taken just 
prior to inhalation of molgramostim. The 2nd sample must be taken 2 hours post dosing, (+/- 10 minutes). See Section 10.8.5.1 
 j
 Trial drug is dispensed to subjects who require treatment according to investigator’s discretion. For Italy only: The visit should take place in during the week on 
treatment. On the day of dosing, the subjects will do the nebulization at the clinic, in order to collect pre-dose PK sample.  
 
 k
 Diary card to collect safety information to be given to the subject and collected at the next visit. The subject will be asked to record any AEs they have 
experienced, enter dates for pregnancy tests taken at home (if applicable) and dates for changing of the nebuliser mouthpiece in the subject diary. 
l
 If the planned trial termination has been declared since the subject’s last visit in the trial, the subject will leave the trial. 
 
* .


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ......................................................................................... 2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES ............................................................................................ 9 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ... 13 
4. 
INTRODUCTION ............................................................................ 16 
4.1. 
Background ....................................................................................... 16 
4.2. 
Rationale ........................................................................................... 20 
4.3. 
Potential Risks and Benefits ............................................................. 20 
5. 
TRIAL OBJECTIVES AND PURPOSE .......................................... 22 
5.1. 
Primary Objective ............................................................................. 22 
5.2. 
Secondary Objectives ....................................................................... 22 
5.3. 
Study Endpoints ................................................................................ 22 
5.3.1. 
Primary Endpoints ............................................................................ 22 
5.3.2. 
Secondary Endpoints ........................................................................ 22 
5.3.3. 
Exploratory Endpoints ...................................................................... 23 
6. 
INVESTIGATIONAL PLAN ........................................................... 24 
6.1. 
Overall Study Design ........................................................................ 24 
6.1.1. 
Trial Period ....................................................................................... 24 
6.1.2. 
End of Trial ....................................................................................... 24 
6.2. 
Number of Subjects .......................................................................... 24 
6.3. 
Treatment Assignment ...................................................................... 24 
6.4. 
Dose Adjustment Criteria ................................................................. 25 
6.4.1. 
Safety Criteria for Adjustment or Stopping Doses ........................... 25 
6.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses .......... 25 
6.5. 
Criteria for Study Termination ......................................................... 25 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS .................... 26 
7.1. 
Subject Inclusion Criteria ................................................................. 26 
7.2. 
Subject Exclusion Criteria ................................................................ 26 
7.3. 
Subject Withdrawal Criteria ............................................................. 27 


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7.3.1. 
Discontinuation of Trial Treatment .................................................. 27 
7.3.2. 
Withdrawal from the Trial ................................................................ 27 
8. 
TREATMENT OF SUBJECTS ........................................................ 28 
8.1. 
Description of Study Drug ................................................................ 28 
8.2. 
Prohibited Treatments ....................................................................... 28 
8.3. 
Treatment Compliance ...................................................................... 28 
8.4. 
Randomisation and Blinding ............................................................ 28 
8.5. 
Subject Identification List ................................................................. 28 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ................. 29 
9.1. 
Study Drug ........................................................................................ 29 
9.2. 
Study Drug Packaging and Labeling ................................................ 29 
9.3. 
Study Drug Storage ........................................................................... 29 
9.4. 
Study Drug Preparation .................................................................... 29 
9.5. 
Administration .................................................................................. 29 
9.6. 
Study Drug Accountability ............................................................... 30 
9.7. 
Study Drug Handling and Disposal .................................................. 30 
10. 
STUDY PROCEDURES AND ASSESSMENTS ............................ 31 
10.1. 
Written Informed Consent ................................................................ 31 
10.2. 
Concomitant Treatments ................................................................... 31 
10.3. 
Medical History ................................................................................ 31 
10.4. 
Demographics ................................................................................... 32 
10.5. 
Subject Diary .................................................................................... 32 
10.6. 
Follow-up Telephone Visit ............................................................... 32 
10.7. 
Efficacy Assessments ....................................................................... 32 
10.7.1. 
Blood Gas Analysis .......................................................................... 32 
10.7.2. 
6-Minute Walk Test (6MWT) .......................................................... 33 
10.7.3. 
Quality of Life Score (QoL) ............................................................. 33 
10.7.4. 
Lung Function Tests ......................................................................... 33 
10.7.5. 
Disease Severity Score ..................................................................... 34 
10.7.6. 
Overall Clinical Assessment ............................................................. 34 
10.7.7. 
Whole Lung Lavage ......................................................................... 35 
10.8. 
Safety Assessments ........................................................................... 35 
10.8.1. 
Adverse Events ................................................................................. 35 


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10.8.2. 
Physical Examination ....................................................................... 35 
10.8.3. 
Vital Signs ........................................................................................ 36 
10.8.4. 
Electrocardiogram (ECG) ................................................................. 36 
10.8.5. 
Laboratory Assessments ................................................................... 36 
10.8.5.1. 
PK assessment (Only for Italy) ......................................................... 37 
10.8.5.2. 
Pregnancy Screen .............................................................................. 37 
10.8.5.3. 
Computed Tomography (CT) ........................................................... 37 
10.9. 
Adverse and Serious Adverse Events ............................................... 38 
10.9.1. 
Definitions of Adverse Events .......................................................... 38 
10.9.1.1. 
Adverse Event (AE) .......................................................................... 38 
10.9.1.2. 
Serious Adverse Event (SAE) .......................................................... 38 
10.9.2. 
Recording Adverse Events ............................................................... 39 
10.9.2.1. 
Severity ............................................................................................. 39 
10.9.2.2. 
Relationship to Study Drug .............................................................. 40 
10.9.2.3. 
Outcome ............................................................................................ 40 
10.9.2.4. 
Follow-up of Subjects after Adverse Events .................................... 40 
10.9.2.5. 
Abnormal Laboratory Values/Vital Signs ........................................ 41 
10.9.3. 
Reporting Adverse Events ................................................................ 41 
10.9.3.1. 
Serious Adverse Event (SAE) Reporting Procedure ........................ 41 
10.9.3.2. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Reporting Procedure ......................................................................... 42 
10.9.3.3. 
Adverse Events of Special Interest ................................................... 43 
10.9.3.4. 
Precautions/Overdose ....................................................................... 43 
10.9.3.5. 
Pregnancy ......................................................................................... 43 
10.9.3.6. 
Safety Management Plan .................................................................. 44 
11. 
STATISTICS .................................................................................... 45 
11.1. 
Primary Endpoints ............................................................................ 45 
11.2. 
Secondary Endpoints ........................................................................ 45 
11.3. 
Exploratory Endpoints ...................................................................... 45 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............... 46 
12.1. 
Access to Source Data and Documentation ...................................... 46 
12.2. 
Subject Records and Source Data ..................................................... 46 
12.3. 
Study Monitoring .............................................................................. 46 


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12.4. 
Audits and Inspections ...................................................................... 47 
12.5. 
Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) ................................................................................................. 47 
13. 
ETHICS ............................................................................................ 48 
13.1. 
Ethics Review ................................................................................... 48 
13.2. 
Ethical Conduct of the Study ............................................................ 48 
14. 
DATA HANDLING AND RECORD KEEPING ............................ 49 
14.1. 
Data Management ............................................................................. 49 
14.1.1. 
Protocol Deviations .......................................................................... 49 
14.2. 
Inspection of Records ....................................................................... 49 
14.3. 
Retention of Records ........................................................................ 49 
15. 
FINANCE AND INSURANCE ....................................................... 51 
16. 
TRIAL ORGANISATION ............................................................... 52 
17. 
PUBLICATION POLICY ................................................................ 53 
18. 
LIST OF REFERENCES .................................................................. 54 
19. 
APPENDICES .................................................................................. 56 
APPENDIX 1 LIST OF REVISIONS OF PROTOCOL ..................................... 56 
APPENDIX 2 SIGNATURE PAGE .................................................................... 60 
APPENDIX 3 TRIAL ORGANISATION ........................................................... 61 
APPENDIX 4 QUESTIONNAIRES ................................................................... 62 
APPENDIX 4.1  BORG CR10 SCALE ............................................................ 62 
APPENDIX 4.2  TRIAL SPECIFIC GUIDELINE FOR THE 6MWT ............ 63 
APPENDIX 4.3  ST GEORGE’S RESPIRATORY QUESTIONNAIRE ........ 66 
 
LIST OF TABLES 
Table 1: 
Study Flow Chart ................................................................................ 6 
Table 2: 
Abbreviations and Specialist Terms ................................................. 13 
Table 3: 
Investigational Product ..................................................................... 28 
Table 4: 
Laboratory Safety Parameters ........................................................... 36 
Table 5: 
Revisions of Protocol ........................................................................ 56 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist 
Term 
Explanation 
6MWD 
6 Minute Walk Distance 
6MWT 
6 Minute Walk Test 
(A-a)DO2 
Alveolar-arterial Oxygen Difference 
aPAP 
Autoimmune Pulmonary Alveolar Proteinosis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society  
AUC 
Area Under the Concentration versus Time Curve  
BAL 
Broncho-alveolar Lavage 
Cmin 
Minimum Measurable Plasma Concentration 
Cmax 
Maximum Measurable Plasma Concentration 
CRO 
Clinical Research Organisation 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
DLCO 
Diffusion Capacity of the Lung for Carbon Monoxide 
DSMB 
Data Safety Monitoring Board 
DSS 
Disease Severity Score 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EFD 
Embryo-foetal Developmental 
ERS 
European Respiratory Society 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 


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Abbreviation or Specialist 
Term 
Explanation 
GMP 
Good Manufacturing Practice 
HEENT 
Head, eyes, ears, nose and throat 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
65TInternational Committee of Medical Journal Editors  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review board 
MAD 
Multiple Ascending Dose 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
MRC 
Medical Research Council 
NOAEL 
No Observed Adverse Effect Level 
PaO2 
Arterial Oxygen Tension 
PAP 
Pulmonary Alveolar Proteinosis 
PAS 
Periodic Acid-Schiff  
PK blood sample 
Pharmacokinetic blood sample 
PT-INR 
Prothrombin Time International Normalised Ratio 
QoL 
Quality of Life 
RBC 
Red Blood Cell  
RDW 
Red Blood Cell Distribution Width 
rhGM-CSF 
Recombinant Human Granulocyte Macrophage Colony 
Stimulating Factor 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SGRQ 
St Georges Respiratory Questionnaire 
SOP 
Standard Operating Procedure 
SpO2 
Oxygen Saturation (indirect measurement) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TC 
Telephone Call 
TLC 
Total Lung Capacity 


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Abbreviation or Specialist 
Term 
Explanation 
VC 
Vital Capacity 
WBC 
White Blood Cell 
WLL 
Whole Lung Lavage 


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4. 
INTRODUCTION 
4.1. 
Background 
Pulmonary alveolar proteinosis (PAP) is a rare autoimmune disease with an estimated 
prevalence of 0.7 per 100,000 individuals [Trapnell 2014]. It is characterised by high 
levels of autoantibodies against Granulocyte Macrophage Colony Stimulating Factor 
(GM-CSF) in alveoli and blood. The autoantibodies neutralise the normal biologic action 
of GM-CSF in the lungs [Khan 2012]. Pulmonary Alveolar Proteinosis is also 
characterised by the accumulation of Periodic Acid-Schiff (PAS)-positive 
lipoproteinaceous material, primarily phospholipid surfactant, and surfactant apoproteins 
in the distal air spaces. Consequently, gas transfer is decreased leading to impairment of 
gas exchange, respiratory failure, and to increased risk of respiratory infections [Trapnell 
2014, Rosen 1958, Trapnell 2003, Inoue 2008]. More than 90% of the reported cases of 
PAP are classified as the autoimmune disorder type associated with GM-CSF 
autoantibodies (aPAP). Less common are the secondary and congenital types [Trapnell 
2003, Inoue 2008]. 
No evidence-based curative treatment exists for patients with PAP. There is, therefore, a 
need for new and modern treatment approaches for PAP patients. Sequential whole lung 
lavage (WLL) under general anaesthesia has become the standard of care. Whole Lung 
Lavage decreases the symptoms and improves the oxygenation in PAP patients. It is not 
possible to predict how many WLL treatments a particular patient will need; a single 
WLL is sufficient for some patients while others require lavage every six to 12 months 
for many years. The observation that mice deficient in the gene for GM-CSF develop 
alveolar accumulations of surfactant substances similar to that seen in PAP led to the 
suggestion of a potential role for recombinant human GM-CSF (rhGM -CSF) in the 
treatment of PAP [Dranoff 1994]. 
Investigational Medicinal Product (IMP) 
The IMP, molgramostim nebuliser solution, is developed by Savara Pharmaceuticals. The 
drug substance molgramostim (rhGM-CSF) is produced in E. coli and has the same 
amino acid sequence as the native protein but is not glycosylated. Another rhGM-CSF 
product, sargramostim, which is produced in S. cerevisiae slightly differs from native 
GM-CSF by having one amino acid difference in position 23 and is glycosylated. 
Production of molgramostim in bacteria circumvents the variability in the molecular 
weight seen in sargramostim. The formulation currently under development is intended 
for inhalation use. No rhGM-CSF products have been approved for respiratory disease 
therapy or for inhalation use in any indication.  
Two rhGM-CSF products for systemic use have been approved, E. coli derived 
molgramostim (Leucomax®) and yeast-derived sargramostim (Leukine®), largely for use 
following chemotherapy and/or bone marrow transplantation to reduce the risks of 
neutropenia such as infection, or in case of graft failure after bone marrow 
transplantation. Published clinical studies of relevance to the development of 
molgramostim nebuliser solution in which investigational or commercially available 


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rhGM-CSF products have been administered are summarised and discussed in the 
Investigator’s Brochure (IB). 
Pre-clinical studies in cynomolgus monkeys show that molgramostim nebuliser solution 
is well tolerated locally and that it has low systemic toxicity. The small fraction of the 
inhaled dose that is absorbed systemically causes increases in stem cell proliferation, 
resulting in increased number of monocytes, eosinophils and neutrophils in the 
circulation; similar to the known effects after intravenous administration of rhGM-CSF. 
Local effects in the lungs are characterised by accumulation of inflammatory cells, 
mostly macrophages, accompanied by an increased cellularity in the lymphoid tissue that 
is associated with the respiratory tract and minimal to mild exudation of red blood cells 
(RBC) into the alveoli. The infiltration of inflammatory cells was not associated with any 
signs of inflammation or impaired lung function, and it is interpreted as an exaggerated 
pharmacological effect of molgramostim. Its severity was graded slight at the 
10 μg/kg/day dose level and moderate above this level. Duration of treatment did not 
affect the severity of this finding. Reduced severity of the lung and tracheobronchial 
changes following 4 weeks off dose in recovery animals suggests partial resolution of the 
changes. 
An embryo-foetal developmental (EFD) toxicity trial in rabbits revealed increases in post 
implantation loss, decreases in the number of live implants, effects on sex ratio and a 
slight increase in the incidence of major malformations in foetuses at the highest dose 
(150 µg/kg/day). Studies in sexually mature monkeys have shown that molgramostim has 
no effect on male and female reproductive organs. Further details are available in the IB. 
The nonclinical data raises a concern about human teratogenicity/fetotoxicity in early 
pregnancy, risk mitigation measures (contraception and pregnancy testing) have therefore 
been implemented in the trial. 
The first clinical trial with molgramostim nebuliser solution has been completed 
(MOL-001). This was a phase I trial to investigate the effects of molgramostim nebuliser 
solution in healthy adult subjects. The trial was a randomised, double-blind, 
placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) 
trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in 
42 adults; non-tobacco using male and non-child bearing female subjects. In the SAD 
part, 18 subjects were included with four subjects in each of the three SAD dose levels 
(150 µg, 300 µg and 600 µg) and six receiving placebo. In the MAD part, 24 subjects 
were included with nine subjects in each of the two MAD dose levels (300 µg or 600 µg) 
and six receiving placebo once daily for six days.  
All 42 subjects enrolled completed the trial. GM-CSF was not measurable in serum 
before trial drug administration. In the SAD part, GM-CSF was absorbed into systemic 
circulation with time of maximum plasma concentration (tmax) of 2 hours after inhalation 
of molgramostim nebuliser solution, however, at picogram levels 50-100 times lower 
than has been observed after similar doses of sargramostim administered intravenously. 
Total systemic exposure (AUClast) increased with dose ranging between 13 and 
138 pg•h/mL and maximum measurable plasma concentrations (Cmax) ranged between 
9.1 and 41 pg/mL. Cmax was similar for the 300 and 600 μg dose levels. In the MAD part, 
despite the short half-life of approximately 4 hours where GM-CSF levels returned to 


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levels below quantification limits after each dose, there was evidence of some 
accumulation after multiple dosing. Cmax increased from 32 pg/mL on Day 1 to 90 pg/mL 
on Day 6 for the 300 μg dose level and from 96 pg/mL to 251 pg/mL from Days 1 to 
6 for the 600 μg dose level. Likewise, AUClast increased from 97 to 248 pg•h/mL from 
Days 1 to 6 for the 300 μg dose level and from 350 to 802 pg•h/mL for the 600 μg dose 
level. Minimum measurable plasma concentrations (Cmin) on Day 6 were 3.6 and 
5.1 pg/mL measured at 8 and 12 hours, respectively for the 300 and 600 μg dose levels.  
Changes in white blood cells (WBC) and differential counts were in line with the 
mode-of-action of GM-CSF and these were not clinically significant in most subjects. In 
subjects treated with molgramostim nebuliser solution a slight increase in total WBC and 
differential counts (primarily within normal reference ranges) was observed in a 
dose-dependent manner. Two subjects had adverse events (AEs) concerning WBC 
differential counts that were considered related to GM-CSF (eosinophilia and white blood 
cell count increased).  
The most common AE was cough, reported for 21/30 (70%) subjects receiving 
molgramostim nebuliser solution and 8/12 (67%) receiving placebo. The AEs considered 
treatment-related reported by two or more (>5%) subjects receiving molgramostim 
nebuliser solution were: cough (50%), productive cough (10%) and headache (6.7%). 
Cough was considered treatment-related for a similar proportion of subjects receiving 
placebo (58%). Number of cough events was 48 in 30 subjects in the combined 
molgramostim groups and 15 in 12 subjects in the placebo groups. A higher number of 
treatment-related AEs were observed in the 600 μg dose level compared to the 300 μg 
dose level and placebo in the MAD part. There was no development of anti-drug 
antibodies up to 28 days after last dose. There were no serious adverse events (SAEs), 
severe AEs, dose-limiting toxicity, or other remarkable findings of clinical concern from 
review of clinical safety data. Further details are available in the IB. 
Study MOL-PAP-002, the IMPALA trial, is a pivotal clinical trial in aPAP being 
conducted in Europe, Australia, Israel, Japan, Russia, South Korea, Turkey, and the US. 
This is a randomised, double-blind, placebo-controlled trial, with an open-label 
follow-up, in which it is planned to enroll 135 patients with aPAP. Double-blind 
treatment consists of daily administration of either molgramostim nebuliser solution 300 
µg, or alternating cycles of molgramostim nebuliser solution 300 µg daily for seven days 
and placebo daily for seven days, or daily administration of placebo for 24 weeks during 
the double-blind period. After the double-blind period, there is a 24- to 48-week 
follow-up period, during which open-label treatment with molgramostim nebuliser 
solution is given using an intermittent dosing regimen (molgramostim nebuliser solution 
300 µg daily for seven days, then seven days off treatment). Unblinded safety data are 
reviewed by an independent data safety monitoring board (DSMB) at 6-monthly 
intervals. The review in April 2018 included 96 randomised patients. Data reviewed 
comprised AEs, safety laboratory data, vital signs and pulmonary function tests up to 
Visit 13 (24 weeks double-blind treatment and 48 weeks of follow-up). No safety signals 
of concern were identified and the DSMB recommended that the trial could continue as 
planned. Further details are available in the IB. 


