Clinical trial NCT02702180
Conditions: Autoimmune Pulmonary Alveolar Proteinosis
Sponsor: Savara Inc.
Start date: 2016-03-21; Completion date: 2019-09-27
Enrollment: 139 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates inhaled molgramostim (recombinant human granulocyte macrophage-colony stimulating factor \[rhGM-CSF\]) in the treatment of autoimmune pulmonary alveolar proteinosis (aPAP) patients. A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks.

Detailed description:
The trial is a phase 2, randomized, double-blind, placebo-controlled multicentre clinical trial investigating efficacy and safety of inhaled molgramostim (rhGM-CSF) in patients with aPAP.

The trial will include 2 periods; a double-blind treatment period consisting of up to 8 trial visits (Screening, Baseline, and at Weeks 4, 8,12, 16, 20 and 24 after randomisation) and a open-label follow-up period consisting of up to 5 trial visits (at Weeks 4, 12, 24, 36 and 48 post-treatment).

In the double-blind treatment period, eligible subjects will be randomised to treatment for up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily (MOL-OD), 2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (7 days on and 7 days off) (MOL-INT) or 3) inhaled placebo once daily (PBO). During the follow-up period, all participants will receive inhaled molgramostim intermittently (7 days on, 7 days off). During the trial, whole lung lavage (WLL) may be applied as rescue therapy in case of significant clinical worsening.

Arms: arm 1: Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks arm 2: Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) arm 3: Inhalation of placebo nebuliser solution once daily for 24 weeks arm 4: Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period
Interventions: intervention 1: Molgramostim intervention 2: Placebo intervention 3: PARI eFlow nebulizer system
Intervention descriptions: intervention 1: 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation intervention 2: Placebo nebulizer solution for inhalation intervention 3: PARI eFlow nebulizer system

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL 
This Clinical Trial Protocol contains privileged or confidential information which is the property of the 
Sponsor. Information may not be disclosed to a third party without written authorisation from the Sponsor. 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
 
 
A Randomised, Double-Blind, Placebo-Controlled Multicentre Clinical Trial of 
Inhaled Molgramostim in Autoimmune Pulmonary AlveoLAr Proteinosis Patients 
“IMPALA” 
Trial code: 
MOL-PAP-002 
Trial development 
phase: 
II/III 
EudraCT number: 
2015-003878-33 
Investigational 
medicinal product: 
Molgramostim 
nebuliser solution 
 
 
Indication: 
Autoimmune 
pulmonary 
alveolar 
proteinosis 
Version: 
5.0 
Date: 
01 Dec 2017 
Amendments included in 
the protocol version 5.0 
Non-substantial amendment 12.0, 30 Oct 2017 
Substantial amendment 13.0, 01 Dec 2017  
Coordinating Principal 
Investigator: 
Cliff Morgan, MD (Dep. of ICU, Royal Brompton Hospital, 
London, United Kingdom) 
Sponsor Representatives: 
Cecilia Ganslandt, MD, Vice President, Head of Clinical 
Development 
Mikkel Walmar, M.Sc. Pharm, Manager, Clinical Operations 
 
Slotsmarken 17. 2.tv., 2970 Hørsholm, Denmark 
 


01-Dec-2017
Cecilia Ganslandt 
I am approving this 
document 
2017.12.01 17:54:43 +01'00'




Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 3 of 83 
1 
SYNOPSIS 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
TITLE OF THE TRIAL: 
A randomised, double-blind, placebo-controlled multicentre clinical trial of inhaled molgramostim in 
autoimmune pulmonary alveolar proteinosis patients 
OBJECTIVES: 
 
Primary objective: 
• 
To compare efficacy of inhaled molgramostim on the Alveolar-arterial oxygen difference 
((A-a)DO2) with placebo after 24-weeks treatment.  
 
Key Secondary objectives: 
• 
To compare efficacy of inhaled molgramostim on tolerance to exercise with placebo after 24-
weeks of treatment 
• 
To compare efficacy of inhaled molgramostim on respiratory disease-related quality of life with 
placebo after 24-weeks of treatment 
• 
To compare efficacy of inhaled molgramostim based on time to Whole Lung Lavage (WLL) with 
placebo during 24-weeks of treatment. 
• 
To compare safety of inhaled molgramostim with placebo in terms of reported adverse events 
(AEs), serious adverse events (SAEs), adverse drug reactions (ADRs), severe AEs and 
withdrawals due to AEs during 24-weeks treatment 
 
Further Secondary objectives: 
• 
To compare efficacy of inhaled molgramostim on Vital Capacity (VC), Diffusion Capacity of the 
Lung for Carbon Monoxide (DLCO), Forced Expiratory Volume in one (1) second (FEV1), Forced 
Vital Capacity (FVC) and Arterial oxygen tension (PaO2) with placebo after 24-weeks treatment 
• 
To compare efficacy of inhaled molgramostim on the categorical change of (A-a)DO2, VC, 
DLCO,  FEV1, FVC, and PaO2 with placebo after 24-weeks treatment  
• 
To compare efficacy of inhaled molgramostim on categorical change in tolerance to exercise 
with placebo after 24-weeks treatment 
• 
To compare efficacy of inhaled molgramostim on dyspnoea, and cough with placebo after 
24-weeks treatment  
• 
To compare efficacy of inhaled molgramostim on disease severity by Computer Tomography 
(CT) scoring with placebo after 24-weeks treatment 
 
 
 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 4 of 83 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
 
Exploratory  objectives: 
Double-blind treatment period 
• 
To compare efficacy of inhaled molgramostim with placebo on (A-a)DO2, VC, DLCO, FEV1, FVC, 
PaO2, and on tolerance to exercise after 4-weeks and 12-weeks treatment 
• 
To compare the duration of response of inhaled molgramostim with placebo in (A-a)DO2 and 
tolerance to exercise  
• 
To compare efficacy of inhaled molgramostim with placebo on dyspnoea and cough after 
4-weeks, and 12-weeks treatment  
• 
To compare efficacy of inhaled molgramostim with placebo on Quality of Life (QoL) after 
4-weeks, 12-weeks, and 24-weeks treatment  
• 
To assess pharmacodynamic effects on selected biomarkers in serum after 4-weeks, 12-weeks, 
and 24-weeks treatment of inhaled molgramostim or placebo  
• 
To assess the effect of molgramostim on Granulocyte Macrophage Colony Stimulating Factor 
(GM-CSF) concentration in serum after the first dose and after 4-weeks treatment, and to 
assess levels of antibodies to GM-CSF (anti-GM-CSF) after 4-weeks, 12-weeks and 24-weeks 
treatment with molgramostim or placebo  
• 
To assess the requirement for oxygen supplementation therapy during 24-weeks treatment with 
molgramostim or placebo 
• 
To assess the change in Disease Severity Score (DSS) from Screening to Week 24 
  
Follow-up period 
• 
To compare the requirement for and time to WLL, or other treatment for autoimmune Pulmonary 
Alveolar Proteinosis (aPAP) after 24-weeks inhaled molgramostim or placebo during a 24-week 
or 48-week post-treatment Follow-up period   
• 
To compare efficacy of 24-weeks inhaled molgramostim with placebo on (A-a)DO2, VC, DLCO, 
FEV1, FVC, PaO2, and on tolerance to exercise during a 24-week or 48-week post-treatment 
Follow-up period  
• 
To compare safety of inhaled molgramostim with placebo during a 24-week or 48-week post-
treatment Follow-up period in terms of reported AEs, severe AEs, SAEs, and ADRs 
• 
To assess levels of anti-GM-CSF at the 12-weeks and 24-weeks post-treatment Follow-up visits  
• 
To assess the change in DSS during a 24-week or 48-week post-treatment Follow-up period 
 
 
 
 
 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 5 of 83 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
OVERALL TRIAL DESIGN:  
A Screening Visit will be conducted 14 days (±7 days) prior to the Baseline Visit to determine eligibility.  
Subjects with aPAP confirmed to be stable or progressive during a period of at least two months prior to 
the Baseline Visit will be eligible for treatment. Subjects are not eligible for treatment if spontaneous 
remission has occurred during this 2-month period, defined as absolute VC improved by more than 5% 
and/or DLCO improved by more than 10%.  
At the Baseline Visit, eligible subjects will be randomised to receive treatment for up to 24 weeks with 
either:  
1) inhaled molgramostim (300 µg) administered once daily,  
2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (12 cycles of seven 
days molgramostim, seven days placebo; both administered once daily) or  
3) inhaled placebo administered once daily.  
The trial will include two phases; a Double-blind treatment period consisting of up to eight trial visits 
(Screening, Baseline, and at Weeks 4,8,12, 16, 20 and 24 after randomisation) and a Follow-up period 
consisting of up to five trial visits (at Weeks 4, 12, 24, 36 and 48 post-treatment). The 36 and 48-weeks 
post-treatment visits will only be applicable to subjects included before amendment 11 to the protocol 
was approved by the national authorities.  Participating subjects will be encouraged to contact the clinic 
between visits if they experience AEs or have any concerns. 
Subjects completing the 24-week Double-blind treatment period will enter a 24-week or 48-week Follow-
up period and will receive treatment with inhaled molgramostim (300 µg) administered once daily in an 
intermittent regimen (12 or 24) cycles of seven days molgramostim, seven days off).  
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 during the Double-blind treatment period will continue double-
blind trial treatment. Treatment with molgramostim in the Follow-up period should be discontinued in 
case of disease worsening and/or safety concerns. 
After completion of both the Double-blind and Follow-up trial periods, subjects who require further 
treatment will be offered treatment with molgramostim in a Compassionate Use Programme, where 
national regulations so allow. 
INVESTIGATIONAL MEDICINAL PRODUCT: 
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) 
 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 6 of 83 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
NUMBER OF SUBJECTS: 
90 subjects (30 in each treatment group) are intended to be randomized.  
The sample size calculation for the primary endpoint was based on data in an earlier trial, where the 
mean (and standard deviation) (A-a)DO2 were 31.3 (7.4) before treatment and 12.9 (7.6) after treatment 
(all measured in mmHg). It was also based on previous assumptions about how the trial would be 
analysed (notably, to combine the two active doses together for the primary analysis). The sample size 
calculation based on an unpaired t-test of mean difference between the two active arms (combined) vs. 
placebo, using a significance level of 0.01 and a power of 90% and a delta of 10 mmH, resulted in a 
required number of 42 subjects, 14 in each treatment arm.  
Based on an evaluation of variability and plausible effect sizes for the key secondary endpoints, the 
sample size is increased to 90 subjects (30 patients in each treatment arm), to increase the power to 
identify statistically significant treatment effects also on one or more of the key secondary endpoints. 
A fully blinded sample size re-estimation procedure will be carried out in January 2018 for the key 
secondary endpoints to assess the standard deviations of the 6 Minute Walk Distance (6MWD) and the 
St. George’s Respiratory Questionnaire (SGRQ), as well as the overall WLL event rate. If the maximum 
of these sample size calculations comes to no more than 33 patients per group, then no change to the 
target sample size will be made.  Otherwise, the sample size will be increased to attain 90% power for at 
least 2 of the 3 key secondary endpoints, subject to the total trial size not exceeding 150 patients. 
NUMBER OF TRIAL CENTRES: 
An appropriate number of specialised sites in (including but not limited to) Europe (United Kingdom, 
Denmark, Germany, Italy, France, Greece, Switzerland, Spain, Slovakia, Poland, Portugal, Romania 
and Netherlands), Turkey, Russia, Israel, Japan, South Korea, Australia, and the United States, will be 
included. 
 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 7 of 83 
MAIN INCLUSION AND EXCLUSION CRITERIA:  
Inclusion Criteria: 
• 
aPAP diagnosed by CT, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by increased 
GM-CSF autoantibodies in serum 
• 
Stable or progressive aPAP (i.e. absolute VC not improved by more than 5% and/or DLCO not 
improved by more than 10% - assessed from medical records) during a minimum period of two 
months prior to the Baseline visit  
• 
PaO2 <75 mmHg/<10 kPa at rest, OR desaturation of >4 percentage points on the 6 Minute 
Walk Test (6MWT)  
• 
An (A-a)DO2 of minimum 25 mmHg/3.33 kPa  
• 
Female or male ≥18 years of age 
• 
Females who have been post-menopausal for >1 year or females of childbearing potential after 
a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with 
<1% failure rate such as combined hormonal contraception, progesterone-only hormonal 
contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomised partner, sexual abstinence), during and until 30 days after last dose of 
trial treatment. Females of childbearing potential must have a negative serum pregnancy test at 
Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit 2) and must 
not be lactating 
• 
Males agreeing to use condoms during and until 30 days after last dose of trial treatment, or 
males having a female partner who is using adequate contraception as described above 
• 
Willing and able to provide signed informed consent 
• 
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial 
procedures specified in the protocol as judged by the investigator 
 
Exclusion criteria: 
• 
Diagnosis of hereditary or secondary pulmonary alveolar proteinosis (PAP) 
• 
WLL within one month of Baseline  
• 
Treatment with GM-CSF within three months of Baseline 
• 
Treatment with rituximab within six months of Baseline 
• 
Treatment with plasmapheresis within three months of Baseline 
• 
Treatment with any investigational medicinal product within four weeks of Screening 
• 
Concomitant use of sputum modifying drugs such as carbocystein or ambroxol 
• 
History of allergic reactions to GM-CSF 
• 
Connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring 
treatment associated with significant immunosuppression, e.g. more than 10 mg/day systemic 
prednisolone  
• 
Previous experience of severe and unexplained side-effects during aerosol delivery of any kind 
of medicinal product 
• 
History of, or present, myeloproliferative disease or leukaemia 
• 
Known active infection (viral, bacterial, fungal or mycobacterial) 
• 
Apparent pre-existing concurrent pulmonary fibrosis 
• 
Any other serious medical condition which in the opinion of the investigator would make the 
subject unsuitable for the trial 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 8 of 83 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
ENDPOINTS:  
 
Endpoint assessments 
Lung function variables – will be assessed in accordance with American Thoracic Society/European 
Respiratory Society (ATS/ERS) Task Force: Standardisation of lung function testing  
CT – A blinded independent assessor will examine the scans and grade the individual subjects 
improvement as: Improved / Worsened / No change / Data missing – impossible to evaluate  
QoL score – St Georges Respiratory Questionnaire (SGRQ) and EuroQol-5D (EQ-5D-5L) 
Dyspnoea score – Borg CR10 Scale for dyspnoea (BDS)  
Cough scores – Cough Questions (CQ) 
6MWT– will be performed in accordance with ATS/ERS guidance 
Laboratory analyses – Central and local laboratory will be used for analysis. Analysis of anti-drug 
antibodies and neutralising antibodies to molgramostim, and anti-drug antibodies to polyethylene glycol 
(PEG) and recombinant human albumin (rHA during the trial period will be performed using Good 
Laboratory Practice (GLP)-validated methods 
 
Primary endpoint  
• 
Absolute change from baseline of (A-a)DO2  after 24-weeks treatment 
 
Key Secondary Endpoints: 
• 
Change from baseline in 6MWD after 24-weeks treatment 
• 
Change from baseline in SGRQ total score after 24-weeks treatment  
• 
Time to WLL during 24-weeks treatment  
• 
Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment discontinuation, 
including clinically significant changes in laboratory tests and electrocardiogram (ECG) 
variables, during 24-weeks treatment 
 
Further Secondary Endpoints: 
• 
Absolute change from baseline in VC (% predicted), DLCO (% predicted), FEV1 (% predicted), 
FVC (% predicted) and and relative change from baseline in PaO2 after 24-weeks treatment  
• 
Number of subjects with >5 mmHg/>0.67 kPa and number of subjects with 
>10 mmHg/>1.33 kPa improvement in (A-a)DO2 after 24-weeks treatment  
• 
Number of subjects with >5 percentage points and number of subjects with >10 percentage 
points improvement in VC (% predicted) after 24-weeks treatment 
• 
Number of subjects with >10 percentage points improvement in DLCO (% predicted) after 
24-weeks treatment  


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 9 of 83 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
• 
Number of subjects with >10 percentage points improvement in FEV1 (% predicted) and FVC (% 
predicted) after 24-weeks treatment  
• 
Number of subjects with >10% relative improvement in PaO2 after 24-weeks treatment 
• 
Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m or 
desaturation <4 percentage points on the 6MWT) after 24-weeks treatment  
• 
Change from baseline in dyspnoea score and cough scores after 24-weeks treatment 
• 
Number of subjects with improved CT score after 24-weeks treatment  
 
Exploratory Endpoints  
Double-blind treatment period 
• 
Absolute change from baseline of (A-a)DO2, VC (% predicted), DLCO (% predicted), FEV1 (% 
predicted), FVC (% predicted), and relative change from baseline of PaO2 after 4 and 12-weeks 
treatment 
• 
Time period during which the (A-a)DO2 level is maintained below Baseline –10mmHg  
• 
Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m or 
desaturation <4 percentage points on the 6MWT) after 4 and 12-weeks treatment  
• 
Time period during which the improvement in tolerance to exercise is maintained   
• 
Change from baseline in dyspnoea score and cough scores after 4 and 12-weeks treatment 
• 
Number of subjects with improved QoL (change of ≥4 units on the SGRQ/number of subjects 
with ‘no problems’ in EQ-5D-5L), after 4, 12, and 24-weeks treatment 
• 
Change in serum concentration of biomarkers: Krebs von den Lungen-6 (KL-6), 
Carcinoembryonic antigen (CEA), Surfactant Protein A (SP-A), Surfactant Protein B (SP-B) , 
Surfactant Protein C (SP-C), Surfactant Protein D (SP-D), Cytokeratin 19 Fragment (Cyfra 21-1) 
and Lactate Dehydrogenase (LDH) after 4, 12, and 24-weeks treatment  
• 
Levels of antibodies towards Granulocyte Macrophage Colony Stimulating Factor (anti-GM-
CSF) after 4, 12 and 24-weeks treatment 
• 
Change in serum concentration of GM-CSF post first dose of trial drug and after 4-weeks of 
treatment 
• 
Number of subjects in need for oxygen supplement therapy during 24-weeks treatment 
• 
The distribution of DSS at Screening and at Week 24  
• 
The percentage of subjects with DSS 1 or 2 at Screening and at Week 24 
 
Follow-up period 
• 
Number of subjects requiring WLL, or other treatment for aPAP and number of treatment 
courses required during 24-weeks or 48-weeks follow-up   
• 
Time to WLL, or other treatment for aPAP during 24-weeks or 48-weeks follow-up   


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 10 of 83 
Name of the Sponsor/Company: 
Savara ApS 
Trial Code:  
MOL-PAP-002 
Name of Investigational Medicinal Product: 
Molgramostim nebuliser solution 
EudraCT No.:  
2015-003878-33 
Development Phase of the Trial: 
II/III 
Trial under an IND:  
No 
• 
Absolute change from baseline in (A-a)DO2 and VC (% predicted), DLCO (% predicted), FEV1 
(% predicted) , FVC (% predicted), and and relative change from baseline of PaO2 after 12, 24, 
36 and 48-weeks follow-up 
• 
Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m or 
desaturation <4 percentage points on the 6MWT) after 12, 24, 36 and 48-weeks follow-up 
• 
Number of AEs, severe AEs, SAEs and ADRs , including clinically significant changes in 
laboratory tests and ECG variables, during 24-weeks or 48-weeks follow-up 
• 
Levels of anti-GM-CSF, after 12 and 24 weeks follow-up 
• 
The distribution of DSS after 24 and 48-weeks follow-up 
• 
The percentage of subjects with DSS 1 or 2 after 24 and 48-weeks follow-up 
STATISTICAL METHODS:  
The trial will be unblinded and primary analysis will be conducted after the 24 week Double-blind 
treatment period. 
The primary efficacy variable, (A-a)DO2, will be tested using an analysis of covariance (ANCOVA) 
model. This model will have change from baseline to Week 24 in (A-a)DO2 as the response variable, 
whilst treatment group and baseline (A-a)DO2 will be predictor variables.  The mean difference between 
each active dose and placebo in change from baseline of (A-a)DO2 will be estimated, along with its 95% 
confidence interval (CI) and associated statistical significance test. 
The key secondary endpoints of change from baseline in 6MWD and in SGRQ will be analysed using 
the same ANCOVA model as for (A-a)DO2. Time to WLL will be analysed by logrank test.   
Comparisons (for the primary and key secondary endpoints) will be carried out as follows. The first will 
be of once daily dosing vs. placebo, and the second will be of intermittent dosing vs. placebo. These 
comparisons will be made in sequence: the once daily dosing group will first be compared with placebo 
for the primary endpoint and, if significant at P<0.05, then the 3 key secondary endpoints will be tested 
at an overall 5% significance level using the Hochberg procedure. If the test is significant for all of the 
key secondary endpoints, then the hierarchical testing will proceed with comparing intermittent dosing 
vs. placebo for the primary, and then the key secondary, endpoints in the same manner as for once daily 
dosing vs. Placebo. 
Subjects who withdraw early will have (A-a)DO2 measurement values imputed by multiple imputation 
used as their endpoint. Sensitivity analyses will be described in the Statistical Analysis Plan (SAP).   
Analyses pertaining to the Further Secondary Endpoints will be described in the SAP. 
Data from the Follow-up period will be reported descriptively in a separate Follow-up report. 
TRIAL PERIOD: 
The duration of trial participation for each subject is approximately 50 to 78 weeks: 
• 
Screening period for the subjects is 14 days (+/- 7 days)  
• 
Double-blind period up to 24 weeks (+/- 7 days) 
• 
Open-label period for 24 or 48 weeks (+/- 14 days) 
 