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Previous experience of inhaled rhGM-CSF in PAP patients 
Based on the findings that PAP may be caused by autoantibodies to GM-CSF, off-label 
administration of subcutaneous and inhaled rhGM-CSF in the marketed formulations 
(molgramostim and sargramostim) has already been explored in the clinic. The results 
have indicated that therapy with rhGM-CSF can offer an effective and safe treatment for 
the patient with aPAP. In a recent meta-analysis, including three subcutaneous studies 
and two inhalation studies, a 59% pooled response rate was calculated with a higher 
response observed with inhalation use [Khan 2012].  
The majority of aPAP patients participating in published clinical studies using inhaled 
rhGM- CSF have been treated with sargramostim (approximately 70 patients). Improved 
pulmonary function was reported from all studies. In three of the six studies the 
alveolar-arterial oxygen difference ((A-a)DO2) has been assessed as a measure of 
response to treatment. In one trial of 39 patients, a mean reduction of 12.3 (8.4-16.2) 
mmHg (p<0.001) was observed in the 35 patients that completed the trial [Tazawa 2010]. 
A reduction of 12.6 mmHg at rest (p=0.00003) and 20 mmHg at exercise from 12 
patients was reported in another trial [Wylam 2006] and a recent trial [Papiris 2014] 
reported a mean decrease of 17.4 mmHg (p=0.031). Patients also experienced 
improvement in dyspnoea, exercise tolerance assessed by the 6 Minute Walk Test 
(6MWT), pulmonary function tests such as Diffusion Capacity of the Lungs for Carbon 
Monoxide (DLCO), Forced Expiratory Volume in one second (FEV1), Forced Vital 
Capacity (FVC), Total Lung Capacity (TLC), Computer Tomography (CT) scans, and 
nutritional status. In line with these results there are reports of less need for further WLLs 
and that patients have been able to come off supplementary oxygen; four out of five 
patients in one trial did not require any further WLL during the course of the trial and the 
remaining patient had a diminished need for WLL for six months and then required no 
further WLL [Morgan 2009] All five patients were able to discontinue supplemental 
oxygen. The results from these studies indicate an improvement that remains present for 
more than one year after treatment has been discontinued [Tazawa 2010, Wylam 2006]. 
Data are available from eight aPAP patients in which molgramostim products other than 
molgramostim nebuliser solution have been administered via inhalation [Tazawa 2005, 
Yamaguchi 2012, Ohashi 2012, Yu 2014]. The treatment duration for all patients was 24 
weeks or more. Three different treatment regimens were applied; three patients received 
250 µg/day every other week for 24 weeks, four patients received 150 µg/day for 24 
weeks, and one patient received 300 µg/day every other week for three months, followed 
by 150 µg/day every other week for six months. In the first trial, a decrease between 17 
and 27 mmHg in (A-a)DO2 was reported for the three patients included [Tazawa 2005]. 
In another trial, a decrease in (A-a)DO2 by more than 10 mmHg was reported in two out 
of four patients, improved vital capacity (VC) and CT score was reported in all four 
patients and improved DLCO, Medical Research Council (MRC) grade (subjective 
dyspnoea index) and Krebs von den Lungen- 6 (KL-6) were reported in three out of four 
patients [Yamaguchi 2012]. After three months treatment every other week with 
300 µg/day rhGM-CSF the patient studied by Yu et al 2014 had an arterial oxygen 
tension (PaO2) of 68 mmHg on room air as well as significant improvement in chest CT 
[Yu 2014]. More details about the clinical studies and case reports using inhaled 
rhGM-CSF are available in the IB. 


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4.2. 
Rationale 
The current trial is an open-label extension trial to the Phase 3 IMPALA trial 
(MOL-PAP-002) to allow patients to continue treatment with inhaled molgramostim 
nebuliser solution, and to investigate long term safety and efficacy of inhaled 
molgramostim nebuliser solution in aPAP patients. The trial consists of an up to 
36-month treatment period during which patients will receive the same dose regimen of 
inhaled molgramostim nebuliser solution as was used in the Follow-up Period of the 
IMPALA trial (cycles of seven days molgramostim 300 µg administered once daily, and 
seven days off treatment). The patient population to be included in the current trial will 
be patients with aPAP who have completed the IMPALA trial. 
The primary objective is safety assessed by AE reporting. In addition to clinical signs and 
symptoms, clinically significant changes in laboratory parameters (haematology and 
clinical chemistry) and electrocardiogram (ECG) variables will be reported as AEs. In 
order to characterize potential systemic adverse effects, GM-CSF levels before dosing 
and at Tmax  (2 hours) will be assessed in a subset of subjects, i.e. subjects enrolled at the 
trial site in Italy.  
Long term efficacy will also be assessed using (A-a)DO2, as a secondary endpoint, which 
has been found to be sensitive to treatment with inhaled rhGM-CSF with a low degree of 
variability in previous literature. In a phase II trial the statistically significant 
improvement in (A-a)DO2 was accompanied by statistically significant improvements in 
dyspnoea, need for oxygen supplement, walking distance and minimal oxygen saturation 
(SpO2) on the 6MWT, VC and DLCO [Tazawa 2010]. Improvements were also 
associated with morphologic changes as evidenced by statistically significant correlations 
between high-resolution CT scores and (A-a)DO2, PaO2 and DLCO both before and after 
treatment.  
Whilst (A-a)DO2 is a calculated biomarker, other secondary endpoints focus on important 
direct clinical outcomes such as the need for WLL and the effect of treatment on exercise 
capacity, and QoL. Currently WLL is the standard of care for aPAP patients but the 
procedure is invasive, and carries a known morbidity to the patient. Potential 
complications associated with WLL include hypoxaemia, hydropneumothorax, adult 
respiratory disease syndrome, post-procedure infections and pneumothorax [Leth 2013] 
Therefore, a reduced requirement for WLL would be of benefit for the patient. As the 
main symptom of aPAP is exercise-induced dyspnoea that may limit the activity level of 
the patient, the 6-minute walking distance (6MWD) and the total score on the St Georges 
Respiratory Questionnaire (SGRQ) were chosen as secondary endpoints, although data 
on these endpoints in aPAP are still limited. In addition, pulmonary function, PaO2 and 
disease severity, need for oxygen supplement therapy, and number of subjects not 
requiring treatment and the time off treatment after discontinuation will assessed as 
secondary endpoints.  
4.3. 
Potential Risks and Benefits 
Currently, no evidence-based curative treatment exists for aPAP. Successive WLL 
procedures remain the standard treatment without a targeted pathophysiological 


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approach. WLL is an intervention which carries a high morbidity, treats only symptoms, 
and is not always successful. Due to the pathophysiology of aPAP, this condition can lead 
to complications, including respiratory infections, pulmonary fibrosis and potentially 
premature death. 
There is currently no approved pharmacological treatment for patients with PAP, and 
therefore an unmet need for further treatment modalities exists.  
Experience with inhaled rhGM-CSF worldwide has demonstrated a reduction in 
symptoms and improvement in exercise tolerance and objective lung function tests, 
reducing or eliminating further WLL episodes. Thus treatment with rhGM-CSF has the 
potential to alter the natural history of PAP [Seymour 2002, Luisetti 2010].  
Clinical studies and case reports thus far have indicated the use of inhaled rhGM-CSF to 
be a well-tolerated, effective and localised treatment that may offer clinical benefits for 
the great majority of patients, including clearance of excess surfactant-related 
lipoproteins and prevention of secondary infections [TOhashi 2012, Leth 2013]. 
Patients with aPAP have been treated with up to 500 µg/day of inhaled rhGM-CSF for up 
to 68 months without chronic toxic effects [Papiris 2014, Wylam 2006]. Results from 
pre-clinical studies with inhaled molgramostim nebuliser solution showed the expected 
pharmacological effects on WBC populations locally and systemically in line with 
observed effects after intravenous administration of molgramostim. No severe, serious or 
dose-limiting AEs were observed in the first clinical trial in humans (MOL-001). The 
most common AE was cough, which was reported at a similar incidence for 
molgramostim nebuliser solution and placebo. Increases of WBC populations in the 
blood consistent with the known mechanism of action were observed; most of which 
were considered not clinically significant. Only two cases (total white blood cell 
increased and eosinophilia) were reported as AEs. No development of anti-drug 
antibodies was observed. In the ongoing IMPALA trial in patients with aPAP, three 
reviews of unblinded safety data by an independent DSMB have not identified safety 
signals of concern and the DSMB recommended that the trial could continue as planned. 
Based on information from similar products, the potential dose-limiting toxicity of 
molgramostim would be based on pulmonary effects, such as bronchoconstriction, 
dyspnoea, cough or decreased pulmonary function. Pulmonary function and respiratory 
symptoms will be monitored during the trial and treatment should be discontinued if 
significant worsening occurs. If there is significant systemic exposure, haematologic 
findings such as leukocytosis and neutrophilia may occur. As non-clinical data indicate 
that systemic exposure to rhGM-CSF may be associated with increased pre- and 
post-implantation losses, pregnancy testing will be performed in women of childbearing 
potential at each trial visit where molgramostim is dispensed and at home at monthly 
intervals during treatment. 
Treatment with molgramostim nebuliser solution is expected to be more effective, less 
invasive, and more convenient, than the currently available symptomatic treatment, WLL, 
for patients with aPAP.  


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
The primary objective is to investigate safety of long term use of inhaled molgramostim. 
5.2. 
Secondary Objectives 
The secondary objectives are  
• To investigate effects of long term use of inhaled molgramostim on 
oxygenation. 
• To investigate effects of long term use of inhaled molgramostim on exercise 
capacity. 
• To investigate effects of long term use of inhaled molgramostim on 
respiratory quality of life. 
• To investigate requirement for WLL during long term use of inhaled 
molgramostim. 
• To investigate effects of long term use of inhaled molgramostim on lung 
function. 
• To investigate maintenance of effect after discontinuation of inhaled 
molgramostim. 
5.3. 
Study Endpoints  
5.3.1. 
Primary Endpoints  
Number of AEs, SAEs, adverse drug reactions (ADRs), and AEs leading to treatment 
discontinuation. 
5.3.2. 
Secondary Endpoints 
• (A-a)DO2 Tduring the trial  
• 6MWD during the trial 
• SGRQ total score during the trial 
• Frequency of WLL during the trial 
• DLCO (% predicted), FEV1 (% predicted), and FVC (% predicted) during the 
trial 
• PaO2 and disease severity score (DSS) during the trial 
• Need for oxygen supplement therapy during the trial 
• Number of subjects not requiring treatment for aPAP and time off treatment 
after discontinuation of inhaled molgramostim 


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5.3.3. 
Exploratory Endpoints  
• GM-CSF levels before and 2 hours after dosing  


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
Subjects with aPAP who have completed the IMPALA (MOL-PAP-002) trial will be 
eligible for this trial.  
At the Baseline visit, eligible subjects may continue or re-start treatment with inhaled 
molgramostim (300 µg) administered intermittently in cycles of seven days 
molgramostim, administered once daily, and seven days off treatment.  
Trial visits will be conducted at 6-monthly intervals until the end of trial. Participating 
subjects will be encouraged to contact the clinic between visits if they experience AEs or 
worsening of aPAP, or if they have any other concerns. 
During the trial, WLL will be applied as rescue therapy. The criterion for performing 
WLL is clinical worsening of aPAP based on symptoms, reduced exercise capacity 
and/or findings of hypoxemia or desaturation according to the investigator’s judgement. 
The reason(s) for conducting WLL will be documented. Subjects undergoing WLL will 
continue treatment with molgramostim, unless discontinuation is medically required, 
according to investigator’s discretion. 
Subjects may discontinue molgramostim due to remission of aPAP, lack of response that 
requires a different treatment modality, or AEs. Subjects becoming pregnant will be 
required to discontinue treatment with molgramostim. Subjects who discontinue 
molgramostim will continue in the trial and attend visits according to the same schedule 
until end of the trial. Molgramostim treatment may be re-started if medically required. 
Subjects not requiring treatment at the Baseline visit may start molgramostim treatment 
during the trial if medically required. 
6.1.1. 
Trial Period 
The first patient will be included in the trial in Q1 2018 and the expected end of trial is in 
Q1 2021. Should the product not have obtained marketing authorization at this date, the 
trial will be amended with an extension of one year at a time to ensure adequate treatment 
options for subjects in the trial who still are in need of treatment with inhaled 
molgramostim. Trial completion, defined as the date of the Clinical Trial Report, is 
expected 1 year after trial end. 
6.1.2. 
End of Trial 
The end of trial is defined as the last subject’s last visit. 
6.2. 
Number of Subjects 
Up to 90 subjects may be included. 
6.3. 
Treatment Assignment 
All subjects in need of treatment will receive inhaled molgramostim. 


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6.4. 
Dose Adjustment Criteria 
6.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.5. 
Criteria for Study Termination 
The investigator or the sponsor may terminate this trial prematurely for any reasonable 
cause. The Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
and Competent Authorities should be informed promptly.  
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the 
subjects enrolled in the trial, or potential trial subjects. 
• A decision on the part of the sponsor to suspend or discontinue development 
of the IMP. 
• Marketing approval of molgramostim nebuliser solution.  
If the Competent Authority obtains information that raises doubts about the safety or 
scientific validity of the clinical trial, the Competent Authority can suspend or prohibit 
the trial. Before the Competent Authority reaches its decision, it shall, except where there 
is imminent risk, ask the sponsor and/or the investigator for their opinion, to be delivered 
within one week (Directive 2001/20/EC, Article 12, Section 1).  
If the trial is prematurely terminated or suspended for any reason, the 
investigator/institution should promptly inform the trial subjects and should assure 
appropriate therapy and follow-up for the subjects. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
1. Completer of the IMPALA trial. 
2. 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 where inhibition of 
ovulation is the primary mode of action, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual 
abstinence*), during and until 30 days after last dose of trial treatment. Females of 
childbearing potential must have a negative urine pregnancy test at Baseline or at 
start of treatment if treatment is not dispensed at Baseline, and must not be 
lactating during and until 30 days after last dose of trial treatment. 
3. 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 above. 
4. Willing and able to provide signed informed consent. 
* Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the female trial participant of child bearing potential and that the vasectomised partner has received medical 
assessment of the surgical success. 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 study 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. [CTFG 2014] 
7.2. 
Subject Exclusion Criteria 
1. Treatment with GM-CSF products other than molgramostim nebuliser solution 
within three months of Baseline. 
2. Treatment with any IMP other than inhaled molgramostim within four weeks of 
Baseline. 
3. History of allergic reactions to GM-CSF. 
4. Connective tissue disease, inflammatory bowel disease or other autoimmune 
disorder requiring treatment associated with significant immunosuppression, e.g. 
more than 10 mg/day systemic prednisolone. 
5. Previous experience of severe and unexplained side-effects during aerosol 
delivery of any kind of medicinal product. 
6. History of, or present, myeloproliferative disease or leukaemia. 
7. Apparent pre-existing concurrent pulmonary fibrosis. 
8. Any other serious medical condition which in the opinion of the investigator 
would make the subject unsuitable for the trial. 


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7.3. 
Subject Withdrawal Criteria 
7.3.1. 
Discontinuation of Trial Treatment 
Subjects may be discontinued from treatment and assessments at any time, if deemed 
necessary by the investigator. Potential reasons for discontinuation of treatment are:  
• Remission of aPAP 
• Lack of efficacy/worsening of disease (e.g. loss of response that requires a 
different treatment modality). 
• Unacceptable AE (including serious hypersensitivity reaction). 
• Pregnancy. 
Those who discontinue treatment will not automatically be withdrawn from the trial but 
will be encouraged to continue to follow the same visit schedule. If medically indicated 
and no safety-related exclusion criteria have emerged, treatment may be restarted at a 
later visit. 
The reason and date the subject is discontinued will be documented in the electronic case 
report form (eCRF).  
Subjects who fulfil the criteria for rescue treatment will be scheduled for a WLL as 
described in Section 10.2. Subjects receiving a WLL should continue treatment and 
attend the remaining visits, unless discontinuation is medically required, according to 
investigator’s discretion. 
7.3.2. 
Withdrawal from the Trial  
Subjects are free to discontinue their participation in the trial at any time. Withdrawal 
from the trial will not affect or prejudice the subject’s further care or treatment. Potential 
reasons for withdrawal of subjects from the trial are:  
• The decision of a subject to withdraw from the trial (including if the subject 
withdraws informed consent)  
• Subject is lost to follow-up 
• Other reason(s) 
The reason and date the subject is withdrawn from the trial will be documented in the 
eCRF (e.g. lost to follow-up, consent withdrawn, AEs, etc.). If a subject is withdrawn 
from the trial, the investigator should attempt to complete all required trial assessments.  
All AEs should be followed-up according to Section 10.9.2.4. 
If a subject is withdrawn from the trial, all data collected until the time of withdrawal will 
be used in the data presentations, unless consent to use the data was withdrawn by the 
subject.  


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
Molgramostim nebuliser solution 
Dosage Form: 
Nebuliser solution 
Unit Dose 
300 µg 
Route of Administration 
Inhalation using the PARI eFlow nebuliser (PARI Pharma GmbH) 
Physical Description 
Clear, colourless solution containing molgramostim, a recombinant 
human Granulocyte Macrophage Colony Stimulating Factor 
(rhGM-CSF).  
Excipients are mannitol, polyethylene glycol 4000, RecombuminP®
P 
Prime, disodium phosphate (anhydrous), citric acid (monohydrate), 
and water for injection 
8.2. 
Prohibited Treatments 
Therapy associated with significant immunosuppression is not allowed (e.g. more than 
10 mg/day systemic prednisolone) while the subject is treated with IMP. Other 
rhGM-CSF products are not allowed within three months of Baseline and during the trial. 
8.3. 
Treatment Compliance 
Subject compliance will be evaluated by unused and used vial counts. Subjects will be 
asked to return all unused and empty vials at the next clinic visit. Vials will be visually 
inspected for opening. The number of unused and empty vials will be counted upon 
return and recorded in the drug accountability log kept at the site. If IMP compliance is 
less than 80% or more than 100 %, the investigator should discuss the reason and educate 
the subject to comply with protocol. 
8.4. 
Randomisation and Blinding 
Not applicable. 
8.5. 
Subject Identification List 
The investigator will maintain a list of all subjects enrolled in the trial at the site. This list 
includes each subject's identity, date of enrolment and corresponding subject number so 
that any subject may be identified if required for any reason. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
Each vial of molgramostim contains 300 µg molgramostim in 1.2 mL solution 
(250 µg/mL).  
9.2. 
Study Drug Packaging and Labeling 
All manufacturing and packaging will be performed in accordance with current Good 
Manufacturing Practice (GMP).  
Individual medication kits containing trial medication for a 26-week treatment period (i.e. 
13 weeks of treatment) will be supplied in adequate amounts at the dispensing visits. 
Every kit will be labelled with a unique medication number, which also appear on a 
tear-off part of the label.  
Labels will comply with local regulations and will be printed in local language. 
9.3. 
Study Drug Storage 
The IMP must be stored at 2-8°C.  
The IMP will be stored at the trial site or the at the site pharmacy as required by local 
regulations and laws for the participating sites. The Investigator will ensure that the IMP 
will be stored in appropriate conditions in a secure location with controlled access. The 
storage compartment must be monitored and the temperature documented. Any 
deviations in storage temperature must be reported to sponsor without delay. In case of a 
temperature deviation, the IMP must not be used until acceptance from the sponsor. 
The IMP kits will be dispensed to the subject at each clinic visit where treatment is 
required, according to Investigator’s discretion, from Baseline through to the penultimate 
visit.  
Subjects will be instructed to store the kit at 2-8°C in a safe and secure place out of the 
reach of children and protected from light. The IMP should not be frozen or shaken and 
not be used beyond the expiration date on the vial. 
Subjects will be asked to return used and unused medication at the next clinic visit to 
check compliance. 
9.4. 
Study Drug Preparation 
Not applicable. 
9.5. 
Administration 
The PARI eFlow nebuliser system (PARI Pharma GmbH, Germany) will be used to 
administer the IMP. The eFlow Nebuliser Handset is a single subject use, reusable 
electronic nebuliser. It includes a fine particle aerosol generator (perforated vibrating 
membrane) defined by a 30L mesh and an aerosol chamber that can produce aerosols 


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with high density of active drug, precisely defined droplet size and a high proportion of 
respirable droplets. 
The subject will administer the first dose of IMP at the Baseline visit (Visit 1) under the 
supervision of trial personnel, unless they have already dosed within the IMPALA trial 
on the same day, and will be retrained in IMP administration and medical device 
maintenance procedure, if required.  
For Italy only: 
Visits 1 to 6 must be placed in a week on treatment. At the day of the visit, the subject 
will administer the dose at the clinic, after collection of the pre-dose PK sample.   
9.6. 
Study Drug Accountability 
It is the responsibility of the investigator or trained designee to determine IMP 
accountability and complete the drug accountability log. Drug accountability will be 
reviewed by the monitor 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. 
9.7. 
Study Drug Handling and Disposal 
Unused IMP must be returned to supply vendor, or sent for destruction after agreement 
with the Sponsor, but only after the trial and overall drug accountability has been 
completed. A list of trial drug, used, or returned must be prepared and signed by the 
investigator or designee; an account must be given for any discrepancies. 


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10. 
STUDY PROCEDURES AND ASSESSMENTS 
The timing of all trial assessments is shown in the Schedule of Procedures in  
10.1. 
Written Informed Consent 
All subjects must provide informed consent in accordance with the origins of the 
Declaration of Helsinki and the applicable laws of the country. The written informed 
consent must be obtained before any trial activities are performed (including any period 
for wash-out of concomitant medication, if applicable). 
It is the responsibility of the principal investigator or a sub-investigator to obtain the 
written informed consent from the subject. 
The investigator must explain the nature of the trial, its purpose, the assessments 
involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail and provide the subject with a copy of the information sheet and 
the consent form. Information to a subject can be delegated to a nurse, but the 
investigator must be available for questions and both the nurse and the investigator must 
sign the consent form to document this. 
The subject must be given sufficient time to consider the trial before deciding whether to 
participate. Each subject must be informed that participation in the trial is voluntary and 
that he/she may withdraw from the trial at any time and that withdrawal of consent will 
not affect his/her subsequent medical treatment or relationship with the treating 
physician. 
The subject must sign and date the informed consent form before he/she enters the trial 
(i.e. before any trial related activity). The investigator must give a copy of the signed 
informed consent to the subject. The investigator should keep the original. 
If information becomes available that may be relevant to the subject’s willingness to 
continued participation in the trial the subject information sheet will be updated by 
Savara and approved by an IEC/IRB and the Competent Authorities. The subject must be 
informed in a timely manner about the updated subject information sheet and written 
informed consent must be obtained. 
10.2. 
Concomitant Treatments 
The subject’s use of all concomitant medication must be recorded in the eCRF. The use 
of concomitant medicines should be kept at a minimum and should be kept as stable as 
possible. Standard information about the medication will be collected including the name 
of medication, dose, frequency, administration route and treatment period.  
Information about WLL performed and oxygen supplementation will be recorded on a 
specific form in the eCRF. 
10.3. 
Medical History 
Medical history assessment will be assessed at Baseline (Visit 1).  


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AEs that occurred during previous treatment with inhaled molgramostim, were reported 
as AEs in IMPALA, and are still ongoing, will be recorded as medical history. AEs that 
occurred after completion of IMPALA but still had a reasonable time-relationship to 
inhaled molgramostim treatment, and were not reported in IMPALA, and are still 
ongoing, will be reported as AEs at Baseline (Visit 1). 
10.4. 
Demographics 
Demographic information including date of birth, age, height, weight sex and race will be 
entered in the eCRF. 
10.5. 
Subject Diary 
The subject will receive a subject diary at the timepoints shown in Table 1. The subject 
will be asked to record the following information in the subject diary: 
• AEs experienced between the visits  
• Dates for changes of the nebuliser mouthpiece. The site should enter the 
expected dates for changing the nebuliser mouthpiece. 
• Dates for taking pregnancy tests at home (if applicable). The site should enter 
the expected dates for taking the pregnancy tests. 
• The subjects will also be asked to place the tear-off label from the IMP box in 
the subject diary. 
10.6. 
Follow-up Telephone Visit 
The site should call the subject approximately one week after the subject has completed 
the last trial visit in order to assess whether any new AEs have occurred after the visit, 
and to obtain follow-up information on any AE ongoing at the last trial visit.  
10.7. 
Efficacy Assessments 
10.7.1. 
Blood Gas Analysis  
The following variables will be assessed from an arterial blood gas sample collected at 
the timepoints shown in Table 1.   
• PaO2T (mmHg/kPa) – arterial partial pressure of oxygen 
• PaCO2 (mmHg/kPa) – arterial partial pressure of carbon dioxide 
• FiO2 – fraction of inspired oxygen 
Patm (ambient atmospheric pressure) must be collected using a bedside barometer. The 
PH2O (saturated vapour pressure of water at body temperature) will be set to 47 mmHg / 
6.266 kPa. 
The Aa Gradient (A-a)DO2 will be calculated centrally using the following formula: 


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Sites that are experienced in the use of capillary sampling for blood gas analysis as part 
of their standard care, may use this option instead of an arterial blood gas sample. 
Subjects should rest for at least 10 minutes before puncture and the sample should be 
taken in supine position. Trial specific instructions will be provided in a separate 
document. The sample will be analysed in accordance with local routines.  
If possible, arterial blood gases should be conducted with the subject breathing room air. 
If the subject cannot tolerate temporary discontinuation of supplemental oxygen during 
blood gas sampling, blood gas sampling at subsequent visits should, if possible, be 
conducted using the same oxygen flow rate as was used in IMPALA and kept constant 
during the trial.  
10.7.2. 
6-Minute Walk Test (6MWT) 
Exercise capacity will be assessed using the 6MWT at the timepoints shown in Table 1. 
The 6MWT will be performed in accordance with European Respiratory 
Society/American Thoracic Society (ERS/ATS) guidance [Holland 2014] by technicians 
with documented training and experience of performing the 6MWT in accordance with 
the referred ERS/ATS guidance. The 6MWT should be performed twice at each visit in 
accordance with the ERS/ATS guidance.  
Data from both tests should be entered in the eCRF. Parameters to be recorded comprise 
pre and post walk dyspnoea score using the Borg (CR-10) Dyspnea Score (Appendix 4.1) 
SpO2 (%) at start, worst SpO2 (%) during the walk, distance walked (6MWD; m), 
duration of the walk (minutes and seconds), oxygen flow rate if applicable, reason for 
stop  ping early (if applicable). 
Trial specific instructions for the 6MWT are provided in Appendix 4.2.  
If possible, the 6MWT should be conducted using room air. If a subject is on long-term 
oxygen therapy, oxygen should be given at their standard flow rate and held constant 
throughout the test. The tests conducted should be performed using the same oxygen 
conditions that were used in IMPALA, if possible.  
10.7.3. 
Quality of Life Score (QoL) 
Subjects will be asked to assess their QoL at the timepoints shown in Table 1. 
Subjects will be asked to complete the SGRQ in the local language Appendix 4.3 This 
disease-specific instrument has been designed to measure impact on QoL in subjects with 
obstructive airway disease. This assessment is considered relevant for use in the subject 
population of this trial.  
10.7.4. 
Lung Function Tests  
The following lung function variables will be assessed at the timepoints shown in 
Table 1: 


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• DLCO (absolute value (measured), absolute value (predicted), % predicted, 
and haemoglobin) 
• 
FEV1 (absolute value and % predicted) 
• FVC (absolute value and % predicted) 
DLCO, FEV1 and FVC will be assessed using local, appropriately calibrated equipment. 
Percent predicted values for FEV1 and FVC will additionally be calculated centrally using 
standard equations. 
DLCO will be done using local appropriately calibrated equipment by site staff with 
documented training in lung function testing at the time points shown in Table 1. 
The DLCO measurements should be performed in accordance ATS/ERS guidelines 
[Graham 2017]. Two acceptable tests should be conducted and the average of these will 
be calculated centrally.  Based on same-day haemoglobin values, the haemoglobin 
corrected DLCO will be calculated centrally. 
FEV1 and FVC will be assessed using a local appropriately calibrated spirometer by site 
staff with documented training in lung function tests at the time points shown in Table 1. 
Measurements should be performed in accordance with ATS/ERS guidelines [Miller 
2005]. 
The FEV1 and FVC are measured as 3 valid measurements and the highest value will be 
entered in the eCRF. 
10.7.5. 
Disease Severity Score  
The DSS will be assessed at the timepoints shown in Table 1. 
The DSS is based on the presence of symptoms and degree of reduction in PaO2 
determined with the individual breathing room air in the supine position [Inoue 2006]. 
The DSS is a 5-point score as follows: 
1 = no symptoms and PaO2 ≥ 70 mmHg  
2 = symptomatic and PaO2 ≥ 70 mmHg 
3 = 60 mmHg ≤ PaO2 < 70 mmHg 
4 = 50 mmHg ≤ PaO2 < 60 mmHg 
5 = PaO2 < 50 mmHg.  
If possible, the blood gas assessment should be conducted with the subject breathing 
room air (see Section 10.7.1). For subjects requiring supplemental oxygen during the 
blood gas assessment the DSS will be based on the PaO2 obtained while breathing 
oxygen. 
10.7.6. 
Overall Clinical Assessment 
An overall clinical assessment will be done at the timepoints shown in Table 1. The status 
of aPAP will be categorised as: in remission, improving, stable, or progressive. The 
assessment will be based on investigator judgement. 


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The requirement for treatment will be categorised as: no treatment required, treatment 
with inhaled molgramostim required, or other treatment required. 
If other treatment is required, such treatment should be recorded as described in 
Section 10.2. 
10.7.7. 
Whole Lung Lavage  
At each visit, information on whether WLL is required will be recorded. The criterion for 
performing WLL is clinical worsening of aPAP based on symptoms, reduced exercise 
capacity and/or findings of hypoxemia or desaturation according to the investigator’s 
judgement. The reason(s) for WLL requirement will be documented. 
Information about any WLL actually performed must be reported in the eCRF. The 
following information will be entered. Date of the WLL and type of WLL (unilateral, 
bilateral) will be recorded. Information about other assessments performed (e.g. blood 
gas measurements, lung function tests and exercise tests) before and after a WLL is 
performed should also be recorded.  
10.8. 
Safety Assessments 
The following safety variables will be assessed: 
• AEs 
• Physical examination 
• Vital signs 
• ECG 
• Laboratory safety assessments 
• CT scan, only if performed according to clinical standard 
10.8.1. 
Adverse Events 
Any AEs will be reported at every visit from Baseline (Visit 1) to the completion of the 
trial. Subjects will be encouraged to contact the clinic in between visits if they experience 
AEs or have any concerns. For further information of definitions and reporting of AEs 
and SAEs, see Section 10.9. 
10.8.2. 
Physical Examination 
All subjects will undergo a standard physical examination at the timepoints shown in 
Table 1. 
Complete physical examinations will include at a minimum a review of the subject’s 
general appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, 
abdomen, extremities, skin, and general neurological system. Any abnormalities will be 
recorded in the eCRF and assessed as ‘clinically significant’ or ‘not clinically 
significant’. 