 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 11 of 83 
2 
TABLE OF CONTENTS 
Section 
Page 
1 
SYNOPSIS ............................................................................................................... 3 
2 
TABLE OF CONTENTS ......................................................................................... 11 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................. 15 
3.1 
List of Abbreviations ................................................................................... 15 
3.2 
Definition of Terms...................................................................................... 18 
4 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ........................ 19 
5 
INTRODUCTION .................................................................................................... 21 
5.1 
Background ................................................................................................. 21 
5.2 
Trial Rationale ............................................................................................. 24 
5.3 
Potential Risks and Benefits ...................................................................... 27 
6 
TRIAL OBJECTIVES ............................................................................................. 28 
6.1 
Primary Objective ........................................................................................ 28 
6.2 
Secondary Objectives ................................................................................. 28 
6.2.1 
Key Secondary objectives: .......................................................... 28 
6.2.2 
Further Secondary objectives: ..................................................... 28 
6.3 
Exploratory Objectives ............................................................................... 28 
6.3.1 
Double-blind treatment period ..................................................... 28 
6.3.2 
Follow-up period ......................................................................... 29 
7 
INVESTIGATIONAL PLAN .................................................................................... 30 
7.1 
Trial Design and Plan-Description ............................................................. 30 
7.2 
Trial Procedures .......................................................................................... 31 
7.2.1 
Schedule of Trial Events ............................................................. 31 
7.2.1.1 
Pre-Screening Visit Period .......................................................... 31 
7.2.1.2 
Screening (Visit 1) ....................................................................... 31 
7.2.1.3 
Baseline (Visit 2) ......................................................................... 32 
7.2.1.4 
Week 4 (Visit 3) ........................................................................... 33 
7.2.1.5 
Week 8 (Visit 4) ........................................................................... 34 
7.2.1.6 
Week 12 (Visit 5) ......................................................................... 34 
7.2.1.7 
Week 16 (Visit 6) ......................................................................... 35 
7.2.1.8 
Week 20 (Visit 7) ......................................................................... 35 
7.2.1.9 
Week 24 (Visit 8) ......................................................................... 35 
7.2.1.10 
4-Week Telephone Follow-up (Visit 9) ........................................ 36 
7.2.1.11 
12-Week Follow-up (Visit 10) ...................................................... 36 
7.2.1.12 
24-Week Follow-up (Visit 11) ...................................................... 37 
7.2.1.13 
36-Week Follow-up (Visit 12) ...................................................... 38 
7.2.1.14 
48-Week Follow-up (Visit 13) ...................................................... 38 
7.2.2 
Trial Flow Chart ........................................................................... 40 
7.3 
Trial Period .................................................................................................. 43 
7.4 
End of Trial .................................................................................................. 43 
8 
SELECTION OF TRIAL POPULATION ................................................................. 44 
8.1 
Number of Subjects .................................................................................... 44 
8.2 
Inclusion Criteria ......................................................................................... 44 
8.3 
Exclusion Criteria ........................................................................................ 44 
8.4 
Withdrawal of Subjects from Therapy or Assessment ............................. 45 
8.4.1 
Withdrawal from the Trial ............................................................ 45 
8.4.2 
Discontinuation of Double-Blind Treatment ................................. 45 
8.5 
Premature Termination of the Trial ............................................................ 46 
9 
TREATMENT OF SUBJECTS ............................................................................... 47 


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9.1 
Investigational Medicinal Products ............................................................ 47 
9.1.1 
Treatment Regimens................................................................... 47 
9.1.2 
Identity of Investigational Medicinal Products .............................. 47 
9.1.3 
Manufacturing, Packaging and Labelling of Investigational 
Medicinal Product ....................................................................... 47 
9.1.4 
Storage and Handling of Investigational Medicinal Product ......... 47 
9.1.5 
Investigational Medicinal Product Administration and Training .... 48 
9.2 
Method of Assigning Subjects to Treatment Groups ............................... 48 
9.2.1 
Randomisation ............................................................................ 48 
9.2.2 
Subject Identification List ............................................................ 48 
9.3 
Blinding........................................................................................................ 48 
9.3.1 
Breaking the Randomisation Code .............................................. 49 
9.4 
Prior and Concomitant Therapy ................................................................. 49 
9.5 
Treatment Compliance ................................................................................ 50 
9.6 
Drug Accountability .................................................................................... 50 
9.7 
Post-Trial Treatment ................................................................................... 50 
10 
TRIAL ASSESSMENTS ......................................................................................... 51 
10.1 Efficacy Assessments ................................................................................ 51 
10.1.1 
Blood Gas Analysis ..................................................................... 51 
10.1.2 
Lung Function Tests ................................................................... 51 
10.1.3 
Tolerance to Exercise ................................................................. 51 
10.1.4 
Dyspnoea Score ......................................................................... 52 
10.1.5 
Cough Scores ............................................................................. 52 
10.1.6 
CT Scoring .................................................................................. 52 
10.1.7 
Quality of Life Score .................................................................... 52 
10.1.8 
Disease Severity Score ............................................................... 53 
10.1.9 
Biomarkers in Serum................................................................... 53 
10.1.9.1 
GM-CSF and Anti-Drug Antibodies ............................................. 53 
10.1.9.2 
Other Biomarkers ........................................................................ 53 
10.2 Primary, Secondary, and Exploratory Endpoints ..................................... 54 
10.2.1 
Primary Endpoint: ....................................................................... 54 
10.2.2 
Secondary Endpoints: ................................................................. 54 
10.2.2.1 
Key Secondary Endpoints ........................................................... 54 
10.2.2.2 
Further Secondary Endpoints: ..................................................... 54 
10.2.3 
Exploratory Endpoints ................................................................. 55 
10.2.3.1 
Double-Blind Treatment Period ................................................... 55 
10.2.3.2 
Follow-up period ......................................................................... 55 
10.3 Demographic and Other Baseline Characteristics.................................... 56 
10.3.1 
Demographic and Baseline Data ................................................. 56 
10.3.2 
Medical History ........................................................................... 56 
10.3.3 
Recording of Prior and Concomitant Medication/Therapy ........... 56 
10.3.3.1 
Whole Lung Lavage .................................................................... 56 
10.3.3.2 
Oxygen Supplementation ............................................................ 57 
10.4 Safety Assessments ................................................................................... 57 
10.4.1 
Safety Variables .......................................................................... 57 
10.4.2 
Adverse Events ........................................................................... 57 
10.4.3 
Physical Examination .................................................................. 57 
10.4.4 
Vital Signs ................................................................................... 57 
10.4.5 
Electrocardiogram ....................................................................... 58 
10.4.6 
Laboratory Safety Assessments .................................................. 58 
10.5 Pregnancy Test ........................................................................................... 58 
10.6 Appropriateness of Measurements ............................................................ 58 
10.7 Handling of Laboratory Samples and Total Blood Volume ...................... 59 


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11 
SAFETY ................................................................................................................. 60 
11.1 Definitions ................................................................................................... 60 
11.1.1 
Adverse Event............................................................................. 60 
11.1.2 
Adverse Drug Reaction ............................................................... 60 
11.1.3 
Unexpected Adverse Reaction .................................................... 60 
11.1.4 
Serious Adverse Event ................................................................ 60 
11.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) .................. 61 
11.3 Reporting of Adverse Events ..................................................................... 61 
11.4 Reporting of Serious Adverse Events ....................................................... 63 
11.5 SUSAR Reporting Procedure ..................................................................... 64 
11.6 Adverse Events of Special Interest ............................................................ 64 
11.7 Precautions/Overdose ................................................................................ 64 
11.8 Pregnancy .................................................................................................... 65 
11.9 Data Safety Monitoring Board .................................................................... 65 
11.10 Safety Management Plan ............................................................................ 65 
12 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................ 67 
12.1 Statistical and Analytical Plans .................................................................. 67 
12.1.1 
Data Sets to be Analysed ............................................................ 67 
12.1.2 
Definitions ................................................................................... 67 
12.1.3 
Statistical Issues ......................................................................... 67 
12.1.4 
Summary Statistics ..................................................................... 68 
12.1.5 
Primary Efficacy Analysis ............................................................ 68 
12.1.6 
Key Secondary Efficacy Analyses ............................................... 69 
12.1.7 
Further Secondary Efficacy Analyses .......................................... 69 
12.1.8 
Exploratory Efficacy Analyses ..................................................... 70 
12.1.9 
Demographic and Other Baseline Characteristics ....................... 71 
12.1.10 
Exposure to Treatment ................................................................ 71 
12.1.11 
Concomitant Treatment ............................................................... 71 
12.1.12 
Adverse Events ........................................................................... 71 
12.1.13 
Other Safety Assessments .......................................................... 71 
12.2 Determination of Sample Size .................................................................... 72 
12.3 Procedures for Reporting any Deviation(s) from the Original Statistical 
Analysis Plan ............................................................................................... 74 
12.4 Interim Analysis .......................................................................................... 74 
13 
INVESTIGATOR/SPONSOR RESPONSIBILITIES ................................................ 75 
13.1 Ethics ........................................................................................................... 75 
13.1.1 
Independent Ethics Committee (IEC) / Institutional Review board 
(IRB) ........................................................................................... 75 
13.1.2 
Ethical Conduct of the Trial ......................................................... 75 
13.1.3 
Subject Information and Consent ................................................ 75 
13.2 Subject Records and Source Data ............................................................. 75 
13.3 Access to Source Data and Documentation.............................................. 76 
13.4 Monitoring ................................................................................................... 76 
13.5 Data Management ....................................................................................... 76 
13.6 Quality Assurance and Audit ..................................................................... 77 
13.7 Record Retention ........................................................................................ 77 
13.8 Protocol Deviations..................................................................................... 77 
13.9 Insurance ..................................................................................................... 77 
13.10 Report and Publication ............................................................................... 77 
14 
REFERENCE LIST ................................................................................................ 79 
15 
APPENDICES ........................................................................................................ 83 
 
 


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LIST OF TABLES 
Table 1 
Trial Flow Chart .................................................................................................. 40 
Table 2 
Laboratory Safety Parameters ............................................................................ 58 
Table 3 
Two Group T-Test of Equal Means (Unequal n's) ............................................... 73 
 
LIST OF FIGURES 
Figure 1 
Overall Trial Design ............................................................................................ 31 
 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
3.1 
List of Abbreviations 
6MWD 
6 Minute Walk Distance 
6MWT 
6 Minute Walk Test 
(A-a)DO2 
Alveolar-arterial Oxygen Difference 
ANCOVA 
Analysis of Covariance 
aPAP 
Autoimmune Pulmonary Alveolar Proteinosis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
anti-GM-CSF 
Antibodies towards Granulocyte Macrophage Colony Stimulating Factor 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
ATS 
American Thoracic Society  
AUC 
Area Under the Plasma Concentration vs Time Curve  
BAL 
Broncho-alveolar Lavage 
BALF 
Broncho Alveolar Lavage Fluid 
BALT 
Bronchi-associated Lymphoid Tissue 
b.i.d 
BDS 
Bis in die (twice daily) 
Borg CR10 Scale for Dyspnoea 
CA 
Competent Authority 
CEA 
Carcinoembryonic Antigen 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
CQ 
Cough Questions 
CT 
Computer Tomography 
CTR 
Clinical Trial Report 
Cyfra 21-1 
Cytokeratin 19 Fragment  
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 


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eGFR 
Estimated Glomerular Filtration Rate 
EEA 
European Economic Area 
eow 
Every Other Week 
EQ-5D-5L 
EuroQol-5D 5 level quality of life questionnaire 
ERS 
European Respiratory Society 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FeNO 
Fraction Exhaled of Nitric Oxide 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
GMP 
Good Manufacturing Practice 
HR-CT 
High Resolution Computed Tomography 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IWRS 
Interactive Web Response System 
KL-6 
Krebs von den Lungen-6 
LDH 
Lactate Dehydrogenase 
LOCF 
Last Observation Carried Forward 
LSLV 
Last Subject Last Visit 
MA 
Marketing Authorisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRC 
Medical Research Council 
NOAEL 
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 
PaO2 
Arterial oxygen tension 
PAP 
Pulmonary Alveolar Proteinosis 
PAS 
Periodic Acid-Schiff  
PBPC 
Peripheral Blood Progenitor Cells 
PCV/EVF 
Packed Cell Volume (PCV) or Erythrocyte Volume Fraction (EVF) also 
known as hematocrit 
PPS 
Per Protocol Set 


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PT 
Preferred Term 
QoL 
Quality of Life 
rhGM-CSF 
Recombinant Human Granulocyte Macrophage Colony Stimulating Factor 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGRQ 
St Georges Respiratory Questionnaire 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SP-A, SP-B, 
SP-C, SP-D 
Surfactant Protein A, Surfactant Protein B, Surfactant Protein C, Surfactant 
Protein D 
SpO2 
Oxygen saturation (indirect measurement) 
TLC 
Total Lung Capacity 
tmax 
Time of maximum plasma concentration 
VC 
Vital Capacity 
WHO 
World Health Organisation 
WLL 
Whole Lung Lavage 
 


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3.2 
Definition of Terms 
(A-a)DO2 
Alveolar-arterial oxygen difference is a measure of the difference 
between the alveolar concentration (A) of oxygen and the arterial 
(a) concentration of oxygen 
DLCO  
Uptake of carbon monoxide from a single inspiration in a standard 
time. 
FEV1 
The volume of air that can forcibly be blown out in one second, 
after full inspiration. 
FVC 
The maximum amount of air a person can expel from the lungs 
after a maximal inhalation and during a forceful expiration. 
SpO2 
Indirect measurement of oxygen saturation using a finger probe, 
ear sensor or similar device. 
6MWD 
Distance in meters walked during the 6MWT. 
6MWT 
Test used to measure the distance that a subject can walk quickly 
on a flat hard surface in a period of 6 minutes (at an individually 
predetermined oxygen supplementation). 
VC 
The maximum amount of air a person can expel from the lungs 
after a maximum inhalation. 
 
 
 


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4 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
COORDINATING PRINCIPAL INVESTIGATOR 
Name:  
Cliff Morgan, MD 
 
 
Address:  Dept. of Intensive Care Unit 
 
Royal Brompton Hospital 
 
London SW3 6NP, United Kingdom  
 
Phone: 
+44 (0)20 7351 85 26 
E-mail:  
c.morgan@rbht.nhs.uk 
 
PARTICIPATING COUNTRIES: 
Countries including but not limited to Europe (United Kingdom, Denmark, Germany, Italy, France, 
Greece, Switzerland, Spain, Slovakia, Poland, Portugal, Romania and Netherlands), Turkey, 
Russia, Israel, Japan, South Korea, Australia and the United States. 
 
SPONSOR’S TRIAL DIRECTOR 
Name: 
Mikkel Walmar 
Address: Savara ApS 
 
Slotsmarken 17, 2.tv. 
 
2970 Hørsholm, Denmark 
Phone: 
+45 30 16 79 06 
E-mail: 
Mikkel.Walmar@Savarapharma.com 
SPONSOR’S MEDICAL EXPERT 
Name: 
Cecilia Ganslandt,  
Address: Savara ApS 
 
Slotsmarken 17, 2. tv. 
 
2970 Hørsholm, Denmark 
Phone: 
+45 7930 1416 
E-mail: 
cega@savarapharma.com 
CONTRACT RESEARCH ORGANISATION 
(CRO)  
Name: 
TFS Trial Form Support AB 
Visiting:  
Ruben Rausings gata 11A 
Address: Box 165 
 
SE-221 00 Lund, Sweden 
Phone: 
+46 (0)46 280 18 00 
Fax: 
+46 (0)46 280 18 01 
CRO PROJECT LEADER 
Name: 
Kit Madsen 
Address:  TFS Trial Form Support AB 
 
Box 165 
 
SE-221 00 Lund, Sweden 
 
Phone: 
+46 (0)46 280 18 62 
Fax: 
+46 (0)46 280 18 01 
E-mail: 
kit.madsen@tfscro.com 
BIOSTATISTICIAN 
Name: 
Jacob Råstam 
Address: TFS Trial Form Support AB 
 
Box 165 
 
SE-221 00 Lund, Sweden 
Phone: 
+46 (0)46 280 19 11 
E-mail:  
Jacob.Rastam@tfscro.com 
DRUG SAFETY OFFICER 
Name: 
Chris deCornet 
Address: Premier Research 
 
1st Floor, Rubra 2,  
 
Mulberry Business Park 
 
Wokingham, RG41 2GY, UK 
Phone:  
+44 118 936 4057 
E-mail: 
Chris.deCornet@premier-
research.com 
Contact  Details For Safety Reporting: 
Fax : +421 2 68203713 
E-mail: savarasafety@premier-research.com 


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PROTOCOL AUTHORS 
PROJECT DIRECTOR 
Name: 
Inge Tarnow 
Address: Savara ApS 
 
Slotsmarken 17, 2.tv. 
 
2970 Hørsholm, Denmark 
Phone: 
+45 20 48 34 30 
E-MAIL:     INTA@SAVARAPHARMA.COM 
 
 
MEDICAL WRITER 
Name: 
Nina Downes BSc (hons), FICR 
Address: Diamond Clinical Ltd 
 
3, Manor Courtyard 
 
Hughenden Avenue 
 
High Wycombe 
 
HP13 5RE, United Kingdom 
Phone:  
+44 (0)1494 566000 
E-mail:  nina.downes@diamondclinical.co.uk 
BIOSTATISTICIAN 
Name: 
Simon Day PhD, CStat 
Address: Clinical Trials Consulting and 
Training Ltd 
 
53, Portway 
 
North Marston 
 
Buckinghamshire 
 
MK18 3PL, United Kingdom 
Phone:  
+44 (0)1296 670776 
E-MAIL:      SIMON.DAY@CTCT-LTD.CO.UK 
 


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5 
INTRODUCTION 
5.1 
Background 
Pulmonary alveolar proteinosis (PAP)  
Pulmonary alveolar proteinosis (PAP) is a rare autoimmune disease with an estimated 
prevalence of 0.7 per 100,000 individuals [1]. It is characterised by high levels of 
autoantibodies against Granulocyte Macrophage Colony Stimulating Factor (auto anti-GM-
CSF) in alveoli and blood. The autoantibodies neutralise the normal biologic action of 
Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in the lungs [2]. 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 [1,3,4,5]. 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 [4,5]. 
The clinical presentation for PAP is variable and nonspecific with subacute symptoms of 
cough, dyspnoea, activity intolerance, occasional chest pain, and general malaise. Although 
PAP spans all ages, the typical adult PAP patient is aged between 41 and 51 years, and has 
a history of progressive dyspnoea and cough. Fifty percent of the patients have the above 
symptoms for less than seven months; another 25% of patients report having symptoms of 
two years or longer. Up to a third of the PAP cases may be minimally symptomatic [6]. 
Spirometry evaluation generally shows a restrictive pattern of ventilatory defect; the 
pulmonary diffusing capacity is reduced, out of proportion with the fall in vital capacity (VC) 
[7,8,9]. Arterial blood gas analysis shows mild to moderate hypoxaemia, with an elevated 
alveolar-arterial gradient and elevation in shunt fraction [6,8,10]. Analysis of Broncho 
Alveolar Lavage Fluid (BALF) may facilitate the diagnosis in clinically suspected cases. The 
BALF may have a ‘milky’ appearance, with large amounts of granular, acellular eosinophilic 
lipoproteinaceous material which is PAS positive [11,12].  
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 anesthesia 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 [13]. 
It is generally accepted today that once the disease is diagnosed its outcome appears to be 
much better compared to old, historical data. Overall disease specific survival rates exceed 
80% at five years [14,15].  
The most common cause of death is respiratory failure, typically occurring within the first 
year after diagnosis. Secondary pulmonary infections with bacteria and other organisms 
occasionally develop due to impaired macrophage function; these infections require 
extensive treatment. 
Investigational Medicinal Product (IMP) 
The IMP, Molgramostim nebuliser solution, has initially been developed by Serendex 
Pharmaceuticals A/S and is now further developed by Savara. 
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 


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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.  
 
Both molgramostim and sargramostim have been approved largely for use following 
chemotherapy and/or bone marrow transplantation to reduce the risks of neutropenia such 
as infection or graft rejection.  Molgramostim has been marketed in Europe and Australia as 
Leucomax®. However it was discontinued in 2002 for unknown reasons. Sargramostim, as 
Leukine®, is currently approved by the US Food and Drug Administration (FDA) for use in five 
indications at a dose of 250 µg/m2 per day using intravenous (IV) and/or subcutaneous 
administration depending on indication [16]. It is reported by the Marketing Authorisation 
(MA) holder that approximately 470,000 patients have received Leukine treatment in the 
post-marketing setting from the time of product launch in March 1991 through December 
2012 [17]. 
 
Pre-clinical studies in cynomolgus monkeys show that rhGM-CSF is deposited in the lungs 
after inhalation of molgramostim. The small fraction of the inhaled dose that is absorbed 
causes increases in stem cell proliferation, resulting in increased number of monocytes and 
neutrophils in the circulation; similar to the known effects after IV administration of 
molgramostim.  
 
Increases in incidence or severity of inflammatory cell infiltration, bronchi-associated 
lymphoid tissue (BALT) hyperplasia, pleural inflammation, and granulomas were similar 
across animals treated with 42 µg/kg/day and those treated with 127 µg/kg/day, likely due to 
anti-drug antibodies. These findings were not associated with any clinically impaired 
respiratory function and in animals sacrificed after a 4-week treatment free period, partial 
resolution of these findings was noted. Bronchopneumonia was found in one animal treated 
at each of the two dose levels. While a relationship to the test item cannot be excluded, 
these findings were likely a consequence of the bronchoalveolar lavage (BAL) procedure, 
which was conducted pre-treatment and at termination in every animal from this study. This 
is supported by the fact that no such lesions were detected in monkeys treated with 40 
µg/kg/day for 13 weeks in a study that did not include the BAL procedure. 
 
The No Observed Adverse Effect Level (NOAEL) was based on the clinical severity of the 
bronchopneumonia in the monkey treated with 127 μg/kg/day, as opposed to the incidental 
histopathologic finding of bronchopneumonia without clinical signs in the animal treated with 
42 μg/kg/day, and consequently was set at the 40 μg/kg/day nominal dose level. This was 
subsequently confirmed by inhalation toxicity studies of longer duration (up to 26 weeks), 
where no bronchopneumonia was reported and no additional dose-limiting toxicity was 
observed. 
Safety margins for local lung burden, that derive from the NOAEL at 40 μg/kg/day and that 
take into consideration the differences in lung deposition between monkeys and man, are 
around 7 for a clinical dose of 300 µg per subject. Safety margins based on a comparison of 
the plasma area under the concentration versus time curve (AUC) between monkeys (at the 
NOAEL) and volunteers from a phase I clinical trial are around 8 for a clinical dose of 300 µg 
per subject. Further details are available in the Investigator’s Brochure (IB). 
 