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Symptom-oriented or brief physical examinations may be performed as clinically 
indicated. New abnormal clinically significant physical examination findings not present 
during the Baseline visits should be recorded as AEs and followed during subsequent 
visits. 
10.8.3. 
Vital Signs 
The following vital signs will be assessed at the timepoints shown in Table 1 
• Resting systolic and diastolic blood pressure (mmHg), after 5 minutes sitting  
• Resting heart rate (beats per minute), after 5 minutes sitting  
• Resting respiration rate (breaths per minute), after 5 minutes sitting  
• Oral body temperature (°C) 
The observed values will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal 
findings will be assessed as ‘clinically significant’ or ‘not clinically significant’. 
10.8.4. 
Electrocardiogram (ECG) 
A 12-lead ECG will be assessed using a standard ECG machine according to local 
procedures at the time points shown in Table 1. No central overreading will be 
performed. 
Heart rate, QRS, PR and QT intervals will be recorded from the ECGs. The ECGs will be 
interpreted and signed and dated by the investigator or his/her designee. Results will be 
classified as normal, having a non-clinically significant abnormality, or having a 
clinically significant abnormality. All clinically significant abnormalities will be recorded 
as AEs. 
10.8.5. 
Laboratory Assessments 
The laboratory safety analyses (haematology and clinical chemistry) will be performed 
by local laboratories at the timepoints shown in Table 1. 
Sampling methods and procedures will be in accordance with local routine care.  
The following laboratory safety parameters will be analysed: 
Table 4: 
Laboratory Safety Parameters 
Category 
Laboratory Parameter 
Haematology 
Haemoglobin, RBC, Red Blood Cell Distribution Width (RDW), 
Haematocrit, Mean cell volume (MCV), Mean cell haemoglobin 
(MCH), Mean cell haemoglobin concentration (MCHC), Platelet 
count, WBC and differential counts (absolute and percentage): 
Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, 
Prothrombin Time International Normalised Ratio (PT-INR) 


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Category 
Laboratory Parameter 
Clinical chemistry 
Aspartate Aminotransferase (AST), Alanine Aminotransferase 
(ALT), Gamma Glutamyl Transpeptidase (GGT), Alkaline 
Phosphatase, Bilirubin, Urea, S-Creatinine, Potassium, Sodium, 
Calcium, Chloride, Phosphate, Total protein, Albumin, C-Reactive 
Protein (CRP), and Glucose (non-fasting) 
All results will be recorded in the eCRF and will be assessed as ‘clinically significant’ or 
‘not clinically significant’. Clinically significant findings identified at Baseline (Visit 1) 
should be recorded as medical history.  Clinically significant findings not present at 
Baseline (Visit 1) should be reported as AEs. 
10.8.5.1. PK assessment (Only for Italy) 
The subjects enrolled in Italy will have Visits 1 - 6 scheduled for an on-treatment week 
during the allowed window of +/- 4 weeks. On the day of the visit, IMP dosing will be 
conducted at the site.  
Two serum samples for analysis of GM-CSF will be collected at each of these visits. The 
first sample will be taken just prior to inhalation of molgramostim. The second sample 
will be taken 2 hours post dosing, (+/- 10 minutes).  Samples will be shipped to a central 
laboratory for analysis. Further description of sample collection, processing, shipment 
and analyzing will be available in the laboratory manual. Timing of dose on the day 
before and on the day of sampling will be recorded in the eCRF. 
10.8.5.2. Pregnancy Screen 
A serum pregnancy test will be performed for female subjects of child-bearing potential 
at each visit. For subjects who have a gap between completion of IMPALA and Baseline 
(Visit 1), a urine pregnancy test will also be performed before dosing at Baseline (Visit 1) 
in order to immediately confirm that the subject is not pregnant. If treatment is not 
dispensed at Baseline (Visit 1), the urine pregnancy test will be performed at start of 
treatment. Female subjects of child-bearing potential will be instructed to conduct a 
monthly urine pregnancy test at home. 
10.8.5.3. Computed Tomography (CT) 
A CT scan is not required as part of this trial. Only if a CT scan is performed according to 
clinical practice or medical need, e.g. in case of a clinical deterioration, the results will be 
recorded in the eCRF as improved / worsened / no change / data missing – impossible to 
evaluate, compared to the last evaluation in IMPALA.   


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10.9. 
Adverse and Serious Adverse Events 
10.9.1. 
Definitions of Adverse Events 
10.9.1.1. Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, 
whether or not considered related to the IMP. 
10.9.1.2. Serious Adverse Event (SAE) 
Any untoward medicinal occurrence or effect that at any dose: 
• Results in death 
• Is life-threatening 
• Requires hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• May jeopardise the subject or may require medical intervention to prevent one 
or more of the outcomes listed above (Important Medical Events). 
Life-threatening in the definition of an SAE or serious adverse reaction refers to an event 
in which the subject was at risk of death at the time of event; it does not refer to an event 
which hypothetically might have caused death if it was more severe. 
For important medical events, medical judgement should be exercised in deciding 
whether an AE/reaction is serious. 
The severity of an adverse reaction is largely determined by the outcome of the medical 
occurrence. An adverse reaction should only be termed "serious" if hospitalisation did in 
fact take place as a result of it. As a rule, hospitalisation is the admission to a hospital 
with at least one overnight stay. 
The presentation of a patient in the emergency room (casualty center, health care center) 
alone without subsequent in-patient admission does not yet fulfill the criterion 
hospitalisation. However, it should be confirmed whether any of the other criteria 
mentioned above justifies an adverse reaction being classified as "serious" or at least 
"medically significant. 
If the Investigator becomes aware of an SAE with a reasonable relationship to the IMP 
after the subject has left the trial, this SAE must also be reported (post-trial event). 
10.9.1.2.1. Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is an AE which 


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• Has a reasonable possibility of causal relationship to an IMP 
• Is serious, and 
• Is unexpected 
Therefore, due to the nature and/or severity of the adverse reaction, a SUSAR is not 
consistent with the applicable product information (i.e. the reference safety information 
in the IB) for the IMP used in this trial. 
10.9.2. 
Recording Adverse Events 
All trial subjects will be carefully monitored for the occurrence of AEs during the trial 
period from Baseline to the last visit. The investigator will collect AEs using a 
non-leading question such as “have you experienced any new health problems or 
worsening of existing conditions” as well as reporting events directly observed or 
spontaneously volunteered by subjects. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be 
grouped together and reported as a single diagnosis or syndrome whenever possible. 
All AEs including but not limited to events reported by the subject, or reported in answer 
to an open question by the investigator or member of this team, which fall into any of the 
above definitions must be recorded as an AE in the eCRF and should include the 
following information: 
• Brief description of the event (diagnosis) 
• Start date (and time, if relevant) 
• Stop date (and time, if relevant) (or resolution) 
• Severity 
• Action taken regarding trial drug 
• Opinion on causality 
• Seriousness 
• Outcome. 
10.9.2.1. Severity 
Severity describes the intensity of an event, and will be assessed as: 
Mild 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate 
The AE interferes with daily activity, but the subject is still able to function. Medical 
intervention may be considered. 
Severe 
The AE is incapacitating and requires medical intervention. 


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If an AE changes in severity, it should be reported as an AE of new severity but with the 
same description. 
10.9.2.2. Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship 
to the investigational product for each AE. Causality will be assessed as: 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the IMP, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfil this definition. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the IMP, but which could also be explained by concurrent disease or 
other drugs or chemicals. Information on IMP withdrawal may be lacking or unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal relationship to 
IMP administration which makes a causal relationship improbable, and in which other 
drugs, chemicals or underlying disease provide plausible explanations. 
Not applicable 
This assessment can be used e.g. in cases where the subject did not receive any treatment 
with IMP or if the causality cannot be judged because information is insufficient or 
contradictory. 
10.9.2.3. Outcome 
The outcome of AEs has to be described by following criteria: 
• Recovered  
• Not Recovered 
• Recovered with sequelae 
• Fatal 
• Unknown. 
10.9.2.4. Follow-up of Subjects after Adverse Events 
Any AE that is ongoing when the subject is withdrawn from the trial should be 
followed-up until the AE is resolved or the investigator decides that the AE is stable and 
needs no further follow-up.  


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10.9.2.5. Abnormal Laboratory Values/Vital Signs 
An asymptomatic abnormal laboratory/vital sign finding should only be reported as an 
AE if it is clinically significant according to the investigator’s assessment, if it fulfils the 
criteria for an SAE or if it causes the subject to discontinue the trial. 
If an abnormal laboratory/vital sign value is associated with clinical signs and symptoms, 
the sign/symptom should be reported as an AE and the associated laboratory/vital sign 
result should be considered additional information. 
10.9.3. 
Reporting Adverse Events 
10.9.3.1. Serious Adverse Event (SAE) Reporting Procedure 
The investigator is responsible for ensuring that all SAEs are reported to the sponsor 
immediately, using a trial-specific SAE form, but in any event no later than 24 hours of 
any site staff becoming aware of the event from the time the informed consent has been 
signed, up to Day 30 after the last visit. Reporting of SAEs will also be described in a 
trial-specific procedure. 
After that period of time only serious adverse reactions (events related to trial 
medication) have to be reported. SAEs occurring to a patient after the patient has 
completed the clinical trial and for which a reasonable possibility of a causal relationship 
is assessed by the Investigator, must be reported by the Investigator to Premier Research 
regardless of the time that has elapsed (post-trial events). The SAE form has to be 
completed in English.  
Initial reports should be followed as soon as possible by detailed written reports. The 
initial and follow-up reports should identify subjects by unique code numbers assigned in 
the trial. The subjects’ names, personal identification numbers, and/or addresses must not 
be included. The following information is mandatory for the initial report: 
• Subject trial ID 
• Trial treatment (blinded, if applicable) 
• Start date (time, if relevant) of the trial treatment 
• Brief description of the event (diagnosis) 
• Start date (time, if relevant) of the event 
• Seriousness criteria 
• Causality assessment. 
For reported deaths, the investigator should supply the sponsor and the IEC/IRB (if 
applicable) with any additional requested information (e.g. autopsy reports and terminal 
medical reports). 
The Investigator must contact Premier Research by email or fax directly to Premier 
Research Pharmacovigilance and Device Safety in case of all SAEs within 24 hours 
after awareness of the event. 


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SAE REPORTING CONTACT DETAILS 
CompanyT: Premier Research 
Department: Pharmacovigilance and Device Safety (PVDS) 
E-mail: SavaraSafety@premier-research.com 
Fax: +421 2 68203713 
Note: If there is local legislation requiring investigators to report AEs to the Competent 
Authority or the IEC/IRB, the investigator should also comply with this legislation. If any 
such reporting is planned, this must be stated in the SAE report, and once the reporting 
has been performed, a copy of the reporting documentation must be enclosed with the 
SAE-Follow-Up report to the sponsor. 
The initial SAE report should be completed by the investigator immediately, even if not 
all data are available. Relevant follow-up information must be faxed or sent by e-mail to 
Premier PVDS as soon as possible. SAE-Follow-Up reports also have to be recorded on 
the trial specific SAE form. A follow-up report should be clearly marked as such and 
linked to the initial report. 
The medical term of the SAE should be an event, reaction or diagnosis rather than a list 
of symptoms. It is important to enter the most appropriate event term in the 
corresponding field.  
The Investigator should complete all the details requested including dates of onset, 
severity, corrective therapies given, outcome and his/her opinion as to whether the 
reported event is possibly drug-related.  
In the case of death of a trial patient, the Investigator has to provide any additional 
information necessary as requested by the sponsor, the Competent Authorities concerned 
and IEC/IRBs concerned. 
10.9.3.2. Suspected Unexpected Serious Adverse Reaction (SUSAR) Reporting 
Procedure 
According to national legislation and European directives and guidelines, the sponsor of 
the clinical trial will report all SUSARs to the Competent Authority and IEC/IRB in all 
Member States concerned, to the European clinical trials database (Eudravigilance 
Clinical Trial Module - EVTCM), and if applicable, to other regulatory authorities 
according to local laws and regulations.  
The Sponsor shall ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the Competent Authorities 
in all the Member States concerned, and to IEC/IRB (if required by local regulations), 
and in any case no later than seven days after knowledge by the Sponsor of such a case, 
and that relevant follow-up information is subsequently communicated within an 
additional eight days. 


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Any other SUSARs shall be reported to the Competent Authorities concerned and to the 
IEC/IRB concerned as soon as possible but within a maximum of 15 days of first 
knowledge by the sponsor.  
The investigator should be aware of local reporting regulations to the IEC/IRB. The 
Sponsor will either supply the investigator with the reports which should be passed on to 
the IEC/IRB or report directly to the IEC/IRB depending on local regulations. 
10.9.3.3. Adverse Events of Special Interest 
There are currently no AEs of special interest identified due to limited previous 
experience of Savara’s molgramostim. 
10.9.3.4. Precautions/Overdose 
No acute systemic or hypersensitivity reactions have been reported in subjects receiving 
inhaled sargramostim or molgramostim products.  
There is no known antidote to molgramostim. In the event of overdose, symptomatic 
management is indicated. 
Based on information from similar products, overdose may manifest with respiratory 
symptoms, e.g. bronchospasm, wheezing, dyspnoea, decreased pulmonary function or 
cough. 
Haematologic findings such as leukocytosis and neutrophilia may occur if overdose 
results in high systemic exposure. With high systemic doses of similar products, the 
following symptoms have been observed: tachycardia, hypotension, dyspnoea, and 
flu-like symptoms. These symptoms abated quickly on symptomatic treatment. More 
information is available in the IB. 
10.9.3.5. 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 be 
withdrawn from further trial treatment. The 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 10.9.3.1. The pregnancy report form should be used instead of the SAE 
form. 
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. 


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10.9.3.6. Safety Management Plan 
The process of SAE-Assessment is performed by Premier Research. In this context a trial 
specific ‘Safety Management Plan’ has to be prepared before first subject is recruited into 
the trial. The Safety Management Plan contains a detailed description of all procedures 
concerning the documentation and reporting of AEs, SAEs and SUSARs. Additionally, 
the Safety Management Plan describes the preparation of the Development Safety Update 
Report (DSUR), the Benefit-Risk-Assessment and the process of immediate actions to 
prevent the trial patients from immediate risks. 


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11. 
STATISTICS 
No formal sample size calculation was done as this is an open-label extension trial. Up to 
90 subjects will be included. 
Data will be summarised using summary statistics. Continuous data will be presented 
with the number of observations, mean value, standard deviation, minimum, quartile 1, 
median, quartile 3 and maximum value. Categorical data will be presented as counts and 
percentages. The data will be presented by visit in tables and graphs. Individual subject 
data will be listed. Further details of all analyses will be given in the statistical analysis 
plan.  
No “analysis sets” (intention to treat, per protocol, etc.) are defined. All subjects will be 
included in the analyses/data presentations (equivalent to a Full Analysis Set). 
Only recorded data will be analysed/presented and any subjects who have missing data 
will only have observed data reported, with no imputation for missing data.  
Interim cuts of data may be done on a yearly basis and as needed for regulatory purposes 
(e.g. 120-day safety update). 
Data listings will show all recorded data. 
Data from the trial is planned to be combined with relevant data from the IMPALA trial; 
these combined analyses will be reported separately. 
11.1. 
Primary Endpoints  
Number of AEs, SAEs, ADRs, and AEs leading to treatment discontinuation. 
11.2. 
Secondary Endpoints 
• (A-a)DO2 during the trial  
• 6MWD during the trial 
• SGRQ total score during the trial 
• Number of WLL and time to WLL during the trial. 
• DLCO (% predicted), FEV1 (% predicted), FVC (% predicted) during the trial 
• PaO2 and DSS during the trial 
• Need for oxygen supplement therapy during the trial. 
• Number of subjects not requiring treatment for aPAP and time off treatment 
after discontinuation of inhaled molgramostim. 
11.3. 
Exploratory Endpoints 
• GM-CSF levels before and 2 hours after dosing. 
 


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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
Access to Source Data and Documentation  
The investigator should guarantee direct access to source documents for the monitor and 
auditors as well as for inspection by appropriate regulatory agencies, and the IEC/IRB, if 
required. 
12.2. 
Subject Records and Source Data 
The origin of source data in the trial will be specified for each trial site in a separate 
document.  
It is the responsibility of the investigator to record essential information in the medical 
records in accordance with national regulations and requirements. The following 
information should be included as a minimum: 
• A statement that the subject is in a clinical trial 
• The identity of the trial e.g. Trial code 
• Subject number 
• That informed consent was obtained and the date 
• Diagnosis 
• Dates of all visits and telephone contacts with the subject during the trial 
period 
• Any information relating to AEs 
• All treatments and medications prescribed/administered (including dosage) 
• Date of subject withdrawal  
• Subject health service identification number. 
The investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the eCRFs. After each subject visit, the eCRF should be 
completed in a timely manner. Data reported in the eCRF that are derived from source 
documents should be consistent with the source documents or the discrepancies should be 
explained. Data recorded in the eCRFs will be monitored. 
12.3. 
Study Monitoring 
Regular monitoring visits will be performed according to International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP). Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents. In 
accordance with written standard operating procedures (SOP)s, the Clinical Research 
Associates (CRAs) will verify that the clinical trial is conducted and data are generated, 
documented and reported in compliance with the protocol, GCP and the applicable 
regulatory requirements. 


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12.4. 
Audits and Inspections 
Authorised representatives of Savara, a regulatory authority, an IEC or an IRB may visit 
the site to perform audits or inspections, including source data verification. The purpose 
of a Savara audit or inspection is to systematically and independently examine all 
trial-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analysed, and accurately reported according to the 
protocol, ICH GCP, and any applicable regulatory requirements. The investigator should 
contact Savara immediately if contacted by a regulatory agency about an inspection. 
12.5. 
Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) 
The investigator must obtain IEC or IRB approval for the investigation. Initial IEC/IRB 
approval, and all materials approved by the IEC/IRB for this trial including the patient 
consent form and recruitment materials must be maintained by the investigator and made 
available for inspection.  
Any modification of the protocol must be documented in a protocol amendment and any 
amendment considered substantial requires approval/favorable opinion by the appropriate 
regulatory authority and IEC/IRB. 


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13. 
ETHICS 
13.1. 
Ethics Review 
This protocol and any amendments will be submitted to a properly constituted IEC/IRB, 
in accordance with the ICH guidelines, the applicable European Directives and local legal 
requirements, for approval/favorable opinion. An approval/favorable opinion must be 
obtained in writing before the first subject can be recruited. 
13.2. 
Ethical Conduct of the Study 
The trial will be conducted in compliance with the protocol, applicable regulatory 
requirements, ICH GCP and the ethical principles of the latest revision of the Declaration 
of Helsinki as adopted by the World Medical Association. 


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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data Management  
Data management and handling of data will be conducted according to the trial specific 
Data Management Plan with ICH guidelines and SOPs. 
An eCRF system, will be used to capture data from the trial. Data entry will be performed 
by the trial site personnel. Validation and data queries will be handled by qualified 
Contract Research Organisation (CRO) staff. The data will be subjected to validation 
according to a data validation plan in order to ensure accuracy in the collected eCRF data. 
Changes to the data in the eCRF will be made at the site by delegated trial site personnel. 
The eCRF will have an audit trail with appropriate functionality for data capture, tracking 
and documentation of any queries or changes. Electronic signatures will be used to lock 
the data and identify the person entering or changing the data. 
Before database closure a reconciliation will be performed between the SAEs entered in 
the safety database and the trial database. After database closure, the database will be 
exported as SAS® data sets. 
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan, will be described in a trial specific Data Management Report. 
14.1.1. 
Protocol Deviations 
The instructions in the protocol must be followed. If deviations occur, the investigator 
must inform the CRA and the implications of the deviation must be reviewed and 
discussed. Deviations must be documented. In addition, deviations must be accompanied 
by a description of the deviation, the relevant dates (start and stop) and the action taken. 
Deviation reports and supporting documentation must be kept in the investigator’s file 
and in the trial master file. 
14.2. 
Inspection of Records 
The Investigator agrees to allow the monitor to inspect the drug storage area, trial drug 
stocks, drug accountability records, subject charts and trial source documents, and other 
records relative to trial conduct. 
14.3. 
Retention of Records 
The investigator/institution should maintain essential documents (as defined in ICH E6 
GCP, Section 8) as required by the applicable regulatory requirement(s). The 
investigator/institution should take measures to prevent accidental or premature 
destruction of the documents. 
Essential documents should be retained according to applicable regulatory requirements 
of the country(ies) where the product is approved, and/or where the sponsor intends to 
apply for approval. If it becomes necessary for Savara or the Competent Authority to 
review any documentation relating to the trial, the Investigator must permit access to such 
records. 


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It is the responsibility of the sponsor to inform the investigator/institution in writing as to 
when the documents no longer need to be retained. 
 


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15. 
FINANCE AND INSURANCE 
The sponsor must provide insurance or must indemnify (legal and financial coverage) the 
investigator/the institution against claims arising from the trial, except for claims that 
arise from malpractice, negligence or non-compliance with the protocol. 
The compensation to the investigators for work performed under this protocol will be set 
out in separate clinical trial agreements with the investigators. 


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16. 
TRIAL ORGANISATION 
The telephone numbers and fax numbers of relevant Sponsor staff are listed in the 
investigator site file. 
The title, name, address and contact details of CROs, laboratories and other vendors are 
listed in Appendix 3 Trial Organisation. 


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17. 
PUBLICATION POLICY 
Information about this clinical trial will be publicly registered on the website 
www.clinicaltrials.gov before the first subject enters into the trial. 
A Clinical Trial Report will be prepared according to the ICH Guideline for Structure and 
Content of Clinical Trial Reports (ICH E3).  
All information supplied by the sponsor in connection with this trial will remain the sole 
property of the sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the 
sponsor. 
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 multicenter trial may publish data subsets from their 
individual institution only after publication of the primary manuscript. 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.  
The sponsor undertakes to publish the results in compliance with the joint position of the 
innovative pharmaceutical industry [Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases, available from 
http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/EN/November_10_2009] 
for public disclosure of clinical trial results in a free, publicly accessible database, 
regardless of outcome, no later than one year after the medicinal product is first approved 
and is commercially available in any country. 


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18. 
LIST OF REFERENCES 
Dranoff G, Crawford AD, Sadelain M, Ream B, Rashid A, Bronson RT, et al. 
Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary 
homeostasis. Science. 1994;264(5159):713-6 
Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 
ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 
2017 Jan 3;49(1).  
Heads of Medicines Agencies; Clinical Trial Facilitation Group: Recommendations 
related to contraception and pregnancy testing in clinical trials. Guidance; 15-Sep-2014. 
Holland AE, Spruit MA, Troosters T et al. An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease. Eur Resp J, 2014;44 (6):1428-1446 
Inoue Y, Nakata K, Arai T, Tazawa R, Hamano E, Nukiwa T, et al. Epidemiological and 
clinical features of idiopathic pulmonary alveolar proteinosis in Japan. Respirology 2006 
Jan;11:S55-60 
Inoue Y, Trapnell BC, Tazawa R, Arai T, Hizawa N et al. Characteristics of a large 
cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J 
Respir Crit Care Med 2008;177:752–62 
Khan A, Agarwal R, Aggarwal AN. Effectiveness of GM-CSF therapy in auto immune 
pulmonary alveolar proteinosis. A meta-analysis of observational studies. Chest 
2012;141(5):1273-83 
Leth S, Bendstrup E, Vestergaard H, Hilberg O. Autoimmune pulmonary alveolar 
proteinosis: treatment options in year 2013. Respirology 2013;18:82-91 
Luisetti M, Kadija Z, Mariani F, Rodi G, Campo I, Trapnell BC. Therapy options in 
pulmonary alveolar proteinosis. Ther. Adv. Resp. Disease 2010;4,239-48  
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-38. 
Molgramostim Concentrated Solution Product Monograph. European Pharmacopeia, 
Edition 8 2015.  
Morgan CJ and Keir G. Treatment of Patients with Severe Pulmonary Alveolar 
Proteinosis using Inhaled GM-CSF. 2009. Royal Brompton Hospital, London, UK. Ref 
Type: Report 
Ohashi K, Sato A, Takada T, Arai T, Nei T, Kasahara Y, et al. Direct evidence that 
GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis. Respir 
Med. 2012;106,284-93 
Papiris SA, Tsirigotis P, Kolilekas L, Papadaki G, Papaioannou AI, Triantafillidou C, et 
al. Long-term inhaled granulocyte macrophage-colony stimulating factor in audoimmune 
pulmonary alveolar proteinosis: Effeciveness, safety, and Lowest effective dose. Clin 
Drug Investig 2014;34:553-64 


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Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med 
1958;258:1123–42 
Sargramostim United States Pharmacopeia 38-NF 33, 2015. 
Seymour JF Presneill JJ. Pulmonary alveolar proteinosis: Progress in the first 44 years. 
Am J Respir Crit Care Med 2002;166:215–35 
Tazawa R, Hamano E, Arai T, Ohta H, Ishimoto O, Uchida K, Watanabe M, Saito J, et al. 
Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary 
alveolar proteinosis. Am J Respir Crit Care Med. 2005;171(10):1142-9 
Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al. Inhaled 
Granulocyte/Macrophage–Colony Stimulating Factor as Therapy for Pulmonary Alveolar 
Proteinosis. Am J Resp Crit Care Med 2010;181:1345-54 
Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 
2003; 349:2527–39 
Trapnell BC, Avetisyan R, Carey B, Zhang W, Kaplan P, Wang H. Prevalence of 
pulmonary alveolar proteinosis (PAP) determined using a large health care claims 
database. ATS, abstract A6582, San Diego 2014. 
Wylam ME, Ten R, Prakash UBS, Nadrous HF, Clawson ML, Andersson PM. Aerosol 
granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. 
Eur Respir J 2006;27:585-93 
Yamaguchi E, Takahashi A, Baba K. Efficacy of inhaled molgramostim in patients with 
autoimmune pulmonary alveolar proteinosis. Am J Respir Crit Care Med 
2012;185:Meeting Abstracts A5803 
Yu HY, Sun XF, Wang YX, Xu ZJ, and Huang H. Whole lung lavage combined with 
Granulocyte-macrophage colony stimulating factor inhalation for an adult case of 
refractory pulmonary alveolar proteinosis. BMC Pulm Med. 2014;14:87 
 


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19. 
APPENDICES 
APPENDIX 1 LIST OF REVISIONS OF PROTOCOL 
Table 5: 
Revisions of Protocol 
Date 
Version 
Description of Document 
 Rationale for change 
23-Oct-
2017 
1.0 
This version was 
never submitted 
to any 
authorities 
Final Protocol 
 NA 
16-Nov-
2017 
2.0 
 
Final Protocol, substantial amendment 
 NA 
31-Jan-
2018 
 
3.0 
This version 
only submitted 
in France and 
Denmark. 
Substantial Amendment 1 to the 
protocol: 
The following updates have been made 
to the protocol: 
 
Protocol synopsis:  
• 
Detailed explanation of the 
possible treatment duration.  
 
Flow chart: 
• 
IMP will not be administered at 
visit 7, which is marked in the 
flowchart in protocol version 2. 
This is an error and will not be 
applicable in any country.   
 
Section 10.8: 
• 
It is clarified that CT scans only 
will be performed, if it is a part 
of clinical praxis.  
 
Section 10.8.5.2: 
• 
It is clarified that CT scan isn’t a 
part of the protocol, and should 
only be performed as part of 
clinical praxis, e.g. clinical 
deterioration 
 
 
 
 
• 
Elaboration of 
treatment duration 
requested by the 
authorities in France 
and Denmark. 
 
• 
Correction of an 
error. 
 
 
 
 
• 
Clarification 
required by the 
French authorities.  
 
 
• 
Clarification 
required by the 
French authorities. 


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Date 
Version 
Description of Document 
 Rationale for change 
15-Mar-
2018 
Version 4.0 
This version was 
only submitted 
in UK 
Substantial amendment 2 to the protocol: 
The following updates have been made 
to the protocol: 
 
Protocol synopsis: 
Inclusion criterion 2: 
Clarification of inclusion criterion, 
including elaboration of sexual 
abstinence  
 
Section 7.1 
Inclusion criterion 2 
Clarification of inclusion criterion, 
including elaboration of sexual 
abstinence  
 
 
 
 
 
 
 
• 
Clarification to 
ensure full 
compliance with 
CTFG guidance 
2014, which is a UK 
requirement but 
applicable for all 
countries 
 
 
• 
Clarification to 
ensure full 
compliance with 
CTFG guidance 
2014, which is a UK 
requirement but 
applicable for all 
countries 
 


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Version 5.0 
Changes 
implemented for 
France and   
Denmark 
(Version 3.0) 
and UK (version 
4.0) are made 
global in version 
5.0 and applies 
to all countries 
in (version 5.0).  
Substantial amendment 3 to the protocol: 
The following updates have been made 
to the protocol: 
 
Protocol synopsis and flow chart: 
The first sentence in the note to 
Inclusion criterion 2 is deleted. 
 
 
 
Exploratory endpoint added for GM-
CSF levels before and 2 hours after 
dosing 
PK samples at visit 1-6 to be collected, 
only for patients in Italy. 
Note J is updated for patients in Italy: 
The visit should take place during the 
week on treatment and the dosing must 
be done at the clinic, in order to collect 
pre-dose PK.  
Clarification that spirometry and DLCO 
should be performed in accordance with 
European Respiratory Society/American 
Thoracic Society (ERS/ATS) guidance 
 
Section 4.1: 
The sentence “consistent with findings 
from other rhGM CSF products” 
deleted. 
For updates on MOL-PAP-002: 
The US added as a country and planned 
number of randomized patients 
increased from 90 to 135.  
Latest DSMB was in April 2018 and not 
October 2017, with 96 randomized 
patients. The last visit reviewed is 
changed from visit 12 to visit 13 and FU 
is now 48 weeks instead of 36 weeks.  
 
Section 4.2 
Rationale for collection of PK samples 
for Italian patients added.  
 
Section 5.3.3 
 
 
 
 
 
• 
Guidance text 
inadvertently 
inserted. This is not 
relevant for 
molgramostim. 
• 
Sponsor decision in 
order to better 
characterize 
systemic safety 
 
 
 
 
 
• 
Missing in previous 
versions 
 
 
 
 
• 
Changes in the 
MOL-PAP-002 trial 
implemented and 
updates found 
relevant for the 
section 
 
 
 
 
 
 
 
• 
Sponsor decision in 
order to better 
characterize 
systemic safety 
• 
Sponsor decision in 
order to better 


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Date 
Version 
Description of Document 
 Rationale for change 
Exploratory endpoint added for GM-
CSF levels before and 2 hours after 
dosing 
 
Section 7.1 
The first sentence in the note to 
Inclusion criterion 2 is deleted. 
 
 
Section 9.5 
A note for the Italy is inserted, to ensure 
the visits are scheduled in a week during 
treatment and the subject will administer 
the dose at the clinic, after collection of 
the pre-dose PK-sample.   
Section 10.4.1: 
6MWT instruction referral is added 
Section 10.4.7: 
Spirometry should be performed 
according to ARA/ERS guidelines. 
Section 10.7.2: 
Instructions for 6MWT is provided in 
Appendix 4.2 and not in a separate 
document. 
Section 10.8.5: 
All laboratory results must be entered in 
the eCRF.  
 
Section 10.8.5.1: 
Additional PK samples requested to be 
collected for Italian patients.  
 
Section 11.3: 
Exploratory endpoint inserted. 
 
Appendix 4.2: 
Instruction for 6MWT added. 
 
characterize 
systemic safety 
 
 
• 
Guidance text 
inadvertently 
inserted. This is not 
relevant for 
molgramostim. 
  
• 
The note is added to 
ensure clarity in 
administration of 
IMP for the Italian 
subjects.  
 
• 
Missing in previous 
versions 
• 
Missing in previous 
versions 
 
• 
Missing in previous 
versions 
 
 
• 
Sponsor decision in 
order to better 
characterize 
systemic safety  
• 
Sponsor decision in 
order to better 
characterize 
systemic safety 
• 
Due to additional 
PK-sample 
collection 
• 
Missing in previous 
versions 
 


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APPENDIX 2 SIGNATURE PAGE 
This Clinical Trial Protocol is approved by: 
BIOSTATISTICIAN 
 
 
 
 
Date: 
Simon Day, PhD  
Director 
Clinical Trials Consulting and Training Ltd  
 
 
 
SPONSOR TRIAL DIRECTOR 
 
 
 
 
Date: 
Mikkel Walmar, MSc, Pharm 
Manager, Clinical Operations  
Savara ApS  
 
 
 
SPONSOR MEDICAL EXPERT 
 
 
 
 
Date: 
Cecilia Ganslandt MD 
Vice President, Head of Clinical Development, 
Savara ApS 
Slotsmarken 17, 2th,  
2970 Hørsholm, Denmark 
+45 79301413 
 


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APPENDIX 3 TRIAL ORGANISATION 
Project Management, Submissions and Monitoring: 
Savara ApS  
Slotsmarken 17, 2tv 
DK-2970 Hørsholm, Denmark 
Phone: +45 7930 1414 
Clinical Research Organisation (Data Management and Biostatistics):  
BioStata 
Bregnerødvej 132 
DK-3460 Birkerød 
Denmark 
Phone: +45 7022 5242 
Manufacturing: 
Name: Miltenyi Biotec GmBH 
Address: Robert-Koch-Straße 1, 17166 Teterow, Germany 
Phone: +49 2204 8306-0 
Web: www.miltenyibiotec.com/ 
Packaging/labelling of IMP: 
Name: KLIFO A/S 
Address: Smedeland 36, 2600 Glostrup, Denmark 
Phone: +45 44 22 29 00 
Web: www.klifo.dk 
Pharmacovigilance 
Name: Premier Research 
Address: 1st Floor, Rubra 2, Mulberry Business Park, Wokingham, RG41 2GY, UK 
Phone: +44 118 936 4000 
Web: 31Twww.premier-research.com31T 
Central Laboratory  
Name: BioAgilytix Europe GmbH  
Address: Lademannbogen, 22339 Hamburg, Germany 
 


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APPENDIX 4 QUESTIONNAIRES 
APPENDIX 4.1  BORG CR10 SCALE 
 
 


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APPENDIX 4.2  TRIAL SPECIFIC GUIDELINE FOR THE 6MWT 
6 MWT AND CR10 (BORG’S) DYSPNOEA SCALE  
6MWT 
The 6MWT should be conducted according to ATS/ERS technical standard (Field 
Walking Tests in Chronic Respiratory Disease – Eue Respir J 2014; 44:1428-1446).  
The 6MWT should be performed on a flat, straight course with a hard surface with little 
pedestrian traffic  
The walking course should be 30 m or more in length.  
The end of the course should be marked such that they are easily visible to patients. The 
same course should be used at each visit.   
The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts  
The test should be completed with the subject breathing room air, if possible. If a patient 
is on chronic oxygen therapy and not able to complete the 6MWT on room air, an oxygen 
titration procedure will be conducted at screening. The procedure described in Appendix 
4 should be followed. The same flow of oxygen should then be used at the subject´s 
subsequent tests in the trial, unless a higher flow is required due to the subject’s medical 
condition.  
Patients should be encouraged every 60 seconds using standard phrases. Other words of 
encouragement and other nonverbal prompts should not be used.  
If the patient stops walking during the test, the timer must not be stopped. The patient 
should be allowed to rest while sitting or standing, as they prefer.  During the stop, 
standard encouragement should be given every 30 seconds. The time the patient stopped 
during the test, should be noted in the eCRF.  
If SpOR2 is < 80% then the test should be stopped  
Two 6MWTs should be performed (due to the learning effect on the test), and the result 
from the test with the longest distance walked should be recorded. If the subject is not 
able to complete more than one test due to exhaustion or adverse events, this should be 
noted on the worksheet. There must be at least 30 minutes between the two tests.  
The total distance walked should be recorded  
SpOR2 should be measured using a pulse oximeter continuously during the test. The start 
value and the lowest value during 6MWT should be recorded  
Start heart rate and end heart rate should also be recorded  
Use the study-specific worksheet  for documenting values, which is provided by sponsor 
to the sites.  
The results from the 6MWT with the longest distance walked and the related SpOR2 and 
CR10 (Borg) scale results should be entered in the eCRF.    


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
64 
Standard encouragement during a 6-minute walk test  
 
1 min: You are doing well. You have 5 minutes to go.   
2 min: Keep up the good work. You have 4 minutes to go.   
3 min: You are doing well. You are halfway.   
4 min: Keep up the good work. You have only 2 minutes left.   
5 min: You are doing well. You have only 1 minute to go.   
6 min: Please stop where you are.   
If the patient stops during the test, every 30 s once SpOR2 is ≥85% the following standard 
phrase should be use:  
“Please resume walking whenever you feel able.”  
CR10 Scale/Borg’s dyspnoea scale  
The CR10 (Borg’s) scale for dyspnoea provided by Savara should be rated before and 
after the 6MWT. Let the patient read the instruction before rating their dyspnoea on the 
CR10 scale. Standard instructions for the CR10 (Borg scale) will be provided in local 
language.  
If possible, the test should be conducted using the same oxygen flow level as was used in 
IMPALA. If a subject has started chronic oxygen therapy after being enrolled in 
IMPALA, an oxygen titration procedure should be conducted as described below.  
This procedure only applies for patients on chronic oxygen supplementation at 
screening:    
The patient will perform an OR2 titration procedure at Screening to determine the amount 
of supplemental oxygen that the patient needs to complete the 6MWT without developing 
OR2 desaturation. This oxygen flow rate will represent the patient’s baseline OR2 flow rate 
for all subsequent 6MWT procedures for this study.  
Equipment and supplies:  
The equipment and supplies needed for the Oxygen Titration Procedure are the same as 
those needed for the 6MWT. Verify that your oxygen flow meter is accurate (to within 
0.5 liters per minute).  
Patient safety:   
The safety precautions for the Oxygen titration procedure at the screening visit are same 
as required for the 6MWT.  
Procedure:  
Step 1: Resting OR2 Titration  
Attach the pulse oximeter. Set it to alarm when SpOR2 falls below 83%.  
Instruct the patient to sit still and not chat.  