The first clinical study with molgramostim nebuliser solution has recently been completed 
(MOL-001). This was a phase I study to investigate the effects of molgramostim nebuliser 
solution in healthy adult subjects. The study was a randomised, double-blind, placebo-
controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study 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 


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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 study. GM-CSF was not measurable in serum before 
study drug administration. In the SAD part, GM-CSF was absorbed into systemic circulation 
with 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 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 halflife of 
approximately 4 hours where GM-CSF levels returned to 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). Additionally, inhalation 
of molgramostim nebuliser solution resulted in increases in exhaled fraction of nitric oxide 
(FeNO) compared with placebo. 
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 were 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 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 Investigator’s Brochure (IB). 
 
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 [2].  
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 


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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 [18]. A reduction of 12.6 mmHg at 
rest (p=0.00003) and 20 mmHg at exercise from 12 patients was reported in another trial [19] 
and a recent trial [20] reported a mean decrease of 17.4 mmHg (p=0.031). Patients also 
experienced improvement in dyspnoea (BDS), 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 (FEV), 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 [21]. All five patients were 
able to discontinue supplemental oxygen. The results from the performed studies indicates 
an improvement that remains present for more than one year after treatment has been 
discontinued [18,19]. 
Molgramostim nebuliser solution has not, as yet, been used in aPAP in the clinical setting. 
However, data are available from eight aPAP patients in which molgramostim products other 
than molgramostim nebuliser solution have been administered via inhalation [22, 23, 24, 25]. 
The treatment duration for all patients was 24 weeks or more. Three different treatment 
regimens 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 [22]. In another trial a decrease in (A-a)DO2 by more than 10 mmHg was reported in 
two out of four patients, improved 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 [23]. 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 [25].  
More details about the clinical studies and case reports using inhaled rhGM-CSF are 
available in the IB. 
This is the first trial sponsored by Savara ApS in which the IMP (molgramostim nebuliser 
solution) is administered to PAP patients.  
5.2 
Trial Rationale 
Today’s standard of care, WLL, does not correct the primary defect in aPAP but provides 
symptomatic benefit to many patients. Whole Lung Lavage is complex to perform, requires 
prolonged general anaesthesia, is associated with morbidities. In addition, a single WLL is 
not effective in all patients. Consequently, there is a need for more effective and less 
invasive therapies for PAP patients [2].  
As outlined above, there is a growing body of evidence indicating that rhGM-CSF 
(molgramostim and sargramostim) may have a positive impact on lung function and 
morphology in aPAP patients.  
 
The current trial has been designed to investigate the efficacy and safety of a molgramostim 
formulation specifically developed for inhalation (molgramostim nebuliser solution) in aPAP 
patients. The trial design is a randomised, double-blind, parallel group comparison of inhaled 
molgramostim with placebo. The trial consists of a Double-blind treatment period of up to 
24 weeks to determine the comparative efficacy and safety of molgramostim. After the 


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Double-blind treatment period, patients will enter a post treatment Follow–up period of up to 
48 weeks to investigate long term outcomes following double-blind treatment.   
 
The randomised, double-blind, placebo-controlled, parallel-group trial design is a scientifically 
robust comparative design. The use of a placebo arm controls for the natural course of 
disease and allows the trial to be powered for statistical significance despite the limited 
number of patients available.  
 
The primary endpoint is (A-a)DO2, 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 2 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 [18]. 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, and thus a surrogate marker for clinical effects, 
the key secondary endpoints focus on important clinical outcomes such as the need for WLL 
and the effect of treatment on exercise capacity, respiratory symptoms and quality of life. In 
order to ensure robust effects on the key secondary endpoints the sample size was further 
increased. 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 [26]. 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 Walk Distance (6MWD) 
and the total score on SGRQ were chosen as key secondary endpoints, although data on 
these endpoints in aPAP are still limited. In addition, pulmonary function and disease severity 
based on HR-CT scoring will assessed as secondary endpoints.  
 
The patient population to be included in the current trial will be patients with aPAP, which 
accounts for over 90% of PAP cases. Patients with congenital and secondary PAP will not be 
included. Congenital PAP is often associated with a receptor defect so these patients would 
be unlikely to benefit from rhGM-CSF treatment and treating the underlying cause of 
secondary PAP is usually sufficient to resolve the disease. Diagnosis of PAP will be by either 
high-resolution computer tomography (HR-CT), by open or transbronchial lung biopsy, or by 
broncho alveolar lavage (BAL) in accordance with current clinical practice. Increased serum 
anti-GM-CSF will be required for confirmation of the autoimmune disease type. Patients with 
aPAP confirmed to be stable or progressive during a period of at least two months prior to 
Baseline will be eligible for treatment.  Patients whose condition is spontaneously improving 
(defined as absolute VC improved by more than 5% and/or DLCO improved by more than 
10%) during a period of at least two months prior to Baseline will be excluded.  
 
The sample size calculation for the primary endpoint required a total of 42 subjects (14 in 
each treatment group) to be randomised. It was also based on previous assumptions about 
how the trial would be analysed (notably, to combine the two active doses together for the 
primary analysis). In order to power the study also to have potential to show effects on the 
key secondary endpoints, additional sample size calculations were conducted and the 
sample size was set at 90 subjects. Because of the limited data available, a fully blinded 
sample size re-estimation procedure will be carried out to assess the standard deviations of 
both the 6MWD and the SGRQ score, as well as the overall WLL event rate, when 
approximately 50 subjects will have completed 24-weeks of treatment.   


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Trial Code: MOL-PAP-002 
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The published rhGM-CSF inhalation studies (mainly sargramostim) in aPAP have utilised 
many different doses, dosing schedules and nebulisers. Doses used include 150 µg 
rhGM-CSF daily, 125 µg twice daily (b.i.d), 250 µg daily, and 500 µg b.i.d. [19, 20, 21, 22, 
23]. Most studies have employed intermittent treatment, most commonly treatment every 
other week (eow), or four days on, four days off treatment. Cyclic dosing with seven days 
on/seven days off was introduced in a phase 1 clinical inhalation trial in oncology [28]. The 
main reason for this cyclic dosing schedule was to reduce potential pulmonary toxicity and 
damage to local tissues. Another reason was that data from granulocyte-colony stimulating 
factor (G-CSF) treatment had shown a peak increase in peripheral blood progenitor cells 
(PBPC) on Days 4-6 of treatment, with a decrease on Day 7. Subsequently, studies in PAP 
adopted this or similar cyclic dosing schedules. Dosing schedules used in published 
inhalation studies include treatment eow for 24 weeks, high and low dose cycles with 
treatment eow for 24 weeks, four treatment days followed by four rest days for six months or 
more [21], more than eight months with two weeks on/two weeks off treatment, and eow for 
up to 32 weeks (up to 64 weeks in a single patient) [18,19,21,29,30].  
 
Due to the wide range of dose regimens used, two different dose regimens of molgramostim 
will be investigated in the current trial. One regimen will be continuous administration of 
molgramostim 300 µg once daily for 24 weeks and the other regimen will be intermittent 
administration (12 cycles of seven days molgramostim 300 µg, seven days placebo; both 
administered once daily). The placebo group will receive continuous daily treatment. Most 
studies have employed a treatment duration of at least 24 weeks. The time to maximum 
response with respect to gas exchange has been found to be 24 weeks and a lag time of 
4-12 weeks until efficacy is seen has been reported [1,19]. Therefore, the proposed 
treatment duration of 24 weeks is expected to be sufficient to obtain optimal responses. 
 
The dose estimation for molgramostim is mainly based on the two largest studies [18, 19], 
which were conducted with sargramostim (only limited data are available for molgramostim). 
Both studies reported the percentage of responders in terms of improvement of at least 
10-12 mmHg in (A-a)DO2. The percentage of responders was 62% with a daily dose of 250 
µg for 12 weeks, followed by 125 µg for 12 weeks [18] and >90% with a daily dose of 500 µg 
[19]. The responder rates were supported by the changes from baseline in gas exchange 
and pulmonary function parameters. There were no signs of dose-related toxicity in these 
studies.  
 
Based on these data with sargramostim, possible differences in biological activity and the 
nebuliser used must be taken into account when selecting an appropriate dose of 
molgramostim. In vitro data indicated a potency difference between the two compounds of 
0.6-0.8 [31, 32], thus a dose of 300 µg molgramostim has been chosen. This dose 
approximately corresponds to the higher, more effective dose of 500 µg sargramostim. The 
PARI eFlow nebuliser system which has been found to be a suitable device to administer the 
molgramostim will be used. Further details are available in the IB. 
 
After completion of the double-blind treatment period, subjects will be assigned to an open-
label treatment Follow-up period of 24-weeks or 48-weeks to collect long term outcomes 
following rhGM-CSF treatment. All subjects who complete the 24-week Double-blind 
treatment period (regardless of whether they completed trial treatment or discontinued trial 
treatment prematurely) will enter the open-label period so that as much information as 
possible can be collected regarding the use of molgramostim in this rare disease. During the 
open-label Follow-up period subjects will be treated with molgramostim 300 µg daily in an 
intermittent regimen of 7 days on- and 7 days off-treatment. The data from the open-label 
Follow-up period will be analysed descriptively and reported separately.  


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Trial Code: MOL-PAP-002 
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5.3 
Potential Risks and Benefits 
Currently, no evidence-based curative treatment exists for aPAP. Successive WLL 
procedures remain the standard treatment without a targeted pathophysiological 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 [14, 33].  
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 [24, 26]. 
Patients with aPAP have been treated with up to 500 µg of inhaled rhGM-CSF for up to a 
year [21, 30, 34, 35]. There have been no reports of chronic toxic effects [19].  
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 IV administration of molgramostim. No severe, serious or dose-limiting 
AEs were observed in the first clinical study in humans (MOL-001). The most common AE 
was cough, which was reported at a similar incidence for the 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.  
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 double-blind trial treatment should be 
discontinued if significant worsening occurs. If there is significant systemic exposure, 
haematologic findings such as leucocytosis and neutrophilia may occur. Therefore, 
laboratory safety monitoring will be conducted during the Double-blind treatment period. As 
non-clinical data on similar products 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 prior to dosing, at monthly intervals during the 
Double-blind treatment period and the open-label treatment Follow-up period. 
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. In the current trial two thirds of the subjects will receive active drug and 
one third will receive placebo. Rescue treatment with WLL will be available for all subjects 
who experience any unacceptable lack of response or disease progression during the trial. 
Subjects requiring WLL during the Double-blind treatment period will continue trial treatment.  
 
 


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6 
TRIAL OBJECTIVES 
6.1 
Primary Objective 
The primary objective is: 
• 
To compare efficacy of inhaled molgramostim on the Alveolar-arterial oxygen 
difference ((A-a)DO2) with placebo after 24-weeks treatment 
6.2 
Secondary Objectives 
6.2.1 Key Secondary objectives: 
• 
To compare efficacy of inhaled molgramostim on tolerance to exercise with placebo 
after 24-weeks of treatment 
• 
To compare efficacy of inhaled molgramostim on respiratory disease-related quality 
of life with placebo after 24-weeks of treatment 
• 
To compare efficacy of inhaled molgramostim based on time to Whole Lung Lavage 
(WLL) with placebo after 24-weeks treatment 
• 
To compare safety of inhaled molgramostim with placebo in terms of reported 
adverse events (AEs), serious adverse events (SAEs), adverse drug reactions 
(ADRs), severe AEs and withdrawals due to AEs during 24-weeks treatment. 
6.2.2 Further Secondary objectives: 
• 
To compare efficacy of inhaled molgramostim on Vital Capacity (VC), Diffusion 
Capacity of the Lung for Carbon Monoxide (DLCO), Forced Expiratory Volume in one 
second (FEV1), Forced Vital Capacity (FVC) and Arterial oxygen tension (PaO2) with 
placebo after 24-weeks treatment 
• 
To compare efficacy of inhaled molgramostim on the categorical change of (A-a)DO2, 
VC, DLCO,  FEV1, and PaO2 with placebo after 24-weeks treatment  
• 
To compare efficacy of inhaled molgramostim on categorical change in tolerance to 
exercise with placebo after 24-weeks treatment 
• 
To compare efficacy of inhaled molgramostim on dyspnoea, and cough with placebo 
after 24-weeks treatment  
• 
To compare efficacy of inhaled molgramostim on disease severity by Computer 
Tomography (CT) scoring with placebo after 24-weeks treatment 
6.3 
Exploratory Objectives 
6.3.1 Double-blind treatment period 
• 
To compare efficacy of inhaled molgramostim with placebo on (A-a)DO2, VC, DLCO, 
FEV1, PaO2, and on tolerance to exercise after 4-weeks and 12-weeks treatment 
• 
To compare the duration of response of inhaled molgramostim with placebo in 
(A-a)DO2 and tolerance to exercise 
• 
To compare efficacy of inhaled molgramostim with placebo on dyspnoea and cough 
after 4-weeks, and 12-weeks treatment  
• 
To compare efficacy of inhaled molgramostim with placebo on Quality of Life (QoL) 
after 4-weeks, 12-weeks, and 24-weeks treatment  


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• 
To assess pharmacodynamic effects on selected biomarkers in serum after 4-weeks, 
12-weeks, and 24-weeks treatment of inhaled molgramostim or placebo  
• 
To assess effect of molgramostim on Granulocyte Macrophage Colony Stimulating 
Factor (GM-CSF) concentration in serum after the first dose and after 4-weeks 
treatment and to assess levels of  antibodies to GM-CSF after 4-weeks, 12-weeks 
and 24-weeks treatment with molgramostim or placebo  
• 
To assess the requirement for oxygen supplementation therapy during 24-weeks 
treatment with molgramostim or placebo 
• 
To assess the change in Disease Severity Score (DSS) from Screening to Week 24  
6.3.2 Follow-up period 
• 
To compare the requirement for and time to WLL, or other treatment for aPAP after 
24-weeks inhaled molgramostim or placebo during a 24-week or 48-week post-
treatment Follow-up period   
• 
To compare efficacy of 24-weeks inhaled molgramostim with placebo on (A-a)DO2, 
VC, DLCO, FEV1, PaO2, and on tolerance to exercise during a 24-week or 48-week 
post-treatment Follow-up period  
• 
To compare safety of inhaled molgramostim with placebo during a 24-week or 48-
week post-treatment Follow-up period in terms of reported AEs, severe AEs, SAEs, 
and ADRs 
• 
To assess levels of antibodies to GM-CSF at 12-weeks and 24-weeks post-treatment 
with molgramostim or placebo 
• 
To assess the change in DSS during a 24-week or 48-week post-treatment Follow-up 
period   


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7 
INVESTIGATIONAL PLAN 
7.1 
Trial Design and Plan-Description 
A Screening Visit will be conducted 14 days (±7 days) prior to the Baseline Visit to determine 
eligibility. Subjects with aPAP  confirmed to be stable or progressive during a period of at 
least two months prior to the Baseline Visit will be eligible for treatment. Subjects are not 
eligible for treatment if spontaneous remission has occured during this two-month period, 
defined as absolute VC improved by more than 5% and/or DLCO improved by more than 
10%.  
At the Baseline Visit, eligible subjects will be randomised to receive treatment for up to 24 
weeks with either: 
1) inhaled molgramostim (300 µg) administered once daily,  
2) inhaled molgramostim (300 µg) and matching placebo administered intermittently 
(12 cycles of seven days molgramostim, seven days placebo; both administered once 
daily) or  
3) inhaled placebo administered once daily.  
The trial will include two phases; a Double-blind treatment period consisting of up to eight  
trial visits (Screening, Baseline, and at Weeks 4, 8, 12, 16, 20 and 24 after randomisation) 
and an open-label treatment Follow-up period consisting of up to five trial visits (at Weeks 4, 
12, 24, 36 and 48 post-treatment). The 36 and 48-weeks post treatment visits are only 
applicable for subjects included before amendment 11 to the protocol was approved by the 
national authorities in the country where the subject originates from. 
Participating subjects will be encouraged to contact the clinic between visits if they 
experience AEs or have any concerns (Figure 1). 
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 during the Double-blind 
treatment period will continue double-blind trial treatment. All subjects completing the 24-
week Double-blind treatment period will enter a 24- or 48-weeks Follow-up period and will 
receive open-label treatment with inhaled molgramostim 300 µg daily for 7 days, followed by 
7 days off-treatment. This cycle will be repeated for 12 or 24 weeks depending on when the 
subject is enrolled in the trial. Open-label treatment in the last 24 weeks of the Follow-up 
period is not mandatory for subjects who have entered this period before amendment 11 was 
approved by the national authorities. 
After completion of both the Double-blind treatment and Follow-up trial periods, subjects who 
require further treatment will be offered treatment with molgramostim in a Compassionate 
Use Programme, where national regulations so allow.  
 
 
 
 
 
 


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Figure 1 
Overall Trial Design 
7.2 
Trial Procedures 
7.2.1 Schedule of Trial Events 
The trial assessments described in the sections below are presented in detail in Section 10.1 
(Efficacy assessments), Section 10.3 (Demographic data and Other Baseline characteristics) 
and Section 10.4 (Safety assessments). Recording and reporting of AEs are described in 
detail in Section 11. 
The timing of all trial events is shown in Table 1  in Section 7.2.2.  
7.2.1.1 Pre-Screening Visit Period 
Only applicable to trial sites that do not analyse anti-GM-CSF using a validated quantitative 
measurement as routine for diagnosis of aPAP and for sites who wish to schedule a CT prior 
to screening. 
TIME WINDOW:  
To be done at a time-point allowing test result availability at Screening or Baseline (Visit 1 or 
2). The procedure and timing will be described in a trial specific instruction. 
ACTIVITIES AND ASSESSMENTS:  
• 
Informed consent - Signed and dated by the subject and by the person who 
conducted the informed consent discussion will be collected prior to any trial related 
procedures described in this protocol (Section 13.1.3). 
• 
Anti-GM-CSF, if applicable (Section 10.1.9.1) 
• 
CT, if applicable (Section 10.1.6) 
7.2.1.2 Screening (Visit 1) 
ACTIVITIES AND ASSESSMENTS:  
At Screening (Visit 1), the following activities and assessments will be performed:  
• 
Informed consent (if not done during pre-screening visit period, Section 7.2.1.1) - 
Signed and dated by the subject and by the person who conducted the informed 
 
Prescreen 
≥2 months 
Double - blind Treatment 
24 weeks
Screening 
Day -14 
To confirm
stable or 
progressive 
disease
Baseline
Day 1 
Week 24
Day 180* 
Week 12 
Day 84* 
Week 8
Day 56* 
Molgramostim intermittent 
OR
In case of AEs of concern
4 - W 
F- up
28 Days
after V8 
12 - W
F- up
84 Days 
after V8 
24 - W
F - up
168 Days
after V8
Follow - Up
24 or 48 weeks
Molgramostim daily 
OR 
Placebo daily 
36 -W 
F- up 
252 Days
after V8 
48 - W 
F- up 
336 Days 
after V8 
V2 
V4 
V5 
V7
V9 
V10 
V11 
V12 
V1 
V13 
V3 
Week 4 
Day 28* 
V6 
V8 
Week 16
Day 112* 
Week 20 
Day 140* 
* Days after 
randomisation 
** 
** 
** Not applicable 
to all subjects 


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consent discussion will be collected prior to any trial related procedures described in 
this protocol (Section 13.1.3)  
• 
Eligibility criteria - Assessment of inclusion and exclusion criteria (Section 8.2 and 
Section 8.3) 
• 
Demographics and Baseline data (Section 10.3.1) 
• 
Medical history (Section 10.3.2) 
• 
Physical examination (Section 10.4.3) 
• 
Vital signs (Section 10.4.4) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Laboratory safety assessments (haematology and clinical chemistry) (Section 10.4.6) 
• 
Serum pregnancy test and instruction in contraceptive measures (Section 10.5) 
• 
DSS (Section 10.1.8) 
• 
Arrangement for trial drug administration training (Section 9.1.5) 
7.2.1.3 Baseline (Visit 2)  
TIME WINDOW:  
14 days (±7 days) after Screening (Visit 1) 
 
The CT scan can be done up to four weeks prior to Baseline (Visit 2) 
 
ACTIVITIES AND ASSESSMENTS:  
At Baseline (Visit 2), the following activities and assessments will be performed:  
• 
Eligibility criteria check– Fulfilment of inclusion and exclusion criteria will be confirmed 
(Section 8.2 and Section 8.3)  
• 
Prior and Concomitant medication (Section 10.3.3) 
• 
Urine and serum pregnancy test and evaluation of contraceptive measures (Section 
10.5) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section  10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
CT (Section 10.1.6 ).  
• 
QoL score (Section 10.1.7) 
• 
Electrocardiogram (ECG) (Section 10.4.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry) (Section 10.4.6) 


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• 
AEs (Section 10.4.2) 
• 
Randomisation to trial treatment (Section 9.2) 
• 
Samples for biomarkers, GM-CSF and anti-drug antibodies prior to administration of 
first dose of trial drug (Section 10.1.9)  
• 
Dispense trial drug (Section 9.1.4) 
• 
Administration of first dose of trial drug (Section 9.1.5)  
• 
Sample for GM-CSF two hours after completion of administration of first dose of trial 
drug (Section 10.1.9) 
• 
Subject Diary Card (Section 10.4.2) 
7.2.1.4 Week 4 (Visit 3)  
TIME WINDOW:  
28 days (±7 days) after Randomisation (Visit 2) 
 
ACTIVITIES AND ASSESSMENTS:  
At Week 4 (Visit 3), the following activities and assessments will be performed:  
• 
Concomitant medication (Section 10.3.3) 
• 
Physical examination (Section 10.4.3) 
• 
Vital signs (Section 10.4.4) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section  10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
QoL score (Section 10.1.7) 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry) (Section 10.4.6) 
• 
Biomarkers and GM-CSF prior to administration of trial drug in clinic (Section 10.1.9). 
• 
Anti-drug antibodies prior to administration of trial drug in clinic (Section 10.1.9 
• 
AEs (Section 10.4.2) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 
• 
Administration of trial drug at the site (Section 9.1.5) 
• 
Dispense trial drug (Section 9.1.4) 
• 
Sample for GM-CSF two hours after completion of administration of trial drug (Section 
10.1.9) 
 