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
65 
Discontinue supplemental oxygen. Start the timer for 10 min. If resting SpOR2 decreases to 
below 83% during the 10 minutes resting period, then start supplemental oxygen at 2 
L/min. If resting SpOR2 again decreases below 83% during the next 10 minutes, then 
increase OR2 to 4 L/min. If resting SpO2 remains below 83% during the next 10 minutes, 
then increase 0R2R to 6 L/min. If resting SpOR2 remains below 83% during the 10 minutes 
at rest on 6 L/min of supplemental oxygen, the patient should not conduct the 6MWT.  
The lowest oxygen flow for which a patient can maintain a resting SpOR2 >83% for 10 
minutes will be the initial flow rate for the Walking portion of the OR2 titration procedure.  
Step 2: Walking OR2 Titration  
Before starting the exercise evaluation, the patient should be seated and resting for at 
least 10 minutes on the oxygen flow rate determined during the resting OR2 titration 
procedure.  
Follow the 6MWT procedures, starting at the OR2 flow rate established in the resting OR2 
titration. Start the timer when the patient begins walking.  
If the patient's SpOR2 decreases to below 83%, stop the walk and increase supplemental 
oxygen by 2 L/min. The patient should then be seated and allowed to rest for 5 min. The 
Walking OR2 titration procedure should then be repeated at the higher OR2 flow rate. If the 
patient's SpOR2 decreases to below 83% at any time, repeat the Walking titration. If during 
the 6MWT on 6 L/min of oxygen SpOR2 drops below 83% (sustained for at least 30 
seconds), stop the walk. If the patient has not completed a distance of >150 meters, the 
patient should not conduct the 6MWT  
The lowest oxygen flow on which a patient can complete the 6MWT without developing 
a SpOR2 below 83% will be the patient's OR2 flow for all subsequent 6MWT conducted 
during the course of the study. 
 


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
66 
APPENDIX 4.3  ST GEORGE’S RESPIRATORY QUESTIONNAIRE  
 
 
 


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
67 
 
 
 
 


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
68 
 
 
 


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
69 
 
 


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
70 
 


Savara Pharmaceuticals 
 
Clinical Trial Protocol, version 5.0, 24-Aug-2018  
71 
 

SAP_001.pdf: 
 
SAV006-03 
An open-label, non-controlled, multicentre clinical trial 
of inhaled molgramostim in autoimmune pulmonary 
proteinosis patients 
 
NCT03482752 
 
Statistical Analysis Plan 
Version 3.0 
21 January 2021 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 1 of 31 
 
Statistical Analysis Plan 
 
Molgramostim Nebuliser Solution 
SAV006-03  
An open-label, non-controlled, multi centre clinical trial of inhaled molgramostim in 
autoimmune pulmonary alveolar proteinosis patients 
 
IMPALA Extension trial 
 
 
 
 
A Phase III Trial 
 
Author: Helle Hartvig 
Princial BioStatistician 
BioStata ApS 
 
 
The content of this document is confidential and must not be communicated to a third party and must not be 
reproduced or quoted without the written consent of Savara Aps. 
 
 
 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 2 of 31 
 
Signature page 
The signatures below confirm that the signees have read, understood and approved of the contents of the 
present statistical analysis plan. 
 
Signature & Date 
 
 
 
 
 
 
 
 
 
 
 
Helle Hartvig, BioStata ApS, Trial statistician 
 
 
 
 
 
 
 
 
 
 
 
 
Maj Dinesen, Savara ApS, Director Clinical Development 
 
 
 
 
 
 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 3 of 31 
 
Table of Contents 
List of Tables ........................................................................................ Error! Bookmark not defined. 
1 
Change Log .............................................................................................................................. 4 
2 
List of Abbreviations ................................................................................................................ 5 
3 
Introduction ............................................................................................................................ 6 
4 
Trial Characteristics ................................................................................................................. 7 
4.1 
Trial Objectives ........................................................................................................................................ 7 
4.1.1 
Primary Objective .................................................................................................................... 7 
4.1.2 
Secondary Objectives .............................................................................................................. 7 
4.2 
Trial Design .............................................................................................................................................. 8 
4.3 
Subject included .................................................................................................................................... 11 
5 
Analysis Sets .......................................................................................................................... 11 
5.1 
Protocol Deviations ............................................................................................................................... 11 
6 
Planned Statistical Methods ................................................................................................... 11 
6.1 
Statistical Considerations ...................................................................................................................... 11 
6.2 
Data Issues due to Covid-19 Pandemic ................................................................................................. 12 
6.3 
Subject Disposition ................................................................................................................................ 12 
6.4 
Baseline Demographics ......................................................................................................................... 13 
6.5 
Medical History ..................................................................................................................................... 13 
7 
Exposure and Other Dosing Information ................................................................................. 13 
7.1 
Exposure ................................................................................................................................................ 13 
7.2 
Concomitant Medication ...................................................................................................................... 14 
8 
Statistical Methodology for Primary and Secondary Endpoints ................................................ 14 
8.1 
Analysis and Presentation of the Primary Endpoint ............................................................................. 14 
8.2 
Analysis and Presentation of the Secondary Endpoints ........................................................................ 15 
8.2.1 
Blood Gas Analysis ................................................................................................................. 15 
8.2.2 
6-minute Walk Test (6MWT) ................................................................................................. 16 
8.2.3 
St Georges Respiratory Questionnaire (SGRQ) ..................................................................... 16 
8.2.4 
Whole Lung Lavage ............................................................................................................... 16 
8.2.5 
Lung Function Test ................................................................................................................ 17 
8.2.6 
Disease Severity Score (DSS) ................................................................................................. 18 
8.2.7 
Need for Oxygen Supplement During the Trial ..................................................................... 18 
8.2.8 
Overall Clinical Assessment ................................................................................................... 18 
8.3 
Exploratory Endpoint ............................................................................................................................ 18 
8.4 
Handling of Missing Values ................................................................................................................... 19 
8.5 
Multiplicity Adjustments ....................................................................................................................... 19 
8.6 
Subgroup and Site Effects ..................................................................................................................... 19 
9 
Statistical Methodology for Safety Endpoints ......................................................................... 19 
9.1 
Safety Parameters ................................................................................................................................. 19 
9.1.1 
Analysis and Presentation of Safety Parameters .................................................................. 19 
9.1.2 
Adverse Events ...................................................................................................................... 19 
9.1.3 
Physical Examination ............................................................................................................. 20 
9.1.4 
Vital Signs .............................................................................................................................. 20 
9.1.5 
Electrocardiogram (ECG) ....................................................................................................... 20 
9.1.6 
Laboratory Safety Data .......................................................................................................... 20 
9.1.7 
CT Scans ................................................................................................................................. 22 
9.2 
Safety Update........................................................................................................................................ 22 
10 Deviations from Protocol ....................................................................................................... 22 
11 Software ............................................................................................................................... 22 
12 Reference List ........................................................................................................................ 23 
13 List of Listings ........................................................................................................................ 24 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 4 of 31 
 
14 List of Tables ......................................................................................................................... 25 
15 List of Figures ........................................................................................................................ 31 
Change Log 
 
Version 
number 
Date 
Change 
1.0 
28NOV2019 
Original version 
2.0 
27JAN2020 
Analysis set for listings updated to all subjects in section 5.1 and 
section 12. 
SAS program inserted as part of section 7.2.5. 
List of output for safety update has been updated in section 8.2. 
QTcF has been added to the list of endpoints in section 8.1.5. 
3.0 
21JAN2021 
Description of early termination added in section 3.2. 
Section 5.2 about issues caused by the COVID-19 pandemic has been 
added including 5 new outputs.  
Listing of screen failures and the definition of a subject being 
terminated early have been added to section 5.3. 
A table of last visit attended before closure is added in section 6.1. 
Furthermore, relative exposure has been defined and two outputs 
have been added to the same section. 
A table and a listing of non-serious adverse events have been added 
in section 7.1. Furthermore, tables of adverse events and non-
serious adverse events by preferred term with frequency ≥ 5% have 
been added to this section. 
Responder endpoints and their analyses have been deleted from 
section 7.2.3  
Summary of evaluation of vital signs has been removed from section 
8.1.4  
Summary of evaluation of ECG has been removed from section 8.1.5 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 5 of 31 
 
1 List of Abbreviations 
ADR 
Adverse Drug Reaction  
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
AE 
Adverse Event 
aPAP 
autoimmune Pulmonary Alveolar Proteinosis 
ATC 
Anatomical Therapeutic Chemical Classification System 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CT 
Computed Tomography 
DBL 
Data Base Lock 
DSS 
Disease Severity Score 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
GGT 
Gamma Glutamyl Transpeptidase 
HEENT 
head, eyes, ears, nose, and throat  
LLOQ 
Lower Level of Quantification 
MCH 
Mean cell haemoglobin 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of Subjects 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan   
SD 
Standard Deviation 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
SGRQ 
St Georges Respiratory Questionnaire 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WLL 
Whole Lung Lavage 
 
 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 6 of 31 
 
2 Introduction 
The statistical analysis plan (SAP) for the trial SAV006-03 is based on the final protocol version 5.0 
24AUG2018. 
The SAP describes in detail the analyses to be conducted and highlights any deviations from the 
analysis described in the protocol (see section 9). Deviations from methods described in this SAP, if 
any, will be specified in the clinical trial report. 
The analysis is performed based on: 
 
The clinical database, which includes the electronic Case Report Forms (eCRF)  
Reporting of the trial will be after the date of last subject last visit except for a safety update during 
the trial. 
The trial is terminated early, and the final reporting will be done when all subjects have attended a 
final visit and the database is considered clean and locked. 
 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 7 of 31 
 
3 Trial Characteristics 
3.1 Trial Objectives 
3.1.1 Primary Objective 
The primary objective is to investigate safety of long-term use of inhaled molgramostim. 
3.1.2 Secondary Objectives  
The secondary objectives are  
 
To investigate effects of long-term use of inhaled molgramostim on oxygenation. 
 
To investigate effects of long-term use of inhaled molgramostim on exercise capacity. 
 
To investigate effects of long-term use of inhaled molgramostim on respiratory quality of 
life. 
 
To investigate requirement for WLL during long term use of inhaled molgramostim. 
 
To investigate effects of long-term use of inhaled molgramostim on lung function. 
 
To investigate maintenance of effect after discontinuation of inhaled molgramostim. 
 
 
 
 
 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 8 of 31 
 
3.2 Trial Design 
The trial is an open-label, non-controlled, multi centre clinical trial of inhaled molgramostim in 
autoimmune pulmonary alveolar proteinosis (aPAP) patients.  
Subjects with aPAP who have completed the IMPALA (MOL-PAP-002) trial will be eligible for this trial.  
At the baseline visit, eligible subjects may continue or re-start treatment with inhaled molgramostim 
(300 µg) administered intermittently in cycles of seven days molgramostim, administered once daily, 
and seven days off treatment.  
Trial visits will be conducted at 6-monthly intervals until the end of trial. Participating subjects will be 
encouraged to contact the clinic between visits if they experience adverse events (AEs) or worsening 
of aPAP, or if they have any other concerns. 
During the trial, Whole Lung Lavage (WLL) will be applied as rescue therapy. The criterion for 
performing WLL is clinical worsening of aPAP based on symptoms, reduced exercise capacity and/or 
findings of hypoxemia or desaturation according to the investigator’s judgement. The reason(s) for 
conducting WLL will be documented. Subjects undergoing WLL will continue treatment with 
molgramostim, unless discontinuation is medically required, according to investigator’s discretion. 
Subjects may discontinue molgramostim due to remission of aPAP, lack of response that requires a 
different treatment modality, or AEs. Subjects becoming pregnant will be required to discontinue 
treatment with molgramostim. Subjects who discontinue molgramostim will be encouraged to 
continue in the trial and attend visits according to the same schedule until end of the trial. 
Molgramostim treatment may be re-started if medically required. Subjects not requiring treatment at 
the Baseline visit may start molgramostim treatment during the trial if medically required. 
Savara received advice on the MOL-PAP-002 trial results from EMA and FDA. The data demonstrated 
more favorable evidence of efficacy on the continuous dosing regimen. Following the advice Savara 
has subsequently decided to conduct an additional Phase III confirmatory trial to support future 
registration of the continuous dosing regimen. The SAV006-03 trial investigates an intermittent dosing 
regimen but considering the MOL-PAP-002 clinical trial results and the received health authority 
advice there will not be adequate efficacy and safety data on the intermittent dosing regimen to 
support a marketing authorization application for this regimen. Consequently, Savara has decided to 
discontinue the SAV006-03 trial and support the continued clinical investigation of the continuous 
dosing regimen in a new trial. 
 
60 subjects have been enrolled in the SAV006-03 trial and enrolled subjects will be able to continue 
treatment until end of 2020. Of these, 55 subjects are on active treatment and 5 subjects do not 
receive treatment at the time of trial termination. The 5 subjects have been allowed to remain in the 
trial to observe development of their disease without receiving treatment.   
 
The data from the SAV006-03 trial will be included in the ongoing safety evaluation of molgramostim 
nebulizer solution. The results of the SAV006-03 trial will also be included as part of a potential future 
marketing authorization application for use of molgramostim nebulizer solution as a potential 
treatment for autoimmune pulmonary alveolar proteinosis, although the intermittent dosing regimen 
will likely not be included as a treatment regimen under posology.  


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 9 of 31 
 
All generated data will be cleaned and assessed according to plan and will contribute to the risk-
benefit profile for molgramostim. The trial will be reported according to ICH GCP requirements. 
 
Table 1 Activities flow chart 
 
Table 1: Visit  Visit 1  
Visit 2 
Visit 3  Visit 4  Visit 5  Visit 6 
Visit 7 
FU TC 
Unscheduled  
Baseline 
a 
Month 
6 
Month 
12  
Month 
18 
Month 
24 
Month 
30 
Month 
36 
2 wks after 
trial 
completion 
Time  
0 
Week 
26  
Week 
52  
Week 
78  
Week 
104  
Week 
130 
Week 
156 
Visit Window  N/A 
± 
4wks 
± 4 
wks 
± 4 
wks  
± 4 
wks 
± 4 
wks 
± 4 
wks 
+ 1 wk 
 
Informed 
consent  
X  
 
 
 
 
 
 
 
 
Eligibility 
criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
 
X 
WLL 
information b 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy 
test and 
contraceptive 
check c 
X 
X 
X 
X 
X 
X 
X 
 
(X)d 
Physical 
Exam 
(X) 
 
X 
 
X 
 
X 
 
(X) d 
Vital signs 
(X) 
X 
X 
X 
X 
X 
X 
 
(X) d 
ECG 
(X) 
X 
X 
X 
X 
X 
X 
 
(X) d 
Blood gas 
analysis e 
(X)T  
X  
X 
X 
X 
X 
X 
 
(X) d 
Lung function 
tests f 
(X)T  
X 
X 
X 
X 
X 
X 
 
(X) d 
6MWT g 
(X)T  
X 
X 
X 
X 
X 
X 
 
(X) d 
Quality of 
Life (SGRQ) 
(X)T  
X 
X 
X 
X 
X 
X 
 
 
DSS 
(X)T  
X 
X 
X 
X 
X 
X 
 
(X) d 
Overall 
Clinical 
Assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
CT Scan 
(X) d 
(X) d 
(X) d 
(X) d 
(X) d 
(X) d 
(X) d 
 
(X) d 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 10 of 31 
 
Table 1: Visit  Visit 1  
Visit 2 
Visit 3  Visit 4  Visit 5  Visit 6 
Visit 7 
FU TC 
Unscheduled  
Baseline 
a 
Month 
6 
Month 
12  
Month 
18 
Month 
24 
Month 
30 
Month 
36 
2 wks after 
trial 
completion 
Time  
0 
Week 
26  
Week 
52  
Week 
78  
Week 
104  
Week 
130 
Week 
156 
Visit Window  N/A 
± 
4wks 
± 4 
wks 
± 4 
wks  
± 4 
wks 
± 4 
wks 
± 4 
wks 
+ 1 wk 
 
Laboratory 
Safety 
Analyses h  
(X)  
X 
X 
X 
X 
X 
X 
 
(X)  d 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samples 
(Italy only) i 
X 
X 
X 
X 
X 
X 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
Dispense trial 
drug j 
X 
X 
X 
X 
X 
X 
 
 
(X) d 
Subject Diary 
Card k 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance 
 