Clinical Trial Protocol 
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Trial Code: MOL-PAP-002 
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Confidential 
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7.2.1.5 Week 8 (Visit 4)  
TIME WINDOW:  
56 days (±7 days) after Randomisation (Visit 2) 
 
ACTIVITIES AND ASSESSMENTS:  
At Week 8 (Visit 4), the following activities and assessments will be performed:  
• 
Concomitant medication (Section 10.3.3) 
• 
Lung function tests (Section 10.1.2) 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 10.4.6) 
• 
AEs (Section 10.4.2) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 
• 
Dispense trial drug (Section 9.1.4) 
7.2.1.6 Week 12 (Visit 5)  
TIME WINDOW:  
84 days (±7 days) after Randomisation (Visit 2) 
 
ACTIVITIES AND ASSESSMENTS:  
At Week 12 (Visit 5), the following activities and assessments will be performed:  
• 
Concomitant medication (Section 10.3.3) 
• 
Physical examination (Section 10.4.3) 
• 
Vital signs (Section 10.4.4) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section 10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
QoL score (Section 10.1.7) 
• 
ECG (Section 10.4.5) 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry) (Section 10.4.6) 
• 
Biomarkers and anti-drug antibodies prior to administration of trial drug in clinic 
(Section 10.1.9) 
• 
AEs (Section 10.4.2)  
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
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• 
Administration of trial drug at the site (Section 9.1.5) 
• 
Dispense trial drug (Section 9.1.4) 
7.2.1.7 Week 16 (Visit 6)  
TIME WINDOW:  
112 days (±7 days) after Randomisation (Visit 2) 
 
ACTIVITIES AND ASSESSMENTS:  
At Week 16 (Visit 6), the following activities and assessments will be performed:  
• 
Concomitant medication (Section 10.3.3) 
• 
Lung function tests (Section 10.1.2) 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 10.4.6) 
• 
AEs (Section 10.4.2) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 
• 
Dispense trial drug (Section 9.1.4) 
7.2.1.8 Week 20 (Visit 7)  
TIME WINDOW:  
140 days (±7 days) after Randomisation (Visit 2) 
 
ACTIVITIES AND ASSESSMENTS:  
At Week 20 (Visit 7), the following activities and assessments will be performed:  
• 
Concomitant medication (Section 10.3.3) 
• 
Lung function tests (Section 10.1.2) 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 10.4.6) 
• 
AEs (Section 10.4.2) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 
• 
Dispense trial drug (Section 9.1.4) 
7.2.1.9 Week 24 (Visit 8)  
TIME WINDOW:  
168 days (±7 days) after Randomisation (Visit 2) 
The CT scan can be performed seven days prior to or after Week 24 (Visit 8) 
 
ACTIVITIES AND ASSESSMENTS:  
At Week 24 (Visit 8), the following activities and assessments will be performed:  


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
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• 
Concomitant medication (Section 10.3.3) 
• 
Physical examination (Section 10.4.3) 
• 
Vital signs (Section 10.4.4) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section  10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
CT (Section 10.1.6)  
• 
QoL score (Section 10.1.7) 
• 
DSS (Section 10.1.8)  
• 
ECG (Section 10.4.5) 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 10.4.6) 
• 
Biomarkers and anti-drug antibodies prior to administration of trial drug in clinic 
(Section 10.1.9) 
• 
AEs (Section 10.4.2) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 
• 
Administration of trial drug at the site (Section 9.1.5) 
• 
Dispense trial drug (Section 9.1.4) 
7.2.1.10 4-Week Telephone Follow-up (Visit 9)  
TIME WINDOW:  
28 days (±3 days) after Week 24 (Visit 8). 
 
ACTIVITIES AND ASSESSMENTS:  
At 4-Week Telephone Follow-up (Visit 9), the following activities and assessments will be 
performed:  
• 
AEs (Section 10.4.2)  
• 
Medication/therapy for aPAP (Section 10.3.3) 
7.2.1.11 12-Week Follow-up (Visit 10)  
TIME WINDOW:  
84 days (±14 days) after Week 24 (Visit 8) 
 
ACTIVITIES AND ASSESSMENTS:  
At 12-week Follow-up (Visit 10), the following activities and assessments will be performed:  
• 
Medication/therapy for aPAP (Section 10.3.3) 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
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Confidential 
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• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section  10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
QoL score (Section 10.1.7) 
• 
AEs (Section 10.4.2) 
• 
Samples for anti-drug antibodies (Section 10.1.9) 
For subjects using molgramostim in the Follow-up period: 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 
10.4.6).  
• 
Administration of trial drug at the site (Section 9.1.5) 
• 
Subject Diary Card (Section 10.4.2)  
• 
Dispense trial drug (Section 9.1.4) 
• 
Treatment compliance (Section 9.5) 
7.2.1.12 24-Week Follow-up (Visit 11)  
TIME WINDOW:  
168 days (±14 days) after Week 24 (Visit 8) 
 
ACTIVITIES AND ASSESSMENTS:  
At 24-week Follow-up (Visit 11), the following activities and assessments will be performed:  
• 
Physical examination (Section 10.4.3) 
• 
Vital signs (Section 10.4.4) 
• 
Medication/therapy for aPAP (Section 10.3.3) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section  10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
QoL score (Section 10.1.7) 
• 
DSS (Section 10.1.8)  
• 
ECG (Section 10.4.5) 
• 
AEs (Section 10.4.2) 
• 
Samples for anti-drug antibodies (Section 10.1.9) 
For subjects using molgramostim in the Follow-up period: 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 38 of 83 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 
10.4.6).  
• 
Administration of trial drug at the site (Section 9.1.5).  
• 
Subject Diary Card (Section 10.4.2).  
• 
Dispense trial drug (Section 9.1.4).  
• 
Treatment compliance (Section 9.5) 
7.2.1.13 36-Week Follow-up (Visit 12)  
Visit 12 is not applicable to subjects where the informed consent was obtained after 
amendment 11 was approved by the national authorities. 
TIME WINDOW:  
252 days (±14 days) after Week 24 (Visit 8) 
 
ACTIVITIES AND ASSESSMENTS:  
At 36-week Follow-up (Visit 12), the following activities and assessments will be performed:  
• 
Medication/therapy for aPAP (Section 10.3.3) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3)  
• 
Dyspnoea score (Section 10.1.4) 
• 
AEs (Section 10.4.2) 
For subjects using molgramostim in the Follow-up period: 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry) (Section 10.4.6) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Dispense trial drug (Section 9.1.4) 
• 
Treatment compliance (Section 9.5) 
 
7.2.1.14 48-Week Follow-up (Visit 13)  
Visit 13 is not applicable to subjects where the informed consent was obtained after 
amendment 11 was approved by the national authorities. 
 
TIME WINDOW:  
336 days (±14 days) after Week 24 (Visit 8) 
ACTIVITIES AND ASSESSMENTS:  
At 48-week Follow-up (Visit 13), the following activities and assessments will be performed:  
• 
Physical examination (Section 10.4.3) 
• 
Vital signs (Section 10.4.4) 


Clinical Trial Protocol 
Sponsor: Savara ApS 
Version: 5.0 
 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No. 2015-003878-33 
Confidential 
Page 39 of 83 
• 
Medication/therapy for aPAP (Section 10.3.3) 
• 
(A-a)DO2 and PaO2 (Section 10.1.1)  
• 
Lung function tests (Section 10.1.2) 
• 
6MWT (Section 10.1.3) 
• 
Dyspnoea score (Section  10.1.4) 
• 
Cough scores (Section 10.1.5) 
• 
QoL score (Section 10.1.7) 
• 
DSS (Section 10.1.8) 
• 
ECG (Section 10.4.5)  
• 
AEs (Section 10.4.2) 
For subjects using molgramostim in the Follow-up period: 
• 
Serum pregnancy test (Section 10.5) 
• 
Laboratory safety assessments (haematology and clinical chemistry), (Section 10.4.6) 
• 
Subject Diary Card (Section 10.4.2) 
• 
Treatment compliance (Section 9.5) 
 


Clinical Trial Protocol  
Sponsor: Savara ApS 
Version: 5.0 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No.: 2015-003878-33 
Confidential 
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7.2.2 Trial Flow Chart 
Table 1 
Trial Flow Chart  
Visit number 
Visit 1  
Visit 2 
Visit 3   
Visit 4  
Visit 5  
Visit 6  
Visit 7  
Visit 8  
Visit 9  
Visit 10  
Visit 11  
Visit 12  
Visit 13 
 
Screen-
ing 
Baseline 
Week 4  
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
4-Week 
Tele-
phone F-
up 
 
12-Week  
F-up 
 
24-Week  
F-up 
 
36-Week  
F-upP 
 
48-Week 
F-upP 
Day 
 
14 days 
after 
Screen-
ing 
28 days 
after 
Randomi
sation 
56 days 
after 
Randomi
sation 
84 days 
after 
Randomi
sation 
112 days 
after 
Randomi
sation 
140 days 
after 
Randomi
sation 
168 days 
after 
Randomi
sation 
28 days 
after Visit 
8 
84 days 
after Visit 
8 
 
168 days 
after Visit 
8 
 
252 days 
after Visit 
8 
 
336 days 
after Visit 
8 
  
Window 
 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 3 Days 
± 14 Days 
± 14 Days 
± 14 Days 
± 14 Days 
Informed consent a 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X b 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
medication/therapy c 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Treatment for aPAP 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Pregnancy test and 
contraceptive check 
Xd 
X d 
X d 
X d 
X d 
X d 
X d 
X d 
 
X d 
X d 
X d 
X d 
Physical Exam 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Vital signs 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
(A-a) DO2, PaO2 e 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Lung function tests f 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
6MWT g 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Laboratory Safety 
Analyses h  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 


Clinical Trial Protocol  
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Visit number 
Visit 1  
Visit 2 
Visit 3   
Visit 4  
Visit 5  
Visit 6  
Visit 7  
Visit 8  
Visit 9  
Visit 10  
Visit 11  
Visit 12  
Visit 13 
 
Screen-
ing 
Baseline 
Week 4  
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
4-Week 
Tele-
phone F-
up 
 
12-Week  
F-up 
 
24-Week  
F-up 
 
36-Week  
F-upP 
 
48-Week 
F-upP 
Day 
 
14 days 
after 
Screen-
ing 
28 days 
after 
Randomi
sation 
56 days 
after 
Randomi
sation 
84 days 
after 
Randomi
sation 
112 days 
after 
Randomi
sation 
140 days 
after 
Randomi
sation 
168 days 
after 
Randomi
sation 
28 days 
after Visit 
8 
84 days 
after Visit 
8 
 
168 days 
after Visit 
8 
 
252 days 
after Visit 
8 
 
336 days 
after Visit 
8 
  
Window 
 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 7 Days 
± 3 Days 
± 14 Days 
± 14 Days 
± 14 Days 
± 14 Days 
ECG 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
GM-CSF i 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Anti-Drug 
antibodies 
Xa 
X j 
X j 
 
X j 
 
 
X j 
 
X j 
X j 
 
 
Biomarkersk 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
CT 
 
X l 
 
 
 
 
 
Xl 
 
 
 
 
 
DSS  
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Dyspnoea score m 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Cough scores 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
QoL score  
 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
Trial drug 
administration 
training  
X n 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Trial drug dosing in 
the clinic 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Diary Cardo 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Xq 
X 
X 
Dispense trial drug 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Xq 
X 
 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 


Clinical Trial Protocol  
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Version: 5.0 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
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Confidential 
Page 42 of 83 
 
a 
Only related to anti-GM-CSF. Anti-GM-CSF blood sampling to be done during pre-screening period at trial sites that do not perform anti-GM-CSF as routine for aPAP diagnosis. Only subjects 
without available data will have a sample taken before screening to confirm diagnosis. Anti-GM-CSF blood sampling should be done only after collection of informed consent at such trial sites. 
Informed consent also to be taken in sites who conduct CT before screening. 
b 
Re-check of eligibility criteria.  
c 
Prior medication/therapy is defined as medication/therapy administered prior to first dose of trial medication. All medication/therapy administered after first dose of trial medication is considered 
concomitant medication/therapy. 
d 
Serum pregnancy test at Screening (Visit 1), at dosing at Baseline (Visit 2) and at all subsequent visits during trial. A urine pregnancy test will also be performed at dosing at Baseline (Visit 2) in 
order to immediately confirm that the subject is not pregnant and meets the inclusion criterion. Pregnancy tests (urine or serum) must continue at monthly intervals during treatment with inhaled 
molgramostim.  Pregnancy tests at visit 10, 11, 12 and 13 for subjects who are not treated with inhaled molgramostim during the follow-up period are not mandatory. 
e 
Capillary sampling for blood gas analysis may be used instead of an arterial blood gas sample at Screening Visit 1, Visit 3, Visit 5 and all Follow-up Visits at sites that routinely use this method. 
Arterial sampling for blood gas is mandatory at Baseline (Visit 2) and Visit 8. 
f 
VC, DLCO, FEV1, and FVC (all % predicted).  
g 
The need for supplemental O2 during the procedure will be determined as part of the test at Screening or Baseline. The same O2 flow will be used at the subsequent tests in the trial. 
h 
Haematology and clinical chemistry. 
i 
Samples for GM-CSF to be collected prior to 1st dose of trial drug and two hours after completion of administration of 1st dose of trial drug at Baseline (Visit 2) and prior to dosing and two hours 
after dosing at Week 4 (Visit 3).  
j 
Samples for anti-drug antibodies to be collected prior to administration of trial drug. 
k 
Biomarkers to be analysed: KL-6, CEA, Cyfra 21-1, SP-A, SP-B, SP-C, SP-D, and LDH. 
l 
CT can be done 4 weeks prior to the baseline visit (informed consent needs to be collected if before screening visit) and 7 days before or after Visit 8. 
m 
Dyspnoea score (BDS) to be performed before the 6MWT and also immediately after the 6MWT. 
n 
The subject must be trained in the inhalation and medical device maintenance procedure prior to administration of first dose of trial drug. The time and place for this training will be agreed upon 
at the screening visit. 
o 
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 and answer questions regarding lung toxicity and 
known systemic effects in the diary card. 
p 
Visit 12 and visit 13 is only applicable to subjects who have signed the informed consent before amendment 11 to the protocol was approved by the local authorities. 
q 
Only applicable for subjects who have signed the informed consent before amendment 11 to the protocol was approved by the local authorities 


Clinical Trial Protocol  
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7.3 
Trial Period 
Expected timelines: 
The duration of trial participation for each subject is approximately 50 to 78 weeks: 
• 
Screening period for the subjects is 14 days (+/- 7 days)  
• 
Double-blind period up to 24 weeks (+/- 7 days) 
• 
Open-label period for 24 or 48 weeks (+/- 14 days) 
7.4 
End of Trial 
The last visit is either the 24-Week Follow-up (visit 11) or  48-Week Follow-up (Visit 13).  
The end of trial is defined as the last subject’s last visit (LSLV).  


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8 
SELECTION OF TRIAL POPULATION 
8.1 
Number of Subjects 
A total of 90 subjects are intended to be randomised. See Section 12.2 for calculation of 
sample size. 
8.2 
Inclusion Criteria 
The patients must meet all of the following criteria to be eligible to enter the trial: 
• 
aPAP diagnosed by CT, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by 
increased GM-CSF autoantibodies in serum 
• 
Stable or progressive aPAP (i.e. absolute VC not improved by more than 5% and/or 
DLCO not improved by more than 10% - assessed from medical records) during a 
minimum period of two months prior to the Baseline visit  
• 
PaO2 <75 mmHg/<10 kPa at rest, OR desaturation of >4 percentage points on the 
6MWT 
• 
An (A-a)DO2 of minimum 25 mmHg/3.33 kPa  
• 
Female or male ≥18 years of age 
• 
Females who have been post-menopausal for >1 year or females of childbearing 
potential after a confirmed menstrual period using a highly efficient method of 
contraception (i.e. a method with <1% failure rate such as  combined hormonal 
contraception, progesterone-only hormonal contraception, intrauterine device, 
intrauterine hormone- releasing system, bilateral tubal occlusion, vasectomised 
partner, sexual abstinence), during and until 30 days after last dose of trial treatment. 
Females of childbearing potential must have a negative serum pregnancy test at 
Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit 2) 
and must not be lactating 
• 
Males agreeing to use condoms during and until 30 days after last dose of trial 
treatment, or males having a female partner who is using adequate contraception as 
described above 
• 
Willing and able to provide signed informed consent 
• 
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures specified in the protocol as judged by the investigator 
8.3 
Exclusion Criteria 
Patients meeting any of the following criteria will not be permitted to enter the trial: 
• 
Diagnosis of hereditary or secondary PAP 
• 
WLL within one month of Baseline  
• 
Treatment with GM-CSF within three months of Baseline 
• 
Treatment with rituximab within six months of Baseline 
• 
Treatment with plasmapheresis within three months of Baseline 


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• 
Treatment with any investigational medicinal product within four weeks of Screening 
• 
Concomitant use of sputum modifying drugs such as carbocystein or ambroxol 
• 
History of allergic reactions to GM-CSF 
• 
Connective tissue disease, inflammatory bowel disease or other autoimmune disorder 
requiring treatment associated with significant immunosuppression, e.g. more than 10 
mg/day systemic prednisolone  
• 
Previous experience of severe and unexplained side-effects during aerosol delivery of 
any kind of medicinal product 
• 
History of, or present, myeloproliferative disease or leukaemia 
• 
Known active infection (viral, bacterial, fungal or mycobacterial) 
• 
Apparent pre-existing concurrent pulmonary fibrosis 
• 
Any other serious medical condition which in the opinion of the investigator would 
make the patient unsuitable for the trial 
8.4 
Withdrawal of Subjects from Therapy or Assessment 
8.4.1 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:  
• 
Screening failure 
• 
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 
electronic case report form (eCRF) (e.g. lost to Follow-up, consent withdrawn, incorrect 
enrolment, AEs, etc.). If a subject is withdrawn from the trial, the investigator should attempt 
to complete all required trial assessments (such as those at Week 24 if withdrawn during the 
Double-blind treatment period).  
All AEs should be followed-up according to Section 11.2.  
If a subject is withdrawn from the trial, all data collected until the time of withdrawal will be 
used in the analyses.  
Subjects who withdraw before randomisation will be considered screen failures. 
8.4.2 Discontinuation of Double-Blind Treatment 
Subjects may be discontinued from double-blind treatment and assessments at any time, if 
deemed necessary by the investigator.  
Potential reasons for discontinuation of double-blind treatment are:  
• 
Lack of efficacy/worsening of disease  
• 
Unacceptable AE 


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• 
Serious hypersensitivity reaction 
• 
Pregnancy 
Those who discontinue double-blind treatment will not automatically be withdrawn from the 
trial but will be encouraged to continue to follow the same visit schedule.  
For example: if double-blind treatment is discontinued at Week 8 (Visit 4) the subject will be 
encouraged to attend the remaining visits in the Double-blind treatment period (Weeks 12, 
16, 20 and 24) and continue into the Follow-up period. If the subject is reluctant to agree to 
4-weekly visits, the investigator should request attendance at Week 24 (Visit 8) as a 
minimum.  
The reason and date the subject is discontinued from double-blind treatment will be 
documented in the eCRF.  
Subjects who fulfil the criteria for rescue treatment will be scheduled for a WLL as described 
in Section 9.4. Subjects receiving a WLL should continue Double-blind treatment and attend 
the remaining visits in the Double-blind treatment period and then continue into the Follow-up 
period. 
8.5 
Premature Termination of the Trial 
The investigator or the sponsor may terminate this trial prematurely for any reasonable 
cause. The Independent Ethics Committees (IECs) and Competent Authorities (CAs) 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 
If the CA obtains information that raises doubts about the safety or scientific validity of the 
clinical trial, the CA can suspend or prohibit the trial. Before the CA 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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9 
TREATMENT OF SUBJECTS 
9.1 
Investigational Medicinal Products 
9.1.1 Treatment Regimens 
Subjects will be randomised to receive double-blind treatment for up to 24 weeks with either: 
• 
inhaled molgramostim (300 µg) administered once daily,  
• 
inhaled molgramostim (300 µg) and matching placebo administered intermittently (12 
cycles of seven days molgramostim followed by seven days placebo; both 
administered once daily) or  
• 
inhaled placebo administered once daily.  
In the Follow-up period all subjects will receive treatment with inhaled molgramostim (300 µg) 
administered intermittently (12 or 24 cycles of seven days molgramostim followed by seven 
days off-treatment) for 24 or 48 weeks. For subjects who entered the Follow-up period before 
Amendment 11 was approved by the national authorities, treatment with molgramostim in the 
Follow-up period is not mandatory. 
Treatment with molgramostim in the Follow-up period should be discontinued in case of 
disease worsening and/or safety concerns. 
9.1.2 Identity of Investigational Medicinal Products 
Each vial of molgramostim contains 250 µg/mL molgramostim in 1.2 mL solution. Matching 
placebo will contain the same constituents but without the active molgramostim.  
9.1.3 Manufacturing, Packaging and Labelling of Investigational Medicinal Product  
All manufacturing and packaging will be performed in accordance with current Good 
Manufacturing Practice (GMP).  
Individual medication kits containing double-blind trial medication for one week 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. 
9.1.4 Storage and Handling of Investigational Medicinal Product 
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 Baseline (Visit 2), and at Weeks 4, 8, 12, 16 
and 20 (Visits 3, 4, 5, 6, and 7) during the Double-blind treatment period.  
Unblinded IMP kits will be dispensed to the subject at Week 24 post-randomisation and at 
Follow-Up Weeks 12, 24 and 36 (Visits 8, 10, 11 and 12).  
Subjects will be instructed to store the kit at 2-8°C in a safe and secure place out of the reach 
of children. The IMP should not be frozen or shaken and not be used beyond the expiration 
date on the vial. 


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Subjects will be asked to return used and unused medication at the next clinic visit to check 
compliance. 
9.1.5 Investigational Medicinal Product Administration and Training  
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 with high density 
of active drug, precisely defined droplet size and a high proportion of respirable droplets. 
All subjects, investigators and trial nurses will be trained in IMP administration and medical 
device maintenance procedure. The training of the subjects will be arranged prior to 
administration of the subject’s first dose of IMP and checked in clinic on first dosing. The 
subject will also receive written instructions.  
The subject will administer the first dose of IMP post randomisation at the Baseline visit (Visit 
2) under the supervision of trial personnel. 
9.2 
Method of Assigning Subjects to Treatment Groups 
At Screening (Visit 1), the subject will be assigned a site-specific subject number that will 
continue to be the unique identifier throughout the trial. The subject number will be generated 
automatically by the electronic data capture system used in the trial. The subject number will 
be in the following format XX-YYY. The letter XX is the site number and YYY the consecutive 
subject number starting at 001 at each site. 
At the Baseline visit, eligible subjects will be centrally assigned to one of the three Double-
blind treatment groups through an interactive web response system (IWRS). Randomisation 
will be stratified according to whether or not a WLL has been conducted within 2 months prior 
to the Baseline visit. The system will assign unique medication kits number to each subject at 
each dispensing visit. 
Medication kits to be used in the Follow-up period are not blinded. 
9.2.1 Randomisation  
A randomisation list will be prepared by TFS’s statistical department, who will store the list in 
a secure folder until unblinding has taken place. 
9.2.2 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.  
9.3 
Blinding 
All subjects will inhale IMP once daily during the Double-blind treatment period. Blinding will 
be ensured by the use of a matching placebo. 
The packaging and labelling of the investigational products for the Double-blind treatment 
period will contain no evidence of their identity and it is not considered possible to 
differentiate between the investigational products solely by sensory evaluation.  


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9.3.1 Breaking the Randomisation Code 
Unblinding of a single subject may occur for emergency purposes only. Investigators should 
note that the occurrence of a Serious Adverse Event (SAE) should not routinely precipitate 
the immediate unblinding of the label. If the treating physician considers it necessary to 
unblind the study medication for medical reasons, unblinding can be done using IWRS – and 
if possible, after prior contact with the Sponsor. The date and the event making it necessary 
to unblind the treatment randomization have to be documented in the patient files and in the 
case report form (CRF). The Sponsor will immediately be notified in case of emergency 
unblinding by an investigational site. In the case of a potential suspected unexpected serious 
adverse reaction (SUSAR) for an individual subject, Premier Research may break the blind. 
All investigational sites and the Sponsor’s Pharmacovigilance Representative (Premier 
Research) have access to unblinding in the IWRS. 
A Data Safety Monitoring Board (DSMB) will review unblinded safety data as part of the 
safety surveillance of the trial. A statistician from TFS who is independent from the trial will 
make the unblinded safety and tolerability data listings available to the DSMB according to 
TFS SOPs and the Statistical Analysis Plan. All study team members will remain blinded. 
Unblinding of the clinical trial will take place when a final validated database for the 24-week 
double-blind period has been produced, the statistical analysis specified in this protocol has 
been reviewed in relation to the blinded data actually obtained and the Statistical Analysis 
Plan (SAP) has been approved. 
9.4 
Prior and Concomitant Therapy 
The use of concomitant medicines or other treatment regimen during the 24-week Double-
blind treatment period should be kept at a minimum and should be kept as stable as 
possible. Medication/treatment, which is considered necessary for subject safety and well-
being, may be given at the discretion of the investigator. Examples of such 
medications/treatments are: 
• 
WLL (rescue therapy) - The criteria 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.  
• 
Oxygen supplementation 
Sputum modifying medications such as carbocystein and ambroxol are prohibited for 
participating subjects in the Double-blind period of this trial. Medications detailed in the 
exclusion criteria which are rituximab and therapy associated with significant 
immunosuppression are also not allowed (e.g. more than 10mg/day systemic prednisolone) 
while the subject is treated with IMP in the Double-blind or Follow-up periods. Other rhGM-
CSF products are not allowed during the Double-blind or Follow-up periods. 
For subjects who discontinue the double-blind trial treatment and for all subjects in the 
Follow-up period, use of medications to specifically treat aPAP will be recorded in the eCRF. 
Information will be collected regarding: 
• 
concomitant medications, treatments and procedures used to treat aPAP 
• 
medication or treatments which may alter the course of aPAP 
• 
medication or treatments used to treat AEs 
No other information on concomitant medications, treatments or procedures in the Follow-up 
period will be collected. 


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The use of concomitant medication by the subject must be recorded in the appropriate 
sections of the eCRF (Section 10.3.3). 
9.5 
Treatment Compliance 
Subject compliance in the Double-blind treatment and Follow-up periods 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. To verify correct treatment in the Double-blind period the subjects will apply the tear-
off label from the weekly kit in the Diary Card (see Section 10.4.2). 
9.6 
Drug Accountability 
It is the responsibility of the investigator or trained designee to determine investigational drug 
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.  
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. 
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 
Post-Trial Treatment 
After completion of the trial, subjects who require further treatment will be offered treatment 
with molgramostim in in a Compassionate Use Programme, where national regulations so 
allow. 


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10 TRIAL ASSESSMENTS 
10.1 Efficacy Assessments 
10.1.1 Blood Gas Analysis  
The following variables will be assessed from an arterial blood gas sample at the timepoints 
shown in Table 1: 
• 
(A-a)DO2 (mmHg/kPa) 
• 
PaO2 (mmHg/kPa) 
• 
PaCO2 (mmHg/kPa) 
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 at Screening 
(Visit 1), Weeks 4 and 12 (Visits 3 and 5) and all Follow-up Visits, but an arterial sample for 
blood gas is mandatory at Baseline (Visit 2) and Week 24 (Visit 8). 
 
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 at Baseline should be conducted with the subject breathing 
room air. If the subject cannot tolerate temporary discontinuation of supplemental oxygen 
during blood gas sampling at Baseline, blood gas sampling at subsequent visits should be 
conducted using the same oxygen flow rate as was used at Baseline.   
 
The (A-a)DO2 will be calculated based on PaO2, PaCO2 and the ambient atmospheric 
pressure based on a standard equation (see section 10.2.1). 
 
10.1.2 Lung Function Tests  
The following lung function variables will be assessed at the timepoints shown in Table 1: 
• 
VC (% predicted)  
 
 
• 
DLCO (% predicted) 
• 
FEV1 (% predicted) 
• 
FVC (% predicted) 
VC, DLCO, FEV1 and FVC will be assessed in accordance with the American Thoracic 
Society/European Respiratory Society (ATS/ERS) Task Force: Standardisation of lung 
function testing [36] by laboratory personnel with documented training in lung function 
testing. DLCO will be adjusted for haemoglobin value. VC, FEV1 and FVC during the Double-
blind period will be assessed using equipment provided by the Sponsor and centrally read. 
he VC (% predicted), FEV1 (% predicted) and FVC (% predicted) for the DB period will be 
calculated based on a known standard. 
VC, FEV1 and FVC in the Follow-up period and DLCO will be assessed using local, 
appropriately calibrated equipment. 
Trial specific instructions will be provided in a separate document. 
10.1.3 Tolerance to Exercise  
Tolerance to exercise will be assessed at the timepoints shown in Table 1: 


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• 
The 6MWT (Pre and Post walk dyspnoea score using the BDS, Blood oxygen 
saturation (SpO2) (%) at start, Worst SpO2 (%) during the walk, Distance walked (m), 
Duration of the walk (minutes and seconds), O2 flow rate, reason for stopping early if 
applicable) 
The 6MWT will be performed in accordance with ATS/ERS Task Force: Standardisation of 
lung function testing [36] by technicians with documented training and experience of 
performing the 6MWT in accordance with the referred ATS/ERS guidance. Trial specific 
instructions will be provided in a separate document. 
If possible, the 6MWT should be conducted using room air. If the subject requires O2 
supplementation at rest, an O2 titration procedure will be followed as part of the 6MWT at 
Screening in order to determine the amount of oxygen supplementation required for the 
subject to complete the test. The same flow of oxygen should then be used at the subject´s 
subsequent tests in the trial, if possible. 
10.1.4 Dyspnoea Score 
The Dyspnoea score will be assessed at the timepoints shown in Table 1. 
Dyspnoea severity will be established using the Borg CR10 Scale (BDS - Appendix C). The 
BDS will be used before the 6MWT and immediately after the 6MWT. Questionnaires in the 
local language will be used.  
10.1.5 Cough Scores 
Subjects will be asked to score the severity and frequency of coughs on a visual analogue 
scale (Cough Questions - CQ - Appendix D) at the timepoints shown in Table 1. Questions 
will be in the local language. 
10.1.6 CT Scoring 
High Resolution CT scans will be performed at the timepoints shown in Table 1 according to 
a trial-specific image acquisition protocol.  
A trial specific instruction describing the handling, transfering, blinding, distribution, 
assessment, result processing, and filing of data will be provided to all concerned personnel. 
Two independent and blinded assessors will examine the scans. The assessments will be 
performed centrally on a per subject basis; the Baseline (Visit 2) and Week 24 (Visit 8) scans 
will be assessed at the same time for the individual subjects. The extent of ground-glass 
opacification in the CT scans will be quantified visually, as previously described [18]. 
The improvement will be graded as: Improved / Worsened / No change / Data missing – 
Impossible to evaluate.  
The CT scans will also be evaluated for safety and any detrimental effects of treatment 
detected at Week 24 (Visit 8) will be recorded as AEs.  
Further the CT scans will be evaluated using quantitative assessment at a sufficiently 
qualified laboratory. 
10.1.7 Quality of Life Score 
Subjects will be asked to assess their QoL at the timepoints shown in Table 1. 
Subjects will be asked to complete the following questionaires: 
• 
The St Georges Respiratory Questionnaire (SGRQ) is a respiratory specific 
questionnaire which is available in the local language. The symptoms component with 
3-month symptoms recall will be used, Appendix A. This disease-specific instrument 


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has been designed to measure impact on QoL in subjects with obstructive airway 
disease. This assessment is considered relevant for use in subject population of this 
trial.  
• 
The EuroQol-5D (EQ-5D) is a more general questionnaire which is widely used to 
measure health outcome in terms of mobility, self care, usual activities, 
pain/discomfort, anxiety/depression. The 5 level instrument (EQ-5D-5L) which uses a 
5-point scale (no problems, slight problems, moderate problems, severe problems, 
and extreme problems) will be used in the local language, Appendix B. This 
instrument will be used to measure overall self-rated health status.  
10.1.8  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 [37]. 
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 10.1.1). For subjects requiring supplemental oxygen during the blood gas 
assessment the DSS will be based on the PaO2 obtained while breathing oxygen. 
10.1.9 Biomarkers in Serum  
10.1.9.1 GM-CSF and Anti-Drug Antibodies 
Blood samples will be taken at the timepoints shown in Table 1.  
At Baseline (Visit 2) and at Week 4 (Visit 3), samples for GM-CSF will be collected prior to 
dosing of trial drug. An additional sample for analysis of GM-CSF will be collected two hours 
after completion of trial drug administration at Baseline (Visit 2) and at Week 4 (Visit 3). 
All samples for anti-drug antibodies will be collected prior to dosing at the appropriate clinic 
visit. 
Analyses for GM-CSF and anti-drug antibodies (anti-GM-CSF, anti-Polyethylene glycol (anti-
PEG) and anti-recombinant Human Albumin (anti-rHA)) antibodies will be performed using a 
GLP validated method. 
10.1.9.2 Other Biomarkers 
Blood samples will be taken at the timepoints shown in Table 1. The following biomarkers will 
be analysed: Krebs von den Lungen-6 (KL-6), Carcinoembryonic antigen (CEA), Surfactant 
Protein A (SP-A), Surfactant Protein B (SP-B) , Surfactant Protein C (SP-C), Surfactant 
Protein D (SP-D), Cytokeratin Fragment 19 (Cyfra 21-1) and Lactate Dehydrogenase (LDH) 
after 4, 12, and 24-weeks treatment.  
 
Analysis for these biomarkers will be performed by a central laboratory using validated 
methods. LDH will be analysed from the standard clinical chemistry sample. 


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10.2 Primary, Secondary, and Exploratory Endpoints 
10.2.1 Primary Endpoint: 
• 
Absolute change from baseline of (A-a)DO2  after 24-weeks treatment. 
At each visit, (A-a)DO2 will be calculated centrally using the equation: 
 
where FiO2 is fraction of inspired oxygen 
 
 
 
Patm is ambient atmospheric pressure 
PH2O is saturated vapour pressure of water at body temperature (set to 47 
mmHg / 6.266 kPa)  
 
PaCO2 is arterial partial pressure of carbon dioxide 
 
PaO2 is arterial partial pressure of oxygen 
10.2.2 Secondary Endpoints: 
10.2.2.1 Key Secondary Endpoints 
• 
Change from baseline in 6MWD after 24-weeks treatment 
• 
Change from baseline in SGRQ total score after 24-weeks treatment  
• 
Time to WLL during 24-weeks treatment 
• 
Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment 
discontinuation, including clinically significant changes in laboratory tests and 
electrocardiographic (ECG) variables, during 24-weeks treatment 
 
10.2.2.2 Further Secondary Endpoints: 
• 
Absolute change from baseline in VC (% predicted) , DLCO (% predicted), FEV1 (% 
predicted) and FVC (% predicted), and relative change from baseline in PaO2 after 
24-weeks treatment  
• 
Number of subjects with >5 mmHg/>0.67 kPa and number of subjects with 
>10 mmHg/>1.33 kPa improvement in (A-a)DO2 after 24-weeks treatment  
• 
Number of subjects with >5 percentage points and number of subjects with 
>10 percentage points improvement in VC (% predicted) after after 24-weeks 
treatment 
• 
Number of subjects with >10 percentage points  improvement in DLCO (% predicted) 
after 24-weeks treatment  
• 
Number of subjects with >10 percentage points  improvement in FEV1 (% predicted), 
FVC (% predicted) after 24-weeks treatment  
• 
Number of subjects with >10% relative improvement in PaO2 after 24-weeks 
treatment 
• 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 24-weeks treatment  
• 
Change from baseline in dyspnoea score and cough scores after 24-weeks treatment 


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• 
Number of subjects with improved CT score after 24-weeks treatment  
10.2.3 Exploratory Endpoints 
10.2.3.1 Double-Blind Treatment Period 
• 
Absolute change from baseline of (A-a)DO2,  VC (% predicted), DLCO (% predicted), 
FEV1 (% predicted), FVC (% predicted), and relative change from baseline of  PaO2 
after 4 and 12-weeks, treatment 
• 
Time period during which the (A-a)DO2 level is maintained below Baseline –10mmHg  
• 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥ 50 m or desaturation <4 percentage points on the 6MWT) after 4 and 12-weeks 
treatment  
• 
Time period during which the improvement in tolerance to exercise is maintained  
• 
Change from baseline in dyspnoea score and cough scores after 4 and 12-weeks 
treatment 
• 
Number of subjects with improved QoL (change of ≥4 units on the SGRQ/number of 
subjects with ‘no problems’ in the EQ-5D-5L), after 4, 12, and 24-weeks treatment 
• 
Change in serum concentration of biomarkers; KL-6, CEA, SP-A, SP-B, SP-C, SP-D, 
Cyfra 21-1 and LDH after 4, 12, and 24-weeks treatment  
• 
Levels of anti-GM-CSF after 4, 12 and 24-weeks treatment 
• 
Change in serum concentration of GM-CSF post first dose of trial drug and after 
4-weeks treatment 
• 
Number of subjects in need for oxygen supplement therapy  during 24-weeks 
treatment 
• 
The distribution of DSS at Screening and at Week 24 
• 
The percentage of subjects with DSS 1 or 2 at Week 24 
10.2.3.2 Follow-up period 
• 
Number of subjects requiring WLL, or other treatment for aPAP and number of 
treatment courses required during 24-weeks or 48-weeks follow-up   
• 
Time to WLL, or other treatment for aPAP during 24-weeks or 48-weeks follow-up   
• 
Absolute change from baseline in (A-a)DO2 and VC (% predicted), DLCO (% 
predicted), FEV1 (% predicted), and FVC (% predicted), and relative change from 
baseline of PaO2 after 12, 24, 36 and 48-weeks follow-up 
• 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 12, 24, 36 and 
48-weeks follow-up 
• 
Number of AEs, severe AEs, SAEs and ADRs, including clinically significant changes 
in laboratory tests and ECG variables, during 24-weeks or 48-weeks follow-up 
• 
Levels of anti-GM-CSF after 12 and 24 weeks follow-up 
• 
The distribution of DSS after 24 and 48-weeks follow-up 
• 
The percentage of subjects with DSS 1 or 2 after 24 and 48-weeks follow-up 


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10.3 Demographic and Other Baseline Characteristics 
10.3.1 Demographic and Baseline Data 
The following demographic and baseline data will be collected at Screening (Visit 1): 
• 
Date of birth 
• 
Weight and height 
• 
Sex 
• 
Race (White/Asian/Black/American Indian or Alaska Native/Native Hawaiian or Other 
Pacific Islander, according to FDA)  
• 
Date of aPAP diagnosis 
• 
Smoking (Previous/Current/Never) 
• 
Previous exposure to GM-CSF (Yes/No) (Administration within three months of 
Baseline is an Exclusion criterion, Section 8.3) 
• 
Previous WLLs (Total number, date for last WLL) (WLL within one month of Baseline 
is an Exclusion criterion, Section 8.3) 
10.3.2 Medical History 
Medical history will be recorded at Screening (Visit 1).  
10.3.3 Recording of Prior and Concomitant Medication/Therapy 
Prior and concomitant therapies allowed during the trial are detailed in Section 9.4. 
Prior medication/therapy is defined as medication/therapy administered prior to first dose of 
trial medication. All medication/therapy administered after first dose of trial medication is 
considered concomitant medication/therapy. 
At Baseline (Visit 2) prior medications/therapies administered within three months will be 
recorded. In the Double-blind treatment period at Weeks 4, 8,12, 16, 20 and 24 (Visits 3, 4, 
5, 6, 7 and 8) concomitant medication/therapy administered from first dose of Double-blind 
treatment given will be recorded.  
In the Follow-up period at 4, 12, 24 and 48 weeks after the end of the Double-blind treatment 
period (4-week FU, 12-week FU, 24-week FU and 48-week FU Visits) only concomitant 
medications and treatments outlined in Section 9.4 will be recorded.   
The following information will be collected and recorded on the concomitant 
medication/therapy page of the eCRF throughout the trial for prior and concomitant 
medications: Drug name (product name), route, dose and units, frequency, indication, 
reference to AE if applicable, start date, end date or ongoing at the end of the trial will be 
recorded. Prior and concomitant medications will be coded using World Health Organisation 
(WHO) Drug Dictionary. 
10.3.3.1 Whole Lung Lavage  
WLL is applied as rescue therapy during the trial. 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 should be documented. The date, when this criterion applies and thus an 
indication for WLL is present, will be recorded in the CRF.  
 


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The following information will be collected and recorded on the concomitant 
medication/therapy page of the eCRF throughout the trial for prior and concomitant WLL 
procedures: Date, start and end time, type of WLL, saline volume. Anesthesia drugs should 
be recorded as concomitant medication(s). 
10.3.3.2 Oxygen Supplementation 
Oxygen supplementation will be collected and recorded on the concomitant 
medication/therapy page of the eCRF throughout the trial for prior and concomitant 
supplementation. 
Oxygen supplementation given only during assessments (according to Section 10.1.1 or 
10.1.3) will not be recorded on the concomitant medication/therapy page, but under lung 
function and 6MWT pages, respectively. 
10.4 Safety Assessments 
10.4.1 Safety Variables 
The following safety variables will be assessed: 
• 
AEs 
• 
Physical examination 
• 
Vital signs 
• 
Laboratory safety assessments 
• 
HR-CT 
10.4.2 Adverse Events 
Any AEs will be reported during the trial period from Baseline (Visit 2) to the completion of 
the 24- week or 48-week Follow-up visits (Visit 11 and 13). The 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 11.  
A Diary Card will be given to the subject at start of treatment at the Baseline Visit (Visit 2) 
and at Weeks 4, 8, 12, 16 and 20 (Visits 3, 4, 5, 6  and 7) at Weeks 12, 24 and 36 of the 
Follow-up period (Visits 10,11 and 12). In the Diary Card the subject will record any AEs and 
answer specific questions regarding potential pulmonary and systemic effects. The 
completed Diary Card will be collected at the next clinic visit (Visits 3, 4, 5, 6, 7, 8, 10, 11, 12 
and 13). At these visits, the investigator will evaluate the safety information on the Diary Card 
and record any AEs on the eCRF.    
10.4.3 Physical Examination 
All subjects will undergo a standard physical examination at the timepoints shown in Table 1. 
Any abnormalities will be recorded in the eCRF. 
10.4.4 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  


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• 
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’. 
10.4.5 Electrocardiogram 
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. 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. 
10.4.6 Laboratory Safety Assessments 
The laboratory safety analyses (haematology and clinical chemistry) will be performed by a 
central laboratory 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 2 
Laboratory Safety Parameters 
Category 
Laboratory Parameter 
Haematology 
Haemoglobin, Red Blood Cell Count (RBC), Red Blood Cell 
Distribution Width (RDW), Haematocrit (PCV/EVF), Mean 
cell volume (MCV), Mean cell haemoglobin (MCH), Mean 
cell haemoglobin concentration (MCHC), Platelet count, 
White cell count, and white cell differential absolute and 
percentage count: Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils, Prothrombin Time International 
Normalised Ratio (PT-INR) 
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, LDH*, C-Reactive 
Protein (CRP), and Glucose (non-fasting)  
 * LDH will be analysed as a biomarker 
The observed values will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal 
findings will be assessed as ‘clinically significant’ or ‘not clinically significant’. 
10.5 Pregnancy Test 
A serum pregnancy test will be performed for female subjects at Screening (Visit 1), at 
dosing at Baseline (Visit 2) and at all subsequent visits during the Double-blind and Follow-
up treatment period. A urine pregnancy test will also be performed before dosing at Baseline 
(Visit 2) in order to immediately confirm that the subject is not pregnant.  
10.6 Appropriateness of Measurements 
Standardised methods for measurements of efficacy and safety variables will be used. 