X 
X 
X 
X 
X 
X 
 
(X) d 
Study 
continuation 
or termination 
l 
 
X 
X 
X 
X 
X 
X 
 
(X) d 
FU = follow-up, TC = telephone call, WLL = whole lung lavage 
a
 Baseline (Visit 1) may coincide with the final visit of the IMPALA (MOL PAP 002) trial; if so, assessments 
performed at Visit 11 (for subjects enrolled under protocol MOL PAP 002 version 4.0 or later), or Visit 13 
(subjects enrolled under a protocol version prior to version 4.0) may serve as the baseline assessments for this 
protocol. If more than 3 months have elapsed since completion of the IMPALA study to Baseline (Visit 1) the 
assessments must be repeated. 
 b
 Requirement for WLL and if required, indication for procedure will be recorded. If WLL is performed date of 
WLL and type of WLL (unilateral, bilateral) will be recorded.  
 c
 Serum pregnancy test at Baseline (Visit 1) and at all subsequent visits during treatment with inhaled 
molgramostim (pregnancy tests for subjects not receiving trial drug are not mandatory). A urine pregnancy test 
will also be performed at dosing at Baseline (Visit 1) to immediately confirm that the subject is not pregnant and 
meets the inclusion criterion for treatment. If treatment is not dispensed at Baseline (Visit 1) the urine pregnancy 
test will instead be performed at the first visit treatment is dispensed. Subjects will be requested to do monthly 
urine testing at home during treatment. 
d
 Only applicable if assessment is done according to clinical practice or medical need, e.g. in case of a clinical 
deterioration. If done, results will be recorded  
 e
O  Capillary sampling for blood gas analysis may be used instead of an arterial blood gas sample at sites that 
routinely use this method. 
 f
 DLCO, FEV1, and FVC (absolute values and % of predicted values).  
 g
 6MWT includes assessment of SpO2 and Borg CR10 score for dyspnoea before, during (SpO2) and after (Borg) 
the test. If the subjects used supplemental O2 during the procedure in IMPALA, the same O2 flow will be used at 
the subsequent tests in this trial, if possible. 
 h
 Haematology and clinical chemistry 
 i
 For Italy only: Patients will have their visits scheduled for an on-treatment week within the allowed window of 
+/- 4 weeks. The first sample must be taken just prior to inhalation of molgramostim. The 2nd sample must be 
taken 2 hours post dosing, (+/- 10 minutes). 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 11 of 31 
 
 j
 Trial drug is dispensed to subjects who require treatment according to investigator’s discretion. For Italy only: 
The visit should take place in during the week on treatment. On the day of dosing, the subjects will do the nebulization at the 
clinic, in order to collect pre-dose PK sample.  
 
 k
 Diary card to collect safety information to be given to the subject and collected at the next visit. The subject will 
be asked to record any AEs they have experienced, enter dates for pregnancy tests taken at home (if applicable) 
and dates for changing of the nebuliser mouthpiece in the subject diary.  
l
 If the planned trial termination has been declared since the subject’s last visit in the trial, the subject will leave the 
trial. 
3.3 Subject included 
No formal sample size calculation was done as this is an open-label extension trial.  
Subjects with aPAP who have completed the IMPALA (MOL-PAP-002) trial will be eligible for this trial. 
Up to 90 subjects may be included. All subjects in need of treatment will receive inhaled 
molgramostim. 
4 Analysis Sets 
All subjects excluding screening failures will be included in the full analysis set. 
All subjects with exposure within the trial will be included in the safety analysis set. 
The full analysis set will be used for demographics and efficacy summaries and the safety analysis set 
will be used for safety summaries. 
Only recorded data will be analyzed/presented and any subjects who have missing data will only have 
observed data reported, with no imputation for missing data.  
4.1 Protocol Deviations 
Before data base lock (DBL) all protocol deviations will be evaluated and classified as minor or major. 
The decisions will be documented. Major protocol deviations will be listed. 
5 Planned Statistical Methods 
5.1 Statistical Considerations 
Baseline is the value measured on visit 1 before first administration of investigational product in 
SAV006-003. For variables/assessments not scheduled to be performed at baseline or that are missing 
at baseline, the baseline value is the value from the IMPALA (MOL-PAP-002) trial measured closest to 
visit 1. 
Numerical data will be presented using number of subjects, mean, standard deviation, median, range 
(minimum and maximum), as well as number of missing data (if relevant).  
All summary tables for categorical variables will display counts, percentages and number of missing 
data (if relevant) by treatment group. 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
Statistical Analysis Plan 
 
 
 
 
 
SAV006-03; Final draft vs 3 21JAN2021 
Confidential 
Page 12 of 31 
 
All tables will include three treatment arms based on the randomized treatment from the IMPALA trial 
in combination with the current treatment in the presentation of data. The treatment labels will be: 
 
MOL OD / MOL INT 
 
MOL INT / MOL INT 
 
PBO / MOL INT 
Furthermore, all tables will include a total column. 
End of trial date is set to the date of completion/discontinuation as entered in the eCRF on the end of 
trial page. 
All listings will be made based on all subjects. They will be sorted by treatment and then subject 
number. A column showing which analysis sets (FAS/Safety) the subject belongs to, will be included. 
Due to early closure of the trial patients will perform the measurements as described in visit 7 even 
though their last visit might not be visit 7.   
5.2 Data Issues due to Covid-19 Pandemic 
To get an overview of the impact the COVID-19 pandemic has on the trial the below output will be 
presented  
 
Listing with COVID-19 positive subjects including country and time since trial start to COVID-19 
start date 
 
Listing of all adverse events occurring in COVID-19 positive patients including time of the 
adverse event relative to the COVID-19 start date 
 
Table with number of missed key secondary endpoints assessments due to pandemic by 
treatment and visit. The key secondary endpoints are (A-a)DO2 , 6MWD, SGRQ total, DLCO (% 
predicted), PaO2 and DSS 
 
Table with number of alternative endpoint ascertainment (telephone visits, allowed out of 
window visits and such) if any due to COVID-19 by treatment and visit 
 
Listing with all protocol deviations due to COVID-19 
5.3 Subject Disposition 
An overall summary table of subject disposition will be prepared with number of patients in the 
following categories (and sub-categories): 
 
Number of subjects included 


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 
Withdrawals (potential reasons are remission of aPAP, lack of efficacy/worsening of disease, 
unacceptable AE, investigator decision, pregnancy, withdrawal by subject, lost to follow-up or 
other) 
 
Early terminators (patients who don’t complete the trial according to protocol due to early 
termination of the trial). 
 
Completers 
All information will be listed including the time (days) between completion of IMPALA and visit 1 in 
this trial.  
A listing of screening failures will be presented including violations of inclusion and/or exclusion 
criteria. 
5.4 Baseline Demographics 
Baseline demographics consists of age, sex, race, body weight, height and BMI. Baseline demographic 
information will be listed and summarized using descriptive statistics. The table will also include 
number and percentage of patients in age groups < 65 years and ≥ 65 years. 
5.5 Medical History 
Medical history will be recorded at visit 1 and coded using medDRA version 21.0.  
Medical history will be summarized and listed. 
6 Exposure and Other Dosing Information 
6.1 Exposure 
Treatment with molgramostim at least once during the trial (yes/no) will be summarized by treatment.   
Exposure will be summarized by treatment showing summary statistics (mean, standard deviation, 
median, p25, p75, minimum and maximum). 
Furthermore, an output will be generated showing number of subjects with ≥ 6 months exposure, ≥ 12 
months exposure, ≥ 18 months exposure etc. 
Exposure will be defined as number of days from visit 1 to last kit date + 21 days or end of trial date 
whatever comes first. 
For the safety update (see section 8.2) exposure will be calculated as number of days from visit 1 to 
Last kit date + 21 days or Date of last visit before cut-off for safety update whatever comes first. 
Relative exposure will be defined as 
Relative exposure = Exposure / number of days in trial 


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where exposure is defined above. Relative exposure will be summarized by treatment and listed.  
Due to premature trial closure a table with last visit attended will be presented showing number of 
patients and percentages. For patients where the last visit was entered as visit 7, the original visit they 
came in for will be presented in this table based on full analysis set. A listing of visits attended will be 
presented.  
6.2 Concomitant Medication 
Concomitant medication is recorded at baseline and during trial. Concomitant medication will be 
coded using WHODrug version June 2017. 
All concomitant medication will be summarized by ATC level 3 and preferred term. All concomitant 
medication will be listed. 
7 Statistical Methodology for Primary and Secondary Endpoints 
7.1 Analysis and Presentation of the Primary Endpoint 
All adverse events (AEs) occurring after informed consent will be reported in the eCRF. AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0.  
Events judged by the investigator to be related (including all events that are judged to be possibly 
related or probably related) to trial treatment are defined as adverse drug reactions (ADRs). 
The primary endpoints are 
 
Adverse events (AEs) 
 
Serious adverse events (SAEs) 
 
Non-serious adverse events 
 
Adverse drug reactions (ADRs) 
 
Adverse events leading to treatment discontinuation 
Adverse events leading to treatment discontinuation are defined as events where action taken with 
trial drug is marked as Drug withdrawn in the eCRF. 
All the above adverse events will be summarized by system organ class (SOC) and preferred term (PT), 
and overall.  
The overall summary will include AEs, serious AEs, non-serious AEs, ADRs, AEs leading to treatment 
discontinuation, fatal AEs and AEs by severity, AEs by action with trial treatment, AEs by outcome.  
The summaries by SOC and PT will include number of events, number of subjects, proportion of 
subjects reporting these events, and rate of events. For each of the primary endpoints, summaries will 
be given by severity, relationship to trial drug, and outcome. 


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A summary of treatment emergent adverse events by preferred term with frequency ≥ 5% will be 
provided together with a summary of treatment emergent non-serious adverse events by preferred 
term with frequency ≥ 5%. 
Patient listings corresponding to the summaries, will be provided. 
In summaries of adverse events by SOC and PT the tables will be sorted first by SOC and then by PT 
based on the frequency in the total column. 
7.2 Analysis and Presentation of the Secondary Endpoints 
The secondary endpoints are 
 
(A-a)DO2 during the trial  
 
6 Minute Walk Distance (6MWD) during the trial 
 
St Georges Respiratory Questionnaire (SGRQ) total score during the trial 
 
Frequency of Whole Lung Lavage (WLL) during the trial 
 
Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) (% predicted), FEV1 (% predicted), 
and FVC (% predicted) during the trial 
 
PaO2 and disease severity score (DSS) during the trial 
 
Need for oxygen supplement therapy during the trial 
 
Overall clinical assessment (status of aPAP and requirement for treatment since last visit)  
 
Number of subjects not requiring treatment for aPAP and time off treatment after 
discontinuation of inhaled molgramostim 
7.2.1 Blood Gas Analysis 
The following variables will be assessed from an arterial blood gas sample collected at the timepoints 
shown in  Table 1.  
 
PaO2 (mmHg) – arterial partial pressure of oxygen 
 
PaCO2 (mmHg) – arterial partial pressure of carbon dioxide 
 
FiO2 – fraction of inspired oxygen 
Patm (ambient atmospheric pressure) must be collected using a bedside barometer. The PH2O (saturated 
vapor pressure of water at body temperature) will be set to 47 mmHg / 6.266 kPa. 
The Aa Gradient (A-a)DO2 will be calculated centrally using the following formula: 
 
The Aa Gradient will be summarized by visit. A corresponding mean and with confidence interval (CI) 
plot over time will be provided. Subjects on supplementary oxygen during blood gas sample are 
excluded from the relevant visits in the summary. 


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A corresponding listing by subject and visit will be provided including all subjects regardless of use of 
supplemental oxygen. 
Any Aa Gradients reported in kPa will be converted to a result in mmHg, this will be done using a 
factor k=7.5 (kPa x 7.5=mmHg). 
7.2.2 6-minute Walk Test (6MWT) 
Exercise capacity will be assessed using the 6MWT to measure the 6-minute walk distance (6MWD) at 
the timepoints shown in Table 1. 
The 6MWT should be performed twice at each visit in accordance with the European Respiratory 
Society (ERS)/American Thoracic Society (ATS) guidance.  
Data from both tests should be entered in the eCRF. Parameters to be recorded comprise pre and post 
walk dyspnea score using the Borg (CR-10) Dyspnea Score (including the difference post minus pre 
dyspnoea score), SpO2 (%) at start, worst SpO2 (%) during the walk, distance walked (m), duration of 
the walk (minutes and seconds), oxygen flow rate if applicable, reason for stopping early (if 
applicable).  For each subject and each visit the results from the test with the longest distance walked 
will be used in the reporting of the trial. 
Distance in meter, Borg score endpoints, and SpO2 and the desaturation (first SpO2-worst SpO2) will be 
summarized by treatment and visit. Furthermore, number of subjects (N, %) who completed the test 
will be presented by treatment and visit. 
A corresponding mean and CI plot over time as well as a corresponding listing by subject and visit will 
be provided for each of the endpoints.  
The listing will include pre and post walk dyspnoea Borg (CR-10) score, start and worst SpO2 (%), 
distance walked, duration, oxygen flow rate (L/min), use of oxygen supplementation during the test 
(yes/no), and stopping early (yes/no) including the reason for stopping early. Both 6MWT at each visit 
will be included in the listing. 
7.2.3 St Georges Respiratory Questionnaire (SGRQ) 
The total SGRQ score and component scores (symptoms, activity and impact scores) will be calculated 
according to the SGRQ scoring manual. Total score as well as the component scores will be 
summarized by treatment and visit. Corresponding mean and CI plots over time will be provided as 
well as a listing by subject and visit. The listing will contain both response to the individual questions in 
SGRQ as well as the total and component scores. 
7.2.4 Whole Lung Lavage 
The number of subjects experiencing whole lung lavage (WLL), and the number of WLLs events will be 
summarized by visit and overall. The summary will also include event rates (95% CI) adjusted for time 
in trial since visit 1.  A separate summary will present the number of subjects and the number of 
events between IMPALA and IMPALA-X. A WLL event is defined as a WLL procedure performed on a 
unilateral lung. These events are entered at visit 1 as part of the overall clinical assessment. 
Time in trial is defined as the number of days from visit 1 to end of trial date. 


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Event rates shown as the number of events per subject year and the 95% confidence intervals (CI) of 
the event rates are estimated using a negative binomial model. 
The 95% CI will be estimated using the below piece of code in SAS. Here the dataset wll_rate has the 
number of whole lung lavage by subject in parameter aval, and the logarithm of the time of exposure 
in parameter called log_dur. The parameter one has the value 1 (one) for all subjects. The dataset final 
include the estimated rate (esti), and the lower limit of the confidence interval (lowci ) and the upper 
limit of the confidence interval (uppci).  
ods output ParameterEstimates=ParameterEstimates; 
proc genmod data= wll_rate; 
class one; 
model aval= one /cl noint dist=negbin offset=log_dur link=log   ; 
lsmeans one / exp cl; 
run; 
data exp; 
  set ParameterEstimates; 
  where parameter="one"; 
  esti = exp(Estimate); * estimate; 
  lowci = exp(LowerWaldCL); * lower limit of confidence interval; 
  uppci = exp(UpperWaldCL); * upper limit confidence interval; 
run; 
Furthermore, the whole lung lavage will be summarized by location (left, right or both) and the 
volume of saline used will be summarized. 
A listing of subjects requiring WLL including reasons for WLL, date of criteria met, and date of 
procedure will be provided. 
7.2.5 Lung Function Test 
The percentage predicted values (DLCO (%), FEV1 (%) and FVC (%)) will be summarized by visit.  
DLCO % predicted will be haemoglobin (Hb) corrected according to the formula: 
𝐷𝐿𝐶𝑂 (% 𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑, 𝐻𝑏 𝑐𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑) = 100 ×
𝐷𝐿𝐶𝑂 (𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑)
𝐷𝐿𝐶𝑂(𝑎𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑) × 1.7𝐻𝑏/(𝑎+ 𝐻𝑏) 


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Where a is 10.22 for males and 9.38 for females, Hb must be measured in g/dL. Corresponding mean 
and CI plots over time will be provided. 
All data will be listed including both actual and % predicted values of DLCO, FEV1 and FVC. 
7.2.6 Disease Severity Score (DSS) 
DSS will be summarized using N (%) in each category over time. Furthermore, a table showing number 
of subjects (N (%)) having improved/unchanged/worsened DSS score from visit 1 will be provided. 
Assessment of DSS from subjects-visits where supplementary oxygen was used during arterial blood 
gas samples will be excluded from both summary tables. 
A corresponding listing by subject and visit will be provided.  
7.2.7 Need for Oxygen Supplement During the Trial 
This endpoint will be assessed through the recordings of concomitant medication. The two medication 
classes V03AN and R07A will be selected. 
Number of subjects requiring oxygen supplement any time during trial will be summarized by 
treatment and listed.  
The summary will be repeated for oxygen supplement  
 
ongoing at baseline 
 
ongoing at end of trial 
 
ongoing at both baseline and end of trial 
 
started after baseline and stopped before end of trial 
The listing will include further details as flow rate and regimen (dose, unit, route and frequency) as 
well as timing compared to baseline and end of trial (ongoing or stopped etc). 
7.2.8 Overall Clinical Assessment 
Overall clinical assessment consists of two endpoints as described below. Both endpoints will be 
summarized by treatment and visit. 
 
Status of aPAP (in remission, improving, stable or progressive) 
 
Requirement for treatment since last visit (no treatment required, treatment with inhaled 
molgramostim required, Whole Lung Lavage, oxygen supplementation or other treatment 
required) 
7.3 Exploratory Endpoint 
The exploratory endpoint is 


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 
GM-CSF levels before and 2 hours after dosing 
All values of GM-CSF above lower level of quantification (LLOQ) will be listed. 
7.4 Handling of Missing Values 
No imputation of missing data is planned. 
7.5 Multiplicity Adjustments 
No multiplicity adjustments are needed since no analyses are to be performed.  
7.6 Subgroup and Site Effects 
No subgroup analyses are planned.  
Adjustments for site effects are not applicable since no analyses are performed. 
8 Statistical Methodology for Safety Endpoints 
Safety will be considered for subjects included in the Safety Analysis Set. No imputation of missing 
data is planned for safety endpoints. 
8.1 Safety Parameters 
The safety parameters are 
 
Adverse events 
 
Physical examination 
 
Vital signs 
 
ECG 
 
Laboratory safety assessments 
 
CT scan  
8.1.1 Analysis and Presentation of Safety Parameters 
8.1.2 Adverse Events 
All adverse events (AEs) occurring after informed consent will be reported in the eCRF. AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0.  
Adverse events are considered treatment emergent if the onset of the events is on or after the first 
exposure date of IMP in this trial and until (estimated) last drug date + 7 days.  Last drug date is 
defined as last kit date + 21 days or end of trial date whatever comes first. Only treatment emergent 
events will be included in the safety summaries. 
Possible or probable related AE’s are defined as ADRs. 
Adverse events will be presented as described in section 7.1. 