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10.7 Handling of Laboratory Samples and Total Blood Volume 
A trial specific laboratory manual for sampling, handling, storage and shipment of samples 
will be provided to the site personnel. The manual will be provided to the site before start of 
the trial. 
Blood samples for efficacy and safety assessments will be taken at all visits, except for Visit 
9, which is a telephone follow-up. For the Double-blind period of 24 weeks the amount of 
blood required per patient per visit varies between 10 mL and 53 mL pr. visit. The total 
amount needed for the Double-blind period is approximately 250 mL. For the Follow-up 
period of 24 or 48 weeks the total amount of blood required per patient is approximately 85 
mL, with a maximum of 26.2 mL for one visit. 


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11 SAFETY 
11.1 Definitions  
11.1.1 Adverse Event 
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. 
Comment: 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. 
11.1.2 Adverse Drug Reaction 
All untoward and unintended responses to an IMP related to any dose administered. 
Comment: All AEs judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse drug reactions. The 
expression reasonable causal relationship means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility i.e. the relationship cannot 
be ruled out.  
11.1.3 Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. IB for an unauthorised IMP or summary of product characteristics 
for an authorised product). 
Comment: When the outcome of the adverse reaction is not consistent with the applicable 
product information this adverse reaction should be considered as unexpected. 
11.1.4 Serious Adverse Event 
Any untoward medicinal occurrence or effect that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
May jeopardise the subject or may require intervention to prevent one or more of the 
other outcomes listed above (Important Medical Events) 
Comments: Life-threatening in the definition of a 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. 


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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).  
11.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is an AE which 
• 
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 study. 
11.3 Reporting of Adverse Events 
All trial subjects will be carefully monitored for the occurrence of AEs during the trial period 
from Screening (Visit 1) to the completion of the 48-week Follow-up visit (Visit 13). The 
investigator will collect AEs with 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 
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. 


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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. 
If an AE changes in severity, it should be reported as an AE of new severity but with the 
same description. 
Causality 
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. 
Outcome 
The outcome of AEs has to be described by following criteria: 
• 
Recovered  
• 
Not Recovered 
• 
Recovered with sequelae 
• 
Fatal 
• 
Unknown. 
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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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. 
11.4 Reporting of Serious Adverse Events 
The investigator is responsible for ensuring that all SAEs are reported to the sponsor 
immediately, using a study-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 study 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 (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 SERIOUS ADVERSE EVENTS (SAES) WITHIN 24 HOURS AFTER 
AWARENESS OF THE EVENT. 
SAE REPORTING CONTACT DETAILS 
Company: Premier Research 
Department: Pharmacovigilance and Device Safety (PVDS) 
 
E-mail: SavaraSafety@premier-research.com 
Fax: +421 2 68203713 


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Note: If there is local legislation requiring investigators to report AEs to the CA or the IEC, 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 Follow-up SAE 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 
PV as soon as possible. SAE-Follow-Up reports also have to be recorded on the study 
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 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 ethics committees concerned. 
11.5 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 Ethics Committee in all 
Member States concerned, to the European clinical trials database (Eudravigilance Clinical 
Trial Module - EVTCM), and if applicable, to FDA using a written Investigational New Drug 
Application (IND) safety report. 
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 Ethics Committee (if required by local regulations), 
and in any case no later than seven (7) days after knowledge by the Sponsor of such a case, 
and that relevant follow-up information is subsequently communicated within an additional 
eight (8) days. 
Any other SUSARs shall be reported to the competent authorities concerned and to the 
Ethics Committee concerned as soon as possible but within a maximum of fifteen (15) days 
of first knowledge by the sponsor.  
The investigator should be aware of local reporting regulations to the Ethics 
Committee/Institutional Review Board (IRB). The Sponsor will either supply the investigator 
with the reports which should be passed on to the Ethics Committee/IRB or report directly to 
the Ethics Committee/IRB depending on local regulations. 
11.6 Adverse Events of Special Interest 
There are currently no AEs of special interest identified due to limited previous experience of 
Savara’s molgramostim. 
11.7 Precautions/Overdose 
No acute systemic or hypersensitivity reactions have been reported in subjects receiving 
inhaled sargramostim or molgramostim products.  


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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 leucocytosis 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. 
11.8 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 11.4. 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. 
11.9 Data Safety Monitoring Board 
A DSMB comprised of independent pulmonologists from lung centers who are experts in 
interstitial lung disease, and in conducting clinical studies will be appointed and assigned for 
safety surveillance of the trial. The DSMB members will not be investigators in the study. All 
members of the DSMB will be unblinded to the treatment received by the subject and the 
subject identification. Unblinded data for DSMB review will be provided by a statistician from 
TFS who is independent of the study (see Section 9.3.1). 
Details of the composition, roles and responsibilities and operating procedures of the DSMB 
will be described in a DSMB Charter. The DSMB will perform safety monitoring of the trial by 
reviewing pertinent safety data and will following the review make recommendations to the 
Sponsor and the coordinating PI whether changes in the study conduct are needed based on 
safety data, including adding additional safety measures. After each review round, the DSMB 
may recommend continuing, modifying or completely stopping the trial. An interim analysis 
will not be part of the DSMB process and the trial will continue during the data review rounds. 
11.10 Safety Management Plan 
The process of SAE-Assessment is performed by Premier Research. In this context a study 
specific “Safety Management Plan” has to be prepared before first subject is recruited into 
the study. The Safety Management Plan contains a detailed description of all procedures 


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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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12 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
12.1 Statistical and Analytical Plans 
The trial will be unblinded and the primary analysis will be conducted after all subjects have 
completed the 24-week Double-blind period. 
A separate SAP, which will provide the technical details of the statistical analysis outlined 
below, will be prepared for use in conjunction with this protocol. 
Before the trial is unblinded, a blind review of the data will be completed. At that time, 
adjustments to the planned analyses may be identified based on, for example, the extent and 
timing of missing data. Confirmation of eligibility for analysis populations (see Section 12.1.1) 
will be confirmed at this time. 
The data from the open-label Follow-up period will be presented descriptively.  
The following details are related to the randomised, double-blind portion of the trial. 
12.1.1 Data Sets to be Analysed 
The subject population sets are defined as follows: 
Full analysis set (FAS): All randomised subjects. 
Per-protocol set (PPS): All randomised subjects who have completed Visit 8 and are 
deemed to have no important protocol deviations that could interfere with the objectives of 
this trial. This is a sub-population of the FAS. 
Note: Important deviations of eligibility criteria and other deviations from the protocol will be 
assessed by TFS in cooperation with the sponsor. Important deviations from the protocol 
may lead to exclusion of a subject from the PPS. All such decisions will be made and 
documented before the trial database is unblinded. 
Safety set: All randomised subjects who received at least one dose of the study medication. 
Although efficacy summaries will be performed on both the FAS and the PPS, the FAS will 
be considered the primary analysis population. 
Safety summaries will be performed on the safety set. 
12.1.2 Definitions 
Baseline measurements are defined as last measurement taken before randomisation.  
12.1.3 Statistical Issues 
Level of Significance, Multiple Comparisons and Multiplicity 
For all significance tests, exact p-values (to four decimal places) will be calculated and 
quoted.   
 
There is one primary efficacy parameter although there are three key secondary efficacy 
endpoints which are intended to support conclusions based on the primary parameter. In 
addition, several other endpoints will be considered as descriptive and supportive, and no 
adjustments for multiplicity will be made for these analyses. 
 
Two comparisons (for the primary and key secondary endpoints) will be carried out. The first 
will be of once daily dosing vs. placebo and the second will be of intermittent dosing vs. 
placebo. These two comparisons are not independent of each other and to account for 
multiplicity, a hierarchical procedure will be used (see below). 


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See also Section 12.1.5 Primary Efficacy Analysis. 
 
Type I Error for Primary and Key Secondary Endpoints 
The primary endpoint of (A-a)DO2  will first be tested for the once daily dosing group versus 
placebo and, if significant at P<0.05, then the 3 key secondary endpoints will be tested at an 
overall 5 % significance level using the Hochberg procedure. If the test is significant for all of 
the key secondary endpoints, then the hierarchical testing will proceed with comparing 
intermittent dosing vs. placebo for the primary, and then the key secondary, endpoints in the 
same manner as for once daily dosing vs. placebo.   
Full details will be provided in the SAP. 
 
Handling of Dropouts and Missing Data 
Different approaches will be used for handling missing data for different endpoints; each is 
described below for the primary and key secondary endpoints. The efficacy variables will 
also be analysed using Observed Cases for the PPS. 
 
Adjustment for Covariates 
In all analyses of ‘change from baseline’, the baseline value of the parameter being analysed 
will be included in an analysis of covariance (ANCOVA) model. The stratification factor ‘WLL 
within 2 months prior to the baseline visit’ will be included in all analysis models. 
 
Multicentre Trial 
Summary statistics will be performed on the whole populations. For baseline demographics 
and disease characteristics, primary endpoint, and key secondary endpoints summary 
statistics will also be performed by centre and for Japan vs. Europe vs. US. Centre will not be 
included as a stratification factor in either the randomisation procedure or data analysis. All 
subject listings will be sorted by centre. 
 
Examination of Subgroups 
Summary statistics will be presented graphically for the subgroups of subjects having a WLL 
within 2 months prior to randomisation vs. the subgroup not doing so. Summary statistics will 
be presented graphically by region and by site. No statistical interaction tests are planned for 
any of the subgroups. 
12.1.4 Summary Statistics 
In general, 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. Individual subject data will be 
listed. 
12.1.5 Primary Efficacy Analysis 
The primary efficacy variable, (A-a)DO2, will be tested using an ANCOVA model. This model 
will have change from baseline to Week 24 in (A-a)DO2 as the response variable, whilst 
treatment group, WLL within 2 months prior to randomisation, and baseline (A-a)DO2 will be 
predictor variables. The mean difference between each active dose and placebo in change 
from baseline of (A-a)DO2 will be estimated, along with its 95% confidence interval (CI) and 
associated statistical significance test. 
Subjects who withdraw from their randomised treatment before week 24 should still be 
followed up through to week 24.  For such patients, their week 24 data will be considered as 
primary, irrespective of treatment discontinuation, treatment interruption(s), use of rescue 


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medication (WLL or other), etc.  The feasibility and likely meaningfulness of this analysis will 
be reviewed in the blind review of the SAP, once the extent and pattern of missing data are 
known. 
A sensitivity analysis will include a mixed model for repeated measures including factors for 
treatment, visit, treatment-by-visit interaction, and baseline (A-a)DO2. 
Subjects who withdraw from the study early and who do not have week 24 data available will 
have their (A-a)DO2 measurement imputed using multiple imputation for which full details will 
be given in the Statistical Analysis Plan. Further sensitivity analyses will include: 
• 
“reasonably worst case” scenario.  For the primary analysis, patients in either of the 
active arms will have the value of the 10th percentile from their dose arm imputed (i.e. 
approximately the 3rd worst case) whilst patients in the placebo arm will have the 
median for the placebo arm imputed. 
• 
Tipping point analysis: Patients in any group with a missing endpoint will be assigned 
progressively worse (A-a)DO2 to find the point at which the results reverse from 
favouring the active treatment to the placebo. 
All attempts will be made to retain subjects in the trial, even if they wish to withdraw from trial 
treatment. Hence it is anticipated that there will be only minimal missing (A-a)DO2 data at 
week 24 and a further sensitivity analysis will use all available Week 24 data with no 
imputation (i.e. a “completers” analysis). 
12.1.6 Key Secondary Efficacy Analyses  
Absolute change from baseline in 6MWD and in SGRQ will be analysed using the same 
ANCOVA model as for (A-a)DO2.  Imputation for missing data will also follow the same rules 
as for (A-a)DO2. 
Time to WLL (time from randomisation to documentation that WLL needs to be carried out) 
will be analysed by the logrank test. The proportion of subjects in each group who require 
WLL at, or before, week 24 will be estimated, along with a 95% CI for the difference in rates 
between each active dose and placebo. Subjects who fulfil the criteria for rescue treatment 
but refuse (or for some other reason do not get) WLL, will be counted as if WLL was 
conducted. This decision will be documented when the trial is complete in the blind review of 
the SAP. 
In addition, the hazard ratio and its 95% confidence interval will be estimated from a Cox 
model with covariates treatment, geographic region, and need for WLL within 2 months 
before randomisation. 
Any patient who withdraws from the trial before week 24 and who has not needed a WLL will 
be considered as censored for the event of WLL. A sensitivity analysis will additionally be 
performed considering any such patients as having the endpoint event at the time they 
withdraw. All patients who reach week 24 and have not needed a WLL will be considered 
censored at week 24. 
Further rules for handling missing data will be confirmed at the blind review of the SAP. 
Assuming that any subjects who withdraw from treatment remain in the trial, the Week 24 
data will be considered as primary, regardless of adherence to treatment. 
12.1.7 Further Secondary Efficacy Analyses 
Analyses of further secondary endpoints will be described in the SAP. 
The following tabulations will be presented: 


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• 
Number of subjects with >5 mmHg/>0.67 kPa and number of subjects with 
>10 mmHg/>1.33 kPa improvement in (A-a)DO2 after 24-weeks treatment  
• 
Number of subjects with >5 percentage points and number of subjects with 
>10 percentage points improvement in VC (% predicted) after after 24-weeks 
treatment 
• 
Number of subjects with >10 percentage points improvement in DLCO (% predicted) 
after 24-weeks treatment  
• 
Number of subjects with >10 percentage points improvement in FEV1 (% predicted) 
and FVC (% predicted) after 24-weeks treatment  
• 
Number of subjects with >10% relative improvement in PaO2 after 24-weeks 
treatment 
• 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 24-weeks treatment  
• 
Number of subjects with improved CT score after 24-weeks treatment  
12.1.8 Exploratory Efficacy Analyses 
The tabulations for the following exploratory endpoints from the Double-blind period will be 
presented and the analyses will be described in the SAP:   
• 
Absolute change from baseline of (A-a)DO2, VC (% predicted), DLCO (% predicted), 
FEV1 (% predicted), FVC (% predicted), and relative change from baseline of  PaO2 
after 4 and 12-weeks treatment 
• 
Time period during which the (A-a)DO2 level is maintained below Baseline –10mmHg  
• 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 4 and 12-weeks 
treatment  
• 
Time period during which the improvement in tolerance to exercise is maintained   
• 
Change from baseline in dyspnoea score and cough scores (severity and frequency) 
after 4 and 12-weeks treatment. 
• 
Number of subjects with improved QoL (change of ≥4 units on the SGRQ/ number of 
subjects with ‘no problems’ in EQ-5D), after 4, 12, and 24-weeks treatment 
• 
Change in serum concentration of possible biomarkers; KL-6, CEA, SP-A, SP-B , SP-
C, SP-D, Cyfra 21-1 and LDH after 4, 12, and 24-weeks treatment  
• 
Levels of anti-GM-CSF after 4, 12 and 24-weeks treatment 
• 
Change in serum concentration of GM-CSF post first dose of trial drug and after 
4-weeks treatment 
• 
Number of subjects in need for oxygen supplement therapy  during 24-weeks 
treatment.  
• 
The distribution of DSS at Screening and at Week 24. 
• 
The percentage of subjects with DSS 1 or 2 at Week 24. 
The tabulations for the following exploratory endpoints from the Follow-up period will be 
presented and the analyses will be described in the SAP:   


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• 
Number of subjects requiring WLL, or other treatment for aPAP and number of 
treatment courses required during 24 or 48-weeks follow-up   
• 
Time to WLL, or other treatment for aPAP during 24 or 48-weeks follow-up   
• 
Absolute change from baseline in (A-a)DO2 and VC (% predicted), DLCO 
(% predicted),  FEV1 (% predicted), FVC (% predicted), and relative change from 
baseline of PaO2 after 12, 24, 36 and 48-weeks follow-up 
• 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 12, 24, 36 and 
48-weeks follow-up 
• 
Levels of anti-GM-CSF after 12 and 24-weeks follow-up 
• 
The distribution of DSS after 24 and 48-weeks follow-up 
• 
The percentage of subjects with DSS 1 or 2 after 24 and 48-weeks follow-up 
Rules for handling missing data for these endpoints, where necessary, will be documented 
before the trial data are unblinded and when the patterns and extent of missing data are 
known. 
12.1.9 Demographic and Other Baseline Characteristics 
Subject disposition, demographic and other baseline data will be presented using summary 
statistics. Both the FAS and the PPS will be used for this presentation. 
12.1.10 
Exposure to Treatment 
Exposure to treatment will be presented using summary statistics. 
12.1.11 
Concomitant Treatment 
Concomitant medication and concomitant therapy will be summarised as number of subjects 
being treated with each type of medication/therapy classified according to Anatomical 
Therapeutic Chemical (ATC) level 3 and WHO Drug Dictionary preferred term. The safety set 
will be used for this presentation. 
12.1.12 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and tabulated by system organ class (SOC) and by preferred term (PT).  
The total number of subjects with at least one AE and the total number of AEs will be 
presented.  
The number of subjects and the number of AEs will be tabulated by SOC and by PT.  
AEs will also be tabulated versus worst severity and worst relationship to treatment.  
12.1.13 
Other Safety Assessments 
Physical Examination 
Physical examination data will be summarised, together with changes from Baseline. 
Vital Signs 
Vital signs will be summarised, together with changes from Baseline. 


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ECG 
Electrocardiogram parameters (heart rate, QRS, PR and QT intervals) will be summarised, 
together with changes from Baseline. QTcF will be calculated and be summarised, together 
with changes from Baseline. 
Laboratory Safety Assessments 
For laboratory data, summary statistics will be produced for observed values and for changes 
from Baseline to each visit. Abnormal values will be flagged in listings.  
Shift tables will show the number of subjects who changed from below, within or above the 
reference range at baseline to below, within or above the reference range at end of 
treatment.  
For laboratory values which are below the limit of quantification, the value corresponding to 
the limit of quantification will be used when summarising data (e.g. if the result is <0.5 then 
the value 0.5 will be used in the statistical analysis). 
12.2 Determination of Sample Size 
The trial is a randomised 3-arm trial in which two thirds of the subjects receive active drug 
and one third receive placebo. 
The sample size calculation was based on data in an earlier trial [19], where the mean (and 
standard deviation) (A-a)DO2 were 31.3 (7.4) before treatment and 12.9 (7.6) after treatment 
(all measured in mmHg). It was also based on previous assumptions about how the trial 
would be analysed (notably, to combine the two active doses together for the primary 
analysis). The minimum clinically relevant difference to detect between active and placebo 
arms is considered to be 10-12 mmHg.  In order to ensure such an effect size can be 
detected, a delta of 10 mmHg has been used in the sample size calculation which is based 
on an unpaired t-test of mean difference between the two active arms (combined) vs. 
placebo, using a significance level of 0.01 and a power of 90%. 
The trial will test the null hypothesis 
H0: μdiff = 0 
Versus the alternative hypothesis 
H1: μdiff ≠ 0. 
 
The calculation was based on an unpaired t-test, combining the two active dose groups 
together and comparing to placebo. Calculations were made using nQuery Advisor® 7.0.  


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Table 3 
Two Group T-Test of Equal Means (Unequal n's) 
 Test significance level, α 
  0.010 
 1 or 2 sided test? 
   2 
 
 
     Difference in means, µ1 - µ2 
   10.000 
     Common standard deviation, σ 
    7.500 
 Effect size, δ = |µ1 - µ2| / σ 
    1.333 
 Power ( % ) 
     90 
     n1 
 14 
     n2 
 28 
 Ratio: n2 / n1 
  2.000 
 N = n1 + n2 
 42 
 
Based on the assumption listed in Table 3, above, 42 subjects will be required to be 
randomised.  
Based on an evaluation of variability and plausible effect sizes for the key secondary 
endpoints, the sample size is increased to 90 subjects (30 patients in each treatment arm), to 
increase the power to identify statistically significant treatment effects also on one or more of 
the key secondary endpoints. 
Very limited data on these secondary endpoints are available but with a sample size of 30 
subjects per group, it would be possible to show a treatment effect of 50 m on the 6MWD 
(assuming a SD of 50) or of 10 points on the SGRQ (assuming a SD of 10) with 
approximately 90 % power.  
Because of the limited data available, a fully blinded sample size re-estimation procedure will 
be carried out to assess the standard deviations of the 6MWD and the SGRQ, and the 
overall event rate of WLL. This will be done in January 2018 when approximately 50 patients 
will have reached 24 weeks of treatment. 
The change from baseline to week 24 in 6MWD [and SGRQ] will be summarised in an 
ANCOVA model including WLL (stratification), and baseline 6MWD [SGRQ].  For the 
purposes of the sample size re-estimation process, only data on patients who have baseline 
and week 24 data will be used and no imputation will be made for missing values. 
Additionally, the overall (pooled) event rate for WLL will be determined including any patients 
who meet the criteria for WLL any time prior to week 24, but excluding any patients 
who withdraw prior to week 24 where WLL has not been required. 
 
Based on a literature review of different pulmonary indications but with main focus on 
Idiopathic Pulmonary Fibrosis carried out in November 2017 [38, 39, 40], the minimal 
clinically important effect sizes for 6MWD and SGRQ in aPAP are considered to be in the 
order of 40-50 m and 7-10 points, respectively.  From each ANCOVA model, the respective 
residual variance for 6MWD [and SGRQ] will be used to calculate sample size based on the 
effect sizes of 50 m and 10 points, respectively.  Similarly, the sample size for comparing 
WLL rates of 5% (active) versus 20% (placebo) at 24 weeks will be checked, based on the 
observed (pooled) WLL rate. All calculations will be made based on a 2-sided 5% 
significance level, and 80% and 90% power. 
 
If the maximum of these sample size calculations comes to no more than 33 patients per 
group, then no change to the target sample size will be made.  Otherwise, the sample size 
will be increased to attain 90% power for at least 2 of the 3 key secondary endpoints, subject 
to the total study size not exceeding 150 patients. 


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The results of the sample size re-estimation will be documented in a report. 
12.3 Procedures for Reporting any Deviation(s) from the Original Statistical Analysis 
Plan 
Any deviation(s) from the original statistical analysis plan (as described in the trial protocol or 
in the SAP) will be described and justified in a protocol amendment and/or in a revised SAP 
and/or in the final report, as appropriate. 
12.4 Interim Analysis 
No interim analyses are planned for this clinical trial. 


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13 INVESTIGATOR/SPONSOR RESPONSIBILITIES 
13.1 Ethics 
13.1.1 Independent Ethics Committee (IEC) / Institutional Review board (IRB) 
This protocol and any amendments will be submitted to a properly constituted IEC/IRB, in 
accordance with the International Conference on Harmonisation (ICH) guidelines, the 
applicable European Directives and local legal requirements, for approval/favourable opinion. 
An approval/favourable opinion must be obtained in writing before the first subject can be 
recruited. 
13.1.2 Ethical Conduct of the Trial 
The trial will be conducted in compliance with the protocol, regulatory requirements, good 
clinical practice (GCP) and the ethical principles of the latest revision of the Declaration of 
Helsinki as adopted by the World Medical Association. 
13.1.3 Subject Information and Consent 
All subjects will receive written and verbal information regarding the trial at a prior meeting. 
This information will emphasise that participation in the trial is voluntary and that the subject 
may withdraw from the trial at any time and for any reason. All subjects will be given the 
opportunity to ask questions about the trial and will be given sufficient time to decide whether 
to participate in the trial. 
Before any trial-related procedures, the informed consent form will be signed and personally 
dated by the subject and by the person who conducted the informed consent discussion. 
The consent includes information that data will be recorded, collected, processed and may 
be transferred to European Economic Area (EEA) or non-EEA countries. In accordance with 
the European Union Data Protection Directive (95/46/EC), the data will not identify any 
persons taking part in the trial. 
A copy of the subject information including the signed consent form will be provided to the 
subject. 
13.2 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 during the trial period 
• 
Any information relating to AEs 


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• 
All treatments and medications prescribed/administered (including dosage) 
• 
Date of trial termination 
• 
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. 
13.3 Access to Source Data and Documentation 
The investigator should guarantee access to source documents for the monitor and auditors 
as well as for inspection by appropriate regulatory agencies, and the IEC, if required. 
13.4 Monitoring 
The monitor will visit the trial site to ensure that the trial is conducted and documented in 
accordance with this protocol, ICH GCP guidelines, regulatory requirements and any trial 
specific documents such as monitoring manual and eCRF completion guidelines. 
Monitoring visits will be conducted to confirm that e.g.: 
• 
The investigational team is adhering to the trial protocol 
• 
Informed consent has been obtained from all participants 
• 
AEs have been reported as required 
• 
Data are being accurately recorded in the eCRFs 
• 
IMP is being stored correctly and drug accountability is being performed on an on-
going basis 
• 
Facilities are, and remain, acceptable throughout the trial 
The investigator and the site are receiving sufficient information and support throughout the 
trial 
Moreover, during monitoring visits the data recorded in the eCRFs, source documents and 
other trial-related records will be compared against each other in order to ensure accurate 
data that reflect the actual existence of the subject in the trial i.e. source data verification. 
13.5 Data Management  
Data management and handling of data will be conducted according to the trial specific Data 
Management Plan with ICH guidelines and TFS’s standard operating procedures (SOPs). 
An eCRF system, Trial-on-Line, 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 Trial-on-
Line and/or the TFS Data Management Team. The data will be subjected to validation 
according to TFS SOPs 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. 


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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. 
13.6 Quality Assurance and Audit 
Audits or inspections, including source data verification, may be performed by 
representatives of TFS, the sponsor, a CA and/or an IEC. 
13.7 Record Retention 
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. 
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. 
13.8 Protocol Deviations 
Deviations to the trial protocol will be documented in a Protocol Deviation Log. 
The classification of subjects into protocol deviators will be made during a meeting before 
database lock. The classification will be mutually agreed between the sponsor and TFS 
before breaking the randomiastion codes. Listings will indicate the allocation of subjects by 
analysis set and the number of subjects per analysis set will be recorded in the clinical trial 
report. 
13.9 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.  
13.10 Report and Publication 
Information about this clinical trial will be publically registered on the website 
www.clinicaltrials.gov before the first subject enters into the trial. 
Two Clinical Trial Reports (CTRs) will be prepared according to the ICH Guideline for 
Structure and Content of Clinical Trial Reports (ICH E3). After the last subject has completed 
the 24-week Double-blind treatment period a CTR detailing the results of double-blind 
treatment will be produced. The results for the Follow-up period will be reported separately.   
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 


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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 multicentre study may publish data subsets from their 
individual institution only after publication of the primary manuscript. A written permission to 
publish must be obtained from the sponsor in advance. As some of the information regarding 
the IMP and development activities at the sponsor may be of a strictly confidential nature, the 
sponsor must be given a 30-day period to review and approve any publication manuscript 
prior to their submission to journals, meetings or conferences. Such a manuscript should 
always reference the primary publication of the entire study.  
The sponsor undertakes to publish the results in compliance with the joint position of the 
innovative pharmaceutical industry [41] 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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Validation of test performance characteristics and minimal clinically important 
difference of the 6-minute walk test in patients with idiopathic pulmonary fibrosis. 
Respir Med 2015; 109(7): 914-22. 
40.  
Swigris JJ, Brown KK, Behr J, du Bois RM, King TE, Raghu G, et al. The SF-36 
and SGRQ: validity and first look at minimum important differences in IPF. Respir 
Med 2010; 104(2): 296-304. 


Clinical Trial Protocol  
Sponsor: Savara ApS 
Version: 5.0 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No.: 2015-003878-33 
Confidential 
Page 82 of 83 
41.  
Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial 
Registries and Databases (2017), available from 
http://clinicaltrials.ifpma.org/resource-centre/clinical-trials-position-papers 


Clinical Trial Protocol  
Sponsor: Savara ApS 
Version: 5.0 
Trial Code: MOL-PAP-002 
Date: 01 Dec 2017 
EudraCT No.: 2015-003878-33 
Confidential 
Page 83 of 83 
15 APPENDICES 
Appendix A:  
St Georges Respiratory Questionnaire (SGRQ) UK/ English  
     
(6 pages)  
 
(original) version,   
Appendix B:  
EuroQol-5D (EQ-5D-5L) questionnaire. English version (3 Pages)  
 
 
Appendix C:  
Borg CR10 Scale. Borg GA. Psycophysical bases of perceived 
perception. Med Sci Sports Exerc 1992;14:377-381.  
Appendix D: 
Cough Questions  
 

SAP_001.pdf: 
 
 
 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN  
 
 
A Randomised, Double-Blind, Placebo-Controlled Multicentre Clinical Trial of 
Inhaled Molgramostim  
in Autoimmune Pulmonary AlveoLAr Proteinosis Patients 
“IMPALA” 
 
 
Sponsor Study Code: MOL-PAP-002 
 
TFS Project Code: SDX004 
 
Sponsor 
Savara ApS. 
Product/Compound Molgramostim nebuliser solution 
Phase of the study 
II/III 
Author 
 
Company 
TFS 
Address 
Box 165, SE-221-00 Lund, Sweden 
Telephone number 
+46(0)46 280 18 00 
Version 
Final 1.0 
Date 
2019-04-25 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
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SIGNATURES 
 
Sponsor Study code:  
 
MOL-PAP-002 
 
 
Author 
 
 
 
 
Name, academic 
level, title: 
Jacob Råstam, BSc, Senior Statistician 
 
Company 
TFS 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
Add time to all dates if on the same 
day as unblinding. 
 
 
 
 
 
 
TFS Reviewing 
Statistician 
 
 
 
Name, academic 
level, title: 
Marie Sandgren, BSc, Principle Statistician 
 
Company 
TFS 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
 
 
Sponsor Reviewing 
Statistician 
 
 
 
Name, academic 
level, title: 
Simon Day, PhD, Director 
 
Company 
Clinical Trials Consulting and Training Ltd 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
 
 
 
Sponsor Approval 
 
 
 
 
Name, academic 
level, title: 
Cecilia Ganslandt, MD, VP, Head of Clinical Development  
Company 
Savara ApS 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
 
 
 
 
29-Apr-2019 | 01:17 PDT
29-Apr-2019 | 09:12 CEST
29-Apr-2019 | 09:15 CEST
29-Apr-2019 | 01:06 PDT


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
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TABLE OF CONTENT 
 
1 
INTRODUCTION .................................................................................................. 6 
2 
STUDY OBJECTIVES ......................................................................................... 6 
2.1 
Primary Efficacy Endpoint ................................................................................. 7 
2.2 
Secondary Efficacy Endpoints .......................................................................... 7 
2.3 
Additional Safety Endpoints .............................................................................. 9 
3 
OVERALL STUDY DESIGN ................................................................................ 9 
3.1 
Overview of Study Design ................................................................................. 9 
3.2 
Determination of Sample Size ......................................................................... 10 
4 
DATA SETS TO BE ANALYSED....................................................................... 12 
5 
STATISTICAL AND ANALYTICAL PLANS ....................................................... 13 
5.1 
Changes in the Planned Analyses .................................................................. 13 
5.2 
Blind Review ..................................................................................................... 13 
5.3 
Hypotheses and Statistical Methods .............................................................. 13 
5.3.1 
General ....................................................................................... 13 
5.3.2 
Definitions ................................................................................... 15 
5.3.3 
Summary Statistics ...................................................................... 15 
5.3.4 
Subject Data Listings ................................................................... 16 
5.3.5 
Demographic and other Baseline Characteristics ........................ 16 
5.3.6 
Primary Efficacy analysis ............................................................. 16 
5.3.7 
Secondary Efficacy Analyses ...................................................... 18 
5.3.8 
Exploratory Efficacy Analyses ..................................................... 21 
5.3.9 
Exposure to Treatment ................................................................ 24 
5.3.10 
Concomitant Medication .............................................................. 25 
5.3.11 
Adverse Events ........................................................................... 25 
5.3.12 
Other Safety Assessments .......................................................... 25 
5.4 
Level of Significance, Multiple Comparisons and Multiplicity ...................... 27 
5.5 
Adjustment for Covariates ............................................................................... 28 
5.6 
Handling of Dropouts and Missing Data ......................................................... 29 
5.7 
Multicentre Studies .......................................................................................... 29 
5.8 
Examination of Subgroups .............................................................................. 29 
5.9 
Interim Analysis ............................................................................................... 29 
5.10 
Data Monitoring ................................................................................................ 30 
6 
REFERENCES................................................................................................... 30 
APPENDIX 1 ........................................................................................................................ 31 
Tables, Figures and Listings to be Produced for the Clinical Study Report (Section 
14 and 16 according to ICH E3) ..................................................................... 31 
APPENDIX 2. SAMPLE SIZE RECALCULATION MOL-PAP-002 ....................................... 42 
1.1 
Introduction .................................................................................................. 42 
1.2 
Methods .......................................................................................................... 42 
1.3 
Results from Sample Size Recalculation ............................................ 43 
1.4 
Conclusion ..................................................................................................... 44 
APPENDIX 3. CONVERSION FACTORS ............................................................................ 45 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
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Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
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ABBREVIATIONS 
6MWD  
6 Minute Walk Distance 
6MWT  
6 Minute Walk Test 
(A-a)DO2 
Alveolar-arterial Oxygen Difference 
ADR 
 
Adverse Drug Reaction 
AE 
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
anti-GM-CSF Antibodies towards Granulocyte Macrophage Colony Stimulating Factor 
aPAP  
Autoimmune Pulmonary Alveolar Proteinosis 
AST 
 
Aspartate Aminotransferase 
ATC 
 
Anatomic Therapeutic Chemical 
CEA 
 
Carcinoembryonic Antigen 
CI 
 
Confidence Interval 
CT 
 
Computer Tomography 
CTR 
 
Clinical Trial Report 
Cyfra 21-1 
Cytokeratin 19 Fragment  
DBL 
 
Data Base Lock 
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 
EQ-5D-5L 
EuroQol-5D 5 level quality of life questionnaire 
FAS 
 
Full Analysis Set 
FEV1  
Forced Expiratory Volume in one second 
FVC 
 
Forced Vital Capacity 
IMP 
 
Investigational Medicinal Product 
KL-6 
 
Krebs von den Lungen-6 
LDH 
 
Lactate Dehydrogenase 
LOCF  
Last Observation Carried Forward 
MA 
 
Marketing Authorisation 
MCAR  
Missing Completely at Random 
MAR  
Missing at Random 
MNAR  
Missing Not at Random 


 
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MedDRA 
Medical Dictionary for Regulatory Activites 
MMRM 
Mixed Model for Repeated Measures 
PaO2  
Arterial oxygen tension 
PaCo2  
Arterial partial pressure of carbon dioxide 
PAP 
 
Pulmonary Alveolar Proteinosis 
PCV/EVF 
Packed Cell Volume (PCV) or Erythrocyte Volume Fraction (EVF) also known 
as haematocrit 
PPS 
 
Per Protocol Set 
PT 
 
Preferred Term 
QoL 
 
Quality of Life 
rhGM-CSF 
Recombinant Human Granulocyte Macrophage Colony Stimulating Factor 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SGRQ  
St Georges Respiratory Questionnaire 
SOC 
 
System Organ Class 
SOP 
 
Standard Operating Procedure 
SP-A, SP-B, Surfactant Protein A, Surfactant Protein B, Surfactant Protein C, Surfactant 
SP-C, SP-D  Protein D 
SpO2  
Oxygen saturation (indirect measurement) 
VC 
 
Vital Capacity 
WHO  
World Health Organisation 
WLL 
 
Whole Lung Lavage 


 
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EudraCT No.: 2015-003878-33 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on Global Clinical Study Protocol (CSP) Version 
5.0, dated 01 December 2017, and Local Versions; 5.3 dated 04 April 2018, only applicable 
for USA, 5.4 dated 04 April 2018, only applicable for France and version 5.5 dated 08 May 
2018, only applicable for Turkey, and in addition Amendment 2.0 dated 14 Dec 2015 and 
Amendment 3.0 dated 18 Feb 2016 (only applicable for Japan) to Protocol Version: 1.0 dated 
15 Oct 2015. 
2 
 STUDY OBJECTIVES 
Primary objective: 
 
To compare efficacy of inhaled molgramostim on the Alveolar-arterial oxygen 
difference (A-a)DO2  with placebo after 24-weeks treatment.  
Key Secondary objectives: 
 
To compare efficacy of inhaled molgramostim on tolerance to exercise with placebo 
after 24-weeks of treatment 
 
To compare efficacy of inhaled molgramostim on respiratory disease-related quality 
of life with placebo after 24-weeks of treatment 
 
To compare efficacy of inhaled molgramostim based on time to Whole Lung Lavage 
(WLL) with placebo after 24-weeks treatment 
 
To compare safety of inhaled molgramostim with placebo in terms of reported 
adverse events (AEs), serious adverse events (SAEs), adverse drug reactions 
(ADRs), severe AEs and withdrawals due to AEs during 24-weeks treatment 
Further Secondary objectives: 
 
To compare efficacy of inhaled molgramstim on the number of WLL over time with 
placebo after 24-weeks treatment (Added in SAP). 
 
To compare efficacy of inhaled molgramostim on Vital Capacity (VC), Diffusion 
Capacity of the Lung for Carbon Monoxide (DLCO), Forced Expiratory Volume in one 
(1) second (FEV1), Forced Vital Capacity (FVC) and Arterial oxygen tension (PaO2) 
with placebo after 24-weeks treatment 
 
To compare efficacy of inhaled molgramostim on the categorical change of (A-a)DO2, 
VC, DLCO,  FEV1, FVC, and PaO2 with placebo after 24-weeks treatment  
 
To compare efficacy of inhaled molgramostim on categorical change to exercise with 
placebo after 24-weeks treatment 
 
To compare efficacy of inhaled molgramostim on dyspnoea, and cough with placebo 
after 24-weeks treatment  
 
To compare efficacy of inhaled molgramostim on disease severity by Computer 
Tomography (CT) scoring with placebo after 24-weeks treatment 
Exploratory  objectives: 
Double-blind treatment period 
 
To compare efficacy of inhaled molgramostim with placebo on (A-a)DO2, VC, DLCO, 
FEV1, FVC, PaO2, and on tolerance to exercise after 4-weeks and 12-weeks treatment 


 
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 
To compare the duration of response of inhaled molgramostim with placebo in (A-
a)DO2 and tolerance to exercise  
 
To compare efficacy of inhaled molgramostim with placebo on dyspnoea and cough 
after 4-weeks, and 12-weeks treatment  
 
To compare efficacy of inhaled molgramostim with placebo on Quality of Life (QoL) 
after 4 weeks, 12-weeks, and 24-weeks treatment  
 
To assess pharmacodynamic effects on selected biomarkers in serum after 4-weeks, 
12-weeks, and 24-weeks treatment of inhaled molgramostim or placebo  
 
To assess the effect of molgramostim on Granulocyte Macrophage Colony 
Stimulating Factor (GM-CSF) concentration in serum after the first dose and after 
4-weeks treatment, and to assess levels of antibodies to GM-CSF (anti-GM-CSF) 
after 4-weeks, 12-weeks and 24-weeks treatment with molgramostim or placebo.  
 
To assess the requirement for oxygen supplementation therapy during 24-weeks 
treatment with molgramostim or placebo. 
 
To assess the change in Disease Severity Score (DSS) from Screening to Week 24.  
Follow-up period 
 
To compare the requirement for and time to WLL, or other treatment for aPAP after 
24-weeks inhaled molgramostim or placebo during a 24-week, or 48-week post-
treatment Follow-up period.   
 
To compare efficacy of 24-weeks inhaled molgramostim with placebo on (A-a)DO2, 
VC, DLCO, FEV1, FVC, PaO2, and on tolerance to exercise during a 24-week or 48-
week post-treatment Follow-up period.  
 
To compare safety of inhaled molgramostim with placebo during a 24-week or 48-
week post-treatment Follow-up period in terms of reported AEs, severe AEs, SAEs, 
and ADRs. 
 
To assess levels of anti-GM-CSF at the 12-weeks and 24-weeks post-treatment 
Follow-up period 
 
To assess the change in DSS during a 24-week or 48-week post-treatment Follow-up 
period 
2.1 
Primary Efficacy Endpoint 
Primary endpoint  
 
Absolute change from baseline of (A-a)DO2  after 24-weeks treatment 
2.2 
Secondary Efficacy Endpoints 
Key Secondary Endpoints: 
 
Change from baseline in 6-minute walking distance (6MWD) after 24-weeks 
treatment 
 
Change from baseline in SGRQ total score after 24-weeks treatment 
 
Time to WLL during 24-weeks treatment  
 
Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment 
discontinuation, including clinically significant changes in laboratory tests and 


 
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echocardiographic (ECG) variables, during 24-weeks treatment (hereafter described 
under Safety Endpoints) 
Further Secondary Endpoints: 
 
Number of WLL over time during 24-weeks treatment (Added in SAP). 
 
Absolute change from baseline in VC (% predicted), DLCO (% predicted), FEV1 (% 
predicted), FVC (% predicted) and relative change from baseline in PaO2 after 24-
weeks treatment  
 
Number of subjects with >5 mmHg/>0.67 kPa and number of subjects with 
>10 mmHg/>1.33 kPa improvement in (A-a)DO2 after 24-weeks treatment  
 
Number of subjects with >5 percentage points and number of subjects with >10 
percentage points improvement in VC (% predicted) after 24-weeks treatment 
 
Number of subjects with >10 percentage points improvement in DLCO (% predicted) 
after 24 weeks treatment  
 
Number of subjects with >10 percentage points improvement in FEV1(% predicted) 
after 24-weeks treatment 
 
Number of subjects with >10 percentage points improvement in FVC (% predicted) 
after 24-weeks treatment  
 
Number of subjects with >10% relative improvement in PaO2 after 24-weeks 
treatment 
 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 24-weeks treatment  
 
Change from baseline in dyspnoea score and cough scores after 24-weeks treatment 
 
Number of subjects with improved CT score after 24-weeks treatment  
Exploratory Endpoints  
Double-blind treatment period 
 
Absolute change from baseline of (A-a)DO2, VC (% predicted), DLCO (% predicted), 
FEV1(% predicted), FVC (% predicted), and relative change from baseline in PaO2 
after 4 and 12-weeks treatment 
 
Time period during which the (A-a)DO2 level is maintained below Baseline minus 
10mmHg  
 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 4 and 12-weeks 
treatment  
 
Time period during which the improvement in tolerance to exercise is maintained   
 
Change from baseline in dyspnoea score and cough scores after 4 and 12-weeks 
treatment 
 
Number of subjects with improved QoL (reduction of ≥4 units on the SGRQ) after 4, 
12, and 24-weeks treatment   
 
Number of subjects with ‘no problems’ in EQ-5D-5L after 4, 12, and 24-weeks 
treatment 
 
Change from baseline in serum concentration of biomarkers: Krebs von den Lungen-
6 (KL-6), Carcinoembryonic antigen (CEA), Surfactant Protein A (SP-A), Surfactant 


 
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Protein B (SP-B), Surfactant Protein C (SP-C), Surfactant Protein D (SP-D), 
Cytokeratin 19 Fragment (Cyfra 21-1) and Lactate Dehydrogenase (LDH) after 4, 12, 
and 24-weeks treatment  
 
Anti Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) antibody titers 
after 4, 12 and 24-weeks treatment 
 
Change in serum concentration of GM-CSF post first dose of trial drug and after 4-
weeks of treatment 
 
Number of subjects in need for oxygen supplement therapy during 24-weeks 
treatment. 
 
The distribution of DSS at Screening and at Week 24 
 
The percentage of subjects with DSS 1 or 2 at Screening and at Week 24. 
Follow-up period 
 
Number of subjects requiring WLL or other treatment for aPAP and number of 
treatment courses required during 48-weeks follow-up.   
 
Time to WLL, or other treatment for aPAP during 48-weeks follow-up.   
 