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8.1.3 Physical Examination 
All subjects will undergo a standard physical examination at the timepoints shown in Table 1. 
Complete physical examinations will include at a minimum a review of the subject’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, extremities, 
skin, and general neurological system.  
No output will be generated for physical examination. 
8.1.4 Vital Signs 
Vital signs (heart rate, temperature, systolic and diastolic blood pressure) will be measured at each 
visit including an evaluation for each parameter.  
Continuous values of vital signs will be summarized by parameter and visit including change from 
baseline.  
8.1.5 Electrocardiogram (ECG) 
A 12-lead ECG will be assessed using a standard ECG machine according to local procedures at the 
time points shown in Table 1. 
Heart rate, QRS, PR and QT intervals will be recorded from the ECGs. The ECGs will be interpreted and 
signed and dated by the investigator or his/her designee.   
The QT interval by be corrected using Fridericia's formula (QTcF) will be added to the summary tables 
as described below. 
Continuous values of ECG will be summarized by parameter and visit including change from baseline.  
8.1.6 Laboratory Safety Data  
Laboratory safety parameters are listed described in Table 2. All results will be recorded in the eCRF 
and will be assessed as clinically significant or not clinically significant. Since local laboratories are used 
laboratory parameters will be converted to units as indicated in Table 2 before summarizing.  


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Table 2 Laboratory safety parameters 
Category 
Laboratory Parameter (unit) 
Haematology 
Haemoglobin (g/dL), 
RBC (10^12/L) 
Red Blood Cell Distribution Width (RDW) (%) 
Haematocrit (%)  
Mean cell volume (MCV) (fL) 
Mean cell haemoglobin (MCH) (pg) 
Mean cell haemoglobin concentration (MCHC) (g/dL) 
Platelet count (10^9/L) 
WBC and differential counts (absolute and percentage): 
Neutrophils (% and 10^9/L) 
Lymphocytes (% and 10^9/L) 
Monocytes (% and 10^9/L) 
Eosinophils (% and 10^9/L) 
Basophils (% and 10^9/L)  
Prothrombin Time International Normalised Ratio (PT-INR) 
Clinical chemistry 
Aspartate Aminotransferase (AST) (U/L) 
Alanine Aminotransferase (ALT) (U/L) 
Gamma Glutamyl Transpeptidase (GGT) (U/L) 
Alkaline Phosphatase (U/L) 
Bilirubin (mg/dL) 
Urea (mg/dL) 
S-Creatinine (mg/dL) 
Potassium (mmol/L) 
Sodium (mmol/L) 
Calcium (mg/dL) 
Chloride (mmol/L) 
Phosphate (mg/dL) 
Total protein (g/dL) 
Albumin (g/dL) 
C-Reactive Protein (CRP) (mg/dL) 
Glucose (non-fasting) (mg/dL) 
 


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Laboratory safety data will be summarized using descriptive statistics, including means, medians, SDs, 
and minimum and maximum by time point and treatment, including changes from baseline. In 
addition, laboratory safety data will be plotted using boxplots by time point and treatment. 
A mean and CI plot over time will be presented for haemoglobin as well as for change from baseline in 
haemoglobin.  
Abnormal values will be listed by subject, visit and safety parameter. 
8.1.7 CT Scans 
A CT scan is not required as part of this trial. Only if a CT scan is performed according to clinical 
practice or medical need, e.g. in case of a clinical deterioration, the results will be recorded in the 
eCRF as improved / worsened / no change / data missing or impossible to evaluate, compared to the 
last evaluation in IMPALA. 
Results of the CT scans will be listed by subject and visit.  
8.2 Safety Update 
A safety update will be performed with a planned data cutoff 1-February 2019. 
The output generated for the safety update is listed below. For the output in section 14.2.4 (Whole 
lung lavage) the date of the cutoff will be used to calculate subject years. 
 
Table 14.1.1, 14.1.3, 14.1.5, 14.1.6  
 
Tables 14.2.4.1, 14.2.4.3 
 
Table 14.2.6.1 
 
All output in section 14.3 
 
Listing 16.2.6.4 
9 Deviations from Protocol 
A safety analysis set has been added. At the time of protocol generation all patients were expected to 
be treated from the beginning of this trial. Since some patients are not treated in this trial it was 
decided to include a safety analysis set 
The secondary endpoint “time off treatment after discontinuation of inhaled molgramostim” is not 
reported due to insufficient data collection.  
10 Software  
All statistical calculations described in this SAP will be done by BioStata Aps using SAS, release 9.4 or 
later (SAS Institute, Cary, NC, USA).  


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11 Reference List 
St George’s respiratory questionnaire manual version 2.3, 2019, Paul Jones 
 
 


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12 List of Listings 
Listing 16.2.1.1 Violations of inclusion and/or exclusion criteria – screening failures  
Listing 16.2.1.2 Individual subject disposition (all subjects) 
Listing 16.2.1.3 Reason for withdrawal from trial (all subjects) 
Listing 16.2.2.1 Protocol deviations (all subjects) 
Listing 16.2.4.1 Individual subject demographics and baseline characteristics (all subjects) 
Listing 16.2.4.2 Individual medical history (all subjects) 
Listing 16.2.4.3 Individual concomitant medication (all subjects) 
Listing 16.2.4.4 COVID-19 positive subjects (all subjects) 
Listing 16.2.4.5 Adverse events occurring in COVID-19 positive subjects (all subjects) 
Listing 16.2.4.6 Protocol deviations due to COVID-19 (all subjects) 
Listing 16.2.5.1 Individual subject exposure (all subjects) 
Listing 16.2.5.2 Individual subject relative exposure (all subjects) 
Listing 16.2.5.3 Individual visits attended (all subjects) 
Listing 16.2.6.1 Individual (A-a)DO2 (all subjects) 
Listing 16.2.6.2 Individual 6-minute walk test (all subjects) 
Listing 16.2.6.3 Individual St Georges respiratory questionnaire scores (all subjects) 
Listing 16.2.6.4 Individual whole lung lavage (all subjects) 
Listing 16.2.6.5 Individual lung function tests (all subjects) 
Listing 16.2.6.6 Individual disease severity scores (all subjects) 
Listing 16.2.6.7 Subjects with oxygen supplement during trial (all subjects) 
Listing 16.2.6.8 Individual overall clinical assessments (all subjects) 
Listing 16.2.6.9 Individual GM-CSF measurements above lower level of quantification (all subjects) 
Listing 16.2.7.1 Adverse events (all subjects) 
Listing 16.2.7.2 Serious adverse events (all subjects) 


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Listing 16.2.7.3 Adverse drug reactions (all subjects) 
Listing 16.2.7.4 Adverse events leading to treatment discontinuation (all subjects) 
Listing 16.2.8.1 Individual haematology (all subjects) 
Listing 16.2.8.2 Individual clinical chemistry (all subjects) 
Listing 16.2.9.1 Individual vital signs (all subjects) 
Listing 16.2.9.2 Individual electrocardiogram (all subjects)  
Listing 16.2.10.1 Individual CT scans (all subjects) 
 
 
 
 
 
 
13 List of Tables 
Section 14.1 
Table 14.1.1 Subject disposition (full analysis set) 
Table 14.1.2 Number of subjects by visit (full analysis set) 
Table 14.1.3 Baseline demographics (full analysis set) 
Table 14.1.4 Medical history (full analysis set) 
Table 14.1.5 Summary of exposure (months) (safety analysis set) 
Table 14.1.6 Summary of cumulative exposure (safety analysis set) 
 
Table 14.1.7 Summary of relative exposure (safety analysis set) 
Table 14.1.8 Summary of last visit attended (full analysis set) 
Table 14.1.9 Concomitant medication (safety analysis set) 


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Table 14.1.10. Summary of missed key secondary endpoints assessments due to COVID-19 pandemic 
(safety analysis set) 
Table 14.1.11 Summary of alternative endpoint ascertainment due to COVID-19 pandemic (safety 
analysis set) 
Section 14.2 
(14.2.1: Blood gas analysis endpoints) 
Table 14.2.1.1 Summary of (A-a)DO2 (mmHg) (full analysis set) 
Table 14.2.1.2 Summary of change from baseline in (A-a)DO2 (mmHg) (full analysis set) 
(14.2.2: 6 minutes walking test endpoints) 
Table 14.2.2.1 Summary of 6 minutes walking distance (m) (full analysis set) 
Table 14.2.2.2 Summary of change from baseline in 6 minutes walking distance (m) (full analysis set) 
Table 14.2.2.3 Summary of pre-walk dyspnoea score (Borg CR10) (full analysis set) 
Table 14.2.2.4 Summary of change from baseline in 6 minutes walking distance (m) (full analysis set) 
Table 14.2.2.5 Summary of post-walk dyspnoea score (Borg CR10) (full analysis set) 
Table 14.2.2.6 Summary of change from baseline in dyspnoea score (Borg CR10) (full analysis set) 
Table 14.2.2.7 Summary of SpO2 at start of walk (%) (full analysis set) 
Table 14.2.2.8 Summary of change from baseline in SpO2 at start of walk (%) (full analysis set) 
Table 14.2.2.9 Summary of worst SpO2 during walk (%) (full analysis set) 
Table 14.2.2.10 Summary of change from baseline in worst SpO2 during walk (%) (full analysis set) 
Table 14.2.2.11 Summary of desaturation during walk (%) (full analysis set) 
Table 14.2.2.12 Summary of change from baseline in desaturation during walk (%) (full analysis set) 
Table 14.2.2.13 Summary of completion of 6 minutes walking test (full analysis set) 
(14.2.3: SGRQ endpoints) 
Table 14.2.3.1 Summary of SGRQ total score (full analysis set) 
Table 14.2.3.2 Summary of change from baseline in SGRQ total score (full analysis set) 
Table 14.2.3.3 Summary of SGRQ symptoms score (full analysis set) 


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Table 14.2.3.4 Summary of change from baseline in SGRQ symptoms score (full analysis set) 
Table 14.2.3.5 Summary of SGRQ activity score (full analysis set) 
Table 14.2.3.6 Summary of change from baseline in SGRQ activity score (full analysis set) 
Table 14.2.3.7 Summary of SGRQ impact score (full analysis set) 
Table 14.2.3.8 Summary of change from baseline in SGRQ impact score (full analysis set) 
(14.2.4: Whole lung lavage endpoints) 
Table 14.2.4.1 Summary of number of subjects with a whole lung lavage between IMPALA and 
IMPALA-Z (safety analysis set) 
Table 14.2.4.2 Summary of whole lung lavage (safety analysis set) 
Table 14.2.4.3 Summary of whole lung lavage by location (safety analysis set) 
Table 14.2.4.4 Summary of volume of saline used during whole lung lavage (L) (safety analysis set) 
(14.2.5: Lung function test endpoints) 
Table 14.2.5.1 Summary of DLCO (%) (full analysis set) 
Table 14.2.5.2 Summary of change from baseline in DLCO (%) (full analysis set) 
Table 14.2.5.3 Summary of FEV1 (%) (full analysis set) 
Table 14.2.5.4 Summary of change from baseline in FEV1 (%) (full analysis set) 
Table 14.2.5.5 Summary of FVC (%) (full analysis set) 
Table 14.2.5.6 Summary of change from baseline in FVC (%) (full analysis set) 
(14.2.6: Disease severity score) 
Table 14.2.6.1 Summary of disease severity score (full analysis set) 
Table 14.2.6.2 Summary of change in disease severity score compared to baseline (full analysis set) 
(14.2.7: Supplemental oxygen during trial) 
Table 14.2.7.1 Summary of oxygen supplement anytime during the trial (full analysis set) 
Table 14.2.7.2: Summary of oxygen supplement ongoing at baseline (full analysis set) 
Table 14.2.7.3: Summary of oxygen supplement ongoing at end of trial (full analysis set) 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
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Table 14.2.7.4: Summary of oxygen supplement ongoing at baseline and ongoing at end of trial (full 
analysis set) 
Table 14.2.7.5: Summary of oxygen supplement started after baseline and stopped before end of trial 
(full analysis set) 
(14.2.8: Overall clinical assessment) 
Table 14.2.8.1 Summary of status of aPAP (full analysis set) 
Table 14.2.8.2 Summary of requirement for treatment since last visit (full analysis set) 
Section 14.3 
(14.3.1: Adverse events) 
Table 14.3.1.1 Overview of adverse events (safety analysis set) 
Table 14.3.1.2 Summary of treatment emergent adverse events by SOC and preferred term (safety 
analysis set) 
Table 14.3.1.3 Summary of treatment emergent adverse events by preferred term - frequency ≥ 5% 
(safety analysis set) 
Table 14.3.1.4 Summary of treatment emergent adverse events by severity and SOC and preferred 
term (safety analysis set) 
Table 14.3.1.5 Summary of treatment emergent adverse events by relationship and SOC and preferred 
term (safety analysis set) 
Table 14.3.1.6 Summary of treatment emergent adverse events by outcome and SOC and preferred 
term (safety analysis set) 
Table 14.3.1.7 Summary of treatment emergent serious adverse events by SOC and preferred term 
(safety analysis set) 
Table 14.3.1.8 Summary of treatment emergent serious adverse events by severity, SOC and preferred 
term (safety analysis set) 
Table 14.3.1.9 Summary of treatment emergent serious adverse events by relationship, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.10 Summary of treatment emergent serious adverse events by outcome, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.11 Summary of treatment emergent non-serious adverse events by SOC and preferred 
term (safety analysis set) 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
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Table 14.3.1.12 Summary of treatment emergent non-serious adverse events by preferred term - 
frequency ≥ 5% (safety analysis set) 
Table 14.3.1.13 Summary of treatment emergent non-serious adverse events by severity, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.14 Summary of treatment emergent non-serious adverse events by relationship, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.15 Summary of treatment emergent non-serious adverse events by outcome, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.16 Summary of treatment emergent adverse drug reactions by SOC and preferred term 
(safety analysis set) 
Table 14.3.1.17 Summary of treatment emergent adverse drug reactions by severity, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.18 Summary of treatment emergent adverse drug reactions by relationship, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.19 Summary of treatment emergent adverse drug reactions by outcome, SOC and 
preferred term (safety analysis set) 
Table 14.3.1.20 Summary of treatment emergent adverse events leading to treatment discontinuation 
by SOC and preferred term (safety analysis set) 
Table 14.3.1.21 Summary of treatment emergent adverse events leading to treatment discontinuation 
by severity, SOC and preferred term (safety analysis set) 
Table 14.3.1.22 Summary of treatment emergent adverse events leading to treatment discontinuation 
by relationship, SOC and preferred term (safety analysis set) 
Table 14.3.1.23 Summary of treatment emergent adverse events leading to treatment discontinuation 
by outcome, SOC and preferred term (safety analysis set) 
(14.3.2: Vital signs) 
Table 14.3.2.1 Summary of vital signs (safety analysis set) 
Table 14.3.2.2 Summary of change from baseline in vital signs (safety analysis set) 
(14.3.3: ECG) 
Table 14.3.3.1 Summary of electrocardiogram (ECG) (safety analysis set) 
Table 14.3.3.2 Summary of change from baseline in electrocardiogram (ECG) (safety analysis set) 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
Version:                             Final 3.0 
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(14.3.4: Safety lab) 
Table 14.3.4.1 Summary of hematology parameters (safety analysis set) 
Table 14.3.4.2 Summary of change from baseline in hematology parameters (safety analysis set) 
Table 14.3.4.3 Summary of clinical chemistry parameters (safety analysis set) 
Table 14.3.4.4 Summary of change from baseline in clinical chemistry parameters (safety analysis set) 
 
 


Sponsor: Savara Aps 
Drug/Project: Molgradex 
Trial: SAV006-03 
Date:                            21-Jan-2021 
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14 List of Figures 
Section 14.2 
(14.2.1: Blood gas analysis endpoints) 
Figure 14.2.1.1 Mean plot of (A-a)DO2 (mmHg) (full analysis set) 
(14.2.2: 6 minutes walking test endpoints) 
Figure 14.2.2.1 Mean plot of 6 minutes walking distance (m) (full analysis set) 
Figure 14.2.2.2 Mean plot of pre-walk dyspnoea score (Borg CR10) (full analysis set) 
Figure 14.2.2.3 Mean plot of post-walk dyspnoea score (Borg CR10) (full analysis set) 
Figure 14.2.2.4 Mean plot of SpO2 at start of walk (%) (full analysis set) 
Figure 14.2.2.5 Mean plot of worst SpO2 during walk (%) (full analysis set) 
Figure 14.2.2.6 Mean plot of desaturation during walk (%) (full analysis set) 
(14.2.3: SGRQ endpoints) 
Figure 14.2.3.1 Mean plot of SGRQ total score (full analysis set) 
Figure 14.2.3.2 Mean plot of SGRQ symptoms score (full analysis set) 
Figure 14.2.3.3 Mean plot of SGRQ activity score (full analysis set) 
Figure 14.2.3.4 Mean plot of SGRQ impact score (full analysis set) 
Section 14.3 
(14.3.1: safety lab) 
Figure 14.3.1.1 Mean plot of haemoglobin (mg/dL) (safety analysis set) 
Figure 14.3.1.2 Mean plot of change from baseline in haemoglobin (mg/dL) (safety analysis set)