Absolute change from baseline in (A-a)DO2 and VC (% predicted), DLCO (% 
predicted), FEV1(% predicted) , FVC (% predicted), and and relative change from 
baseline of PaO2 after 12, 24, 36 and 48-weeks follow-up 
 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) after 12, 24, 36 and 48-
weeks follow-up 
 
Number of AEs, severe AEs, SAEs and ADRs , including clinically significant changes 
in laboratory tests  and ECG variables, during 48-weeks follow- up 
 
Levels of anti-GM-CSF after 12 and 24 weeks follow-up. 
 
The distribution of DSS after 24 and 48-weeks follow-up 
 
The percentage of subjects with DSS 1 or 2 after 24 and 48-weeks follow-up. 
2.3 
Additional Safety Endpoints 
The following safety variables will be assessed: 
 
Physical examination during 24-weeks of treatment and 48-weeks follow-up 
 
Electrocardiogram during 24-weeks of treatment and 48-weeks follow-up 
 
Vital signs during 24-weeks of treatment and 48-weeks follow-up 
 
Laboratory safety assessments during 24-weeks of treatment and 48-weeks follow-up 
3 
OVERALL STUDY DESIGN 
3.1 
Overview of Study Design 
This is a parallel, double-blind, multicentre, randomised clinical trial in autoimmune 
pulmonary alveolar proteinosis subjects, where a planned total of 135 subjects (see section 
3.2) are stratified according to whether or not a WLL has been conducted within 2 months 
prior to the Baseline (according to protocol version 4.0 and later versions), or whether or not 


 
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WLL was conducted between the screening visit and the randomization visit (according to 
protocol versions before version 4.0). Subjects will be randomised 1:1:1 to receive treatment 
for up to 24 weeks with either; 
 
1) Inhaled molgramostim (300 µg) administered once daily,  
2) Inhaled molgramostim (300 µg) and matching placebo administered intermittently 
(12 cycles of seven days molgramostim, seven days placebo; both administered once daily) 
or  
3) Inhaled placebo administered once daily.  
The trial includes two phases; a Double-blind treatment period consisting of up to eight trial 
visits (Screening, Baseline, and at Weeks 4, 8, 12, 16, 20 and 24 after randomisation) and a 
Follow-up period consisting of up to five trial visits (at Weeks 4, 12, 24, 36 and 48 post-
treatment). During the follow-up period all subjects recruited under protocol version 4.0 or 
later versions will receive treatment with inhaled molgramostim (300 μg) administered once 
daily in an intermittent regimen for 24 weeks (12 cycles of seven days molgramostim, seven 
days off). Patients recruited under protocol version 2.0 were only to receive treatment in the 
follow-up period in case of worsening of aPAP, and patients recruited under protocol version 
3.0 were treated (if needed) using the intermittent regimen for 24 weeks and according to 
investigator’s discretion for 24 additional weeks. Likewise, the 36 and 48-weeks post 
treatment visits are only applicable for subjects included before approval of protocol version 
4.0. 
 
Figure 1 
Overall Trial Design 
 
 
 
3.2 
Determination of Sample Size 
The trial is a randomised 3-arm trial in which two thirds of the subjects receive active drug 
and one third receive placebo. 
The sample size calculation was based on data in an earlier trial, where the mean (and 
standard deviation) (A-a)DO2 were 31.3 (7.4) before treatment and 12.9 (7.6) after treatment 


 
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(all measured in mmHg). The minimum clinically relevant difference to detect between active 
and placebo arms is considered to be 10-12 mmHg.  In order to ensure such an effect size 
can be detected, a delta of 10 mmHg has been used in the sample size calculation which is 
based on an unpaired t-test of mean difference between the two active arms (combined) vs. 
placebo, using a significance level of 0.01 and a power of 90%. 
The trial will test the null hypothesis 
H0: μdiff = 0 
Versus the alternative hypothesis 
H1: μdiff ≠ 0. 
The calculation was based on an unpaired t-test using nQuery Advisor® 7.0.  In versions of 
the protocol including Version 4 and earlier, it was intended that an analysis of the two active 
dose groups combined, versus placebo, would be carried out, hence the sample size 
calculation was made based on a 2:1 allocation. 
 
Table 1 
Two Group T-Test of Equal Means (Unequal n's) 
 Test significance level,  
0.010 
 1 or 2-sided test? 
2 
     Difference in means, 1 - 2 
10.000 
     Common standard deviation,  
7.500 
 Effect size,  = |1 - 2| /  
1.333 
 Power (%) 
90 
     n1 
14 
     n2 
28 
 Ratio: n2 / n1 
2.000 
 N = n1 + n2 
42 
 
Based on the assumption listed in Table 1, above, 42 subjects would initially be required to 
be randomised.   
Based on a subsequent evaluation of variability and plausible effect sizes for the key 
secondary endpoints, the sample size was increased to 90 subjects (30 subjects in each 
treatment arm) in Substantial Protocol Amendment 11 (06 June 2017), to increase the power 
to identify statistically significant treatment effects also on one or more of the key secondary 
endpoints.  
Very limited data on these secondary endpoints are available but with a sample size of 30 
subjects per group, it would be possible to show a treatment effect of 50 m on the 6MWD 
(assuming a SD of 50) or of 10 points on the SGRQ (assuming a SD of 10) with 
approximately 90% power. 
Because of the limited data available, a fully blinded sample size re-estimation procedure 
was carried out to assess the standard deviations of the 6MWD and the SGRQ, and the 
overall event rate of WLL. This was planned to be done in January 2018 when approximately 
50 patients were expected to have reached 24 weeks of treatment. 
The change from baseline to week 24 in 6MWD [and SGRQ] was analysed in an ANCOVA 
model including WLL (stratification) and baseline 6MWD [SGRQ] in order to estimate the SD.  
For the purposes of the sample size re-estimation process, only data on patients who had 
baseline and week 24 data was used, and no imputations were made for missing values.  
Additionally, the event rate for WLL was determined including any patients who met the 
criteria for WLL any time prior to week 24, but excluding any patients who withdrew prior to 
week 24 where WLL had not been required. 
 


 
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Based on a literature review of different pulmonary indications but with main focus on 
Idiopathic Pulmonary Fibrosis carried out in November 2017, the minimal clinically important 
effect sizes for 6MWD and SGRQ in aPAP were considered to be in the order of 40-50 m 
and 7-10 points, respectively. From each ANCOVA model, the respective residual variance 
for 6MWD [and SGRQ] were used to calculate sample size based on the effect sizes of 50 m 
and 10 points, respectively. Similarly, the sample size for comparing WLL rates of 5% 
(active) versus 20% (placebo) at 24 weeks was evaluated, based on the observed (pooled) 
WLL rate. All calculations were made based on a 2-sided 5% significance levels, and 80% 
and 90% power. 
 
If the maximum of these sample size calculations were to be no more than 33 patients per 
group, then no change to the target sample size would be made.  Otherwise, the sample size 
would be increased to attain 90% power for at least 2 of the 3 key secondary endpoints, 
subject to the total study size not exceeding 150 patients. 
 
From these sample size calculations conducted in January 2018 it was clear that the two key 
secondary endpoints with highest power to detect a clinically relevant difference between 
treatment groups based on the least number of subjects were SGRQ Total Score and 
6MWD. Based on the pre-defined criterion that the sample size would be increased to attain 
90% power for at least 2 of the 3 key secondary endpoints, the results indicate that the 
critical endpoint is the 6MWD, which would require that the sample size should be increased 
to at least 43x3=129 randomised subjects. After reviewing the results from the sample-size 
recalculation it was decided by Savara ApS to increase the sample size to 45x3=135 
randomised subjects. Any subjects already in screening at the time of reaching 135 
randomised subjects would also be randomised, if otherwise eligible for the trial.  
 
The detailed results of the sample size re-estimation were documented in a separate report 
and are available in Appendix 2 to the SAP. 
4 
DATA SETS TO BE ANALYSED 
The following analysis sets will be used for the statistical analysis and presentation of data 
during the DB (Double Blind) period:  
Safety set (DB-SAF): All randomised subjects who received at least one dose of the trial 
drug, will be analysed according to actual treatment. 
Full analysis set (DB-FAS): All randomised subjects, will be analysed according to 
randomised treatment. 
Per-protocol set (DB-PPS): All randomised subjects who have completed Visit 8 and are 
deemed to have no important protocol deviations that could interfere with the objectives of 
this trial, will be analysed according to actual treatment. 
Important deviations of eligibility criteria and other deviations from the protocol will be 
assessed by TFS in cooperation with the sponsor. Important deviations from the protocol 
may lead to exclusion of a subject from the DB-PPS. All such decisions will be made and 
documented before the trial database is unblinded. 
If not otherwise stated, all efficacy endpoints will be analysed based on DB-FAS. Although 
analyses of primary and key efficacy endpoints will be performed on both the DB-FAS and 
the DB-PPS, the DB-FAS will be considered the primary analysis population. 
Safety summaries will be performed on the safety set (DB-SAF). 


 
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Analysis sets to be applied for the follow-up period will correspond to the analysis sets for the 
double-blind period, although the follow-up period analysis sets will include only subjects not 
withdrawing from the trial before the follow-up period begins and who has at least one follow-
up period data-point. The follow-up period FAS and SAF will be denoted FU-FAS and FU-
SAF, respectively. In addition, the subgroup of subjects receiving the intermittent dosing 
regimen during the follow-up period (i.e. the vast majority of follow-up period subjects) will be 
evaluated alone (FU-MOL-INT).  
5 
STATISTICAL AND ANALYTICAL PLANS 
The planned tables, figures and listings are presented in Appendix 1. 
5.1 
Changes in the Planned Analyses 
This SAP is based on protocol versions and amendments described in section 1.  Compared 
to these, the following changes have been implemented in the SAP: 
 
All model-based analyses will include adjustment for a dicotomeous categorization of 
country as Japan vs other countries. 
 
A number of additional subgroup analyses were added, as described in section 5.8. 
 
An additional sensitivity analysis for the primary endpoint was added for handling of 
subjects who had a WLL (section 5.3.6) 
 
Number of WLLs over time, was included as a further secondary endpoint in the 
double-blind period, as described in section 5.3.7.   
5.2 
Blind Review 
The trial will be unblinded and the primary analysis will be conducted after all subjects have 
completed the 24-week Double-blind period. Data will be reviewed on an ongoing basis 
before the database is locked and unblinded. Clarifications of specific data decisions, having 
an impact on the planned analyses, which are identified in connection to the blind review, 
after finalization of the SAP, will be included in a separate “pre-analysis review” document, 
which will be signed before unblinding. Final classification of subjects according to study 
populations will be also documented and included in the pre-analysis-review document.   
 
In this trial, analyses related to the double-blind (DB) treatment period will be reported after 
last subject has completed the treatment period, thus a partial DB data base lock will be held 
and all data up to that point will be cleaned and locked before unblinding. Further data review 
and cleaning, related to the open label follow-up period, will be done and any new decisions 
will be documented in a separate pre-analysis review document before a final complete FU 
data base lock. Locked data for the double-blind period cannot be changed after the partial 
data base lock, except for any ongoing safety evaluations that have not yet been resolved at 
the time point of the partial DB data base lock.  
5.3 
Hypotheses and Statistical Methods 
5.3.1 
General 
For all efficacy analyses, primary and secondary, where statistical tests are conducted (see 
separate sections below) the null hypothesis is that there is no treatment difference, which 


 
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will be tested against the alternative hypothesis, that there is a treatment difference. All tests 
will be two-sided.  
In general, all summary statistics will be presented for all treatment groups. 
In this trial, for subjects withdrawing from treatment early, attempts will be made to continue 
follow-up and collect the planned data, as described in protocol.  If a subject is withdrawn 
from the trial early, the investigator should attempt to complete all required trial assessments 
(such as those at Week 24 if withdrawn during the Double-blind treatment period). 
Assessments for subjects withdrawing from trial early, and where any measurements related 
to endpoints to be statistically analysed are collected on the Week 24 Visit in the eCRF, (i.e. 
if intermittent visits are missing), then these assessments will be reallocated to the visits 
closest in time to the time point of withdrawal. This is done in order to avoid an unintended 
partial LOCF approach to analysis of data. 
 
For statistical analyses of the primary and key secondary efficacy endpoints, the type-1 error 
rate will be controlled, as described in section 5.4. In addition a number of sensitivity 
analyses will be conducted, as described in the following sections. An overview of the 
planned statistical analyses and how inflation of alpha, due to multiple testing, will be 
prevented can be seen in figure 2. 
Results applicable to the follow-up period will be summarised both according to randomised 
treatment arms under the double-blind treatment period and in total.  
 


 
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5.3.2 
Definitions 
Baseline 
Baseline measurements refers to the last non-missing assessment 
made before randomisation. If a measurement is intended to be 
collected at the baseline visit, but is missing, then a corresponding 
measurement taken at the screening visit may be used to replace the 
missing assessment at the baseline visit.  
Relative day  
The relative day of an event is derived as follows: 
 
 
 
Relative day = (Start date)-(Date of first administration of IMP)+1.  
For days before the start date, calculate as Relative day = (Start date)-
(Date of first administration of IMP). In this way, there will be no day=0. 
So, Day 1 is the same day as the day of first administration of IMP, 
and Day -1 is the day before. 
(A-a)DO2  
Alveolar-arterial oxygen difference is a measure of the difference 
between the alveolar concentration (A) of oxygen and the arterial (a) 
concentration of oxygen 
DLCO  
Uptake of carbon monoxide from a single inspiration in  standard time. 
FEV1 
The volume of air that can forcibly be blown out in one second, after 
full inspiration. 
FVC 
The maximum amount of air a person can expel from the lungs after a 
maximal inhalation and during a forceful expiration. 
SpO2 
Indirect measurement of oxygen saturation using a finger probe, ear 
sensor or similar device. 
6MWT 
Test used to measure the distance that a subject can walk quickly on a 
flat hard surface in a period of 6 minutes (at an individually 
predetermined oxygen supplementation). 
VC 
The maximum amount of air a person can slowly expel from the lungs 
after a maximum slow inhalation. 
% predicted  
Calculation of % predicted of spirometry parameters collected during 
the double-blind period will be made centrally for statistical analysis 
using the same equation for all sites.  
Region  
For summaries and figures split by region ‘Europe’ will include: 
Denmark, France, Germany, Greece, Italy, Netherlands, Portugal, 
Russia, Slovakia, Spain, Switzerland and United Kingdom. ‘Other’ will 
include: Australia, Israel, South Korea and Turkey while Japan and the 
United States will be defined as their own regions. 
 
5.3.3 
Summary Statistics 
Data will be summarised by means of summary statistics. For continuous data the following 
summary statistics will be presented: number of observations, mean value, standard 
deviation, minimum, first quartile, median, third quartile and maximum value. Categorical 
data will be presented as counts and percentages. The data will be presented by visit.  
Baseline, demographics, primary endpoint, and key secondary endpoints will also be 
summarised by region. 


 
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Summary statistics will be presented by treatment group and assessment time and/or visit, 
as applicable.  
5.3.4 
Subject Data Listings 
Data collected in the eCRF, as well as any derived assessments used for statistical 
analyses, will generally be listed in Appendix 16.2 (see section 7.2). eCRF check questions 
[e.g. lab samples taken (Yes/No)] and reminders may not be listed. Listings will primarily be 
sorted by centre, subject-number and visit and/or any other natural ordering related to the 
applicable assessment. 
In CRF modules where a date is recorded, the date and the relative day (in relation to date of 
randomisation) will be printed in the corresponding listing. In modules where both a start date 
and stop date is recorded, also a duration will be included in the listings. 
5.3.5 
Demographic and other Baseline Characteristics 
A subject disposition will be produced, including number of subjects screened, randomised, 
withdrawn from trial (with reason for withdrawal), number of subjects withdrawing from 
treatment but remaining in trial, number of subjects completing double-blind treatment period 
and follow-up, number of subjects included in the safety analysis, full analysis and per 
protocol sets.  Demographics, standard baseline characteristics and aPAP history data will 
be presented using summary statistics. Data that is measured both before baseline and at 
other visits following randomisation will in general be presented in other sections in by visit 
displays.  
5.3.6 
Primary Efficacy analysis 
The primary efficacy variable, (A-a)DO2, will be collected at Screening, Baseline 
(randomisation), Week 4, 12 and 24 during treatment period, and at Week 12, 24, 36 and 48 
during the follow-up period. All (A-a)DO2 values reported in the CRF will be recalculated for 
statistical analyses using the equation: 
 
where FiO2 is fraction of inspired oxygen 
 
 
 
Patm is ambient atmospheric pressure 
PH2O is saturated vapour pressure of water at body temperature (set to 47 
mmHg / 6.266 kPa)  
 
PaCO2 is arterial partial pressure of carbon dioxide 
 
PaO2 is arterial partial pressure of oxygen 
 
Any of these assessments reported in kPa will be converted to a result in mmHg before the 
calculations, this will be done using a factor k=7.5. 
The primary efficacy endpoint, absolute change from baseline of (A-a)DO2 after 24-weeks 
treatment, will be analysed based on an ANCOVA model including treatment group, WLL 
(stratification), Japan vs other countries, and baseline (A-a)DO2. The data from the three 
treatment groups will be analysed all together (all treatment groups included in one model). 
Contrasts will be set up to estimate treatment differences in change from baseline with 95% 
confidence intervals (CI) and the corresponding p-value for Molgramostim OD vs. Placebo 
and for Molgramostim intermittently vs. Placebo.  
For each analysis two sided tests will be performed where the null hypothesis is that there is 
no difference between treatment groups, which will be tested against the alternative that 


 
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there is a difference. Control for type-1 error inflation due to multiple testing will be handled 
as described in section 5.4. 
A de-facto estimand approach will be applied, where for the primary analysis, all observed 
data will be included, irrespective of subject adherence to the randomised treatment. 
Subjects who withdraw from their randomised treatment before week 24 will be followed up 
through to week 24, and their week 24 data will be considered as primary, irrespective of 
treatment discontinuation, treatment interruption(s), use of rescue medication (WLL or other), 
etc. 
All assessed (A-a)DO2 measurements, and the corresponding changes from baseline will be 
summarised by visit and treatment group. In addition, similar summaries of (A-a)DO2 will also 
be produced excluding data collected during treatment discontinuation, treatment 
interruption(s) and use of rescue medication (WLL or other). The decision of what data will 
be excluded and the reason will be identified during the blind review of data and documented 
in the “Pre-analysis-review”-document before data base lock (DBL). 
Mean profiles for (A-a)DO2 observed values and change from baseline over time will be 
provided.  
 
Sensitivity Analyses 
The following sensitivity analyses for the primary endpoint will be done in order to evaluate 
the robustness of the results in relation to influence of any missing data. The sensitivity 
analyses should be considered supportive analyses and will thus not be part of the 
procedures applied to control type-1 error rate for testing hypotheses for primary and key 
secondary efficacy endopints as described in section 5.4.  
 
 
A mixed model for repeated measures (MMRM) will be applied including fixed, 
categorical effects for treatment, WLL (stratification), visit, treatment-by-visit 
interaction, Japan vs other countries, and fixed covariates for baseline (A-a)DO2. An 
unstructured covariance matrix will be applied to model the within-subject errors, if 
possible. If this analysis fails to converge, compound symmetry will be tested. 
Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. This methodology does not require imputation of missing data. Instead 
missing data is modelled based on the subjects’ available data and on other subjects’ 
data over time (this approach is valid under assumption that data is missing 
according to ‘Missing at Random’ (MAR)) [2]. 
 
Subjects who withdraw from the study early and who do not have week 24 data 
available will have their (A-a)DO2 measurement imputed using multiple imputation 
(MI). This will be done by first ensuring a monotone missing data pattern by 
imputation of intermediate missing data (baseline, Week 4 and Week 12) by a Markov 
chain Monte Carlo (MCMC) approach, where imputations are done by treatment 
group Japan vs other countries, and WLL (stratification) if possible (strata may be 
dropped depending on the number of observations per combination). The imputation 
will be done generating 10 data sets. When monotone missingness has been 
accomplished, then the remaining missing data, up to and including Week 24, will be 
imputed using a monotone regression approach using treatment and WLL 
(stratification) as class variables. Each replication of the data, including the imputed 
missing values, will then be analysed using the ANCOVA used in the primary 
analyisis, and estimates will be pooled using proc MIANALYZE SAS®. (this approach 
is valid under assumption that data is missing according to MAR). 


 
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 
If superiority has been determined for any of the comparisons planned for the primary 
endpoint, a tipping point analysis (TP) will be applied where subjects with a missing 
endpoint (Week 24) in the group for which superiority has been determined will be 
assigned progressively worse (A-a)DO2. This will be done by generating imputed data 
according to the previous step and using the MNAR option in proc MI SAS® to adjust 
imputed Week 24 data with an appropriate sized shift paramter in the superior arm in 
an iterative manner until the results shift from significant (P<0.05) to non-significant 
(P>0.05). From this analysis, results will be presented including overall estimates at 
the tipping point, as well as descriptive statistics for imputed data vs non-imputed 
data.  
 
A “reasonably worst case” scenario. For the primary analysis, patients in either of the 
active arms will have the value of the 10th percentile from their dose arm imputed (i.e. 
approximately the 3rd worst case) whilst patients in the placebo arm will have the 
median for the placebo arm imputed. This analysis will be based on the same 
ANCOVA model as applied for the primary analysis. 
The above sensitivity analyses can be considered as de-facto approaches. The following 
sensitivity analyses will also be conducted as de-jure estimation approaches to 
evaluating data: 
 
A sensitivity analysis will be done in order to evaluate the robustness of the results 
due to subjects having WLL, open-label molgramostim or rituximab (rescue 
treatment). For these subjects, all (A-a)DO2 measurements following the rescue 
treatment will be excluded and then re-imputed using multiple imputation (in the same 
way as described above for imputing data for subjects withdrawn from the study 
early, and who do not have week 24 data available).  These subjects will contribute 
with their data available prior to the rescue treatment and imputed data following the 
rescue treatment 
 
A completer analysis will be done, including only data for subjects who completed the 
24 weeks and who did not discontinue treatment. This analysis will be based on the 
same ANCOVA model as applied for the primary analysis. 
 
The primary analysis will be repeated for PPS. 
 
5.3.7 
Secondary Efficacy Analyses 
 
Key Secondary Efficacy Analyses 
The following key secondary efficacy endpoints are considered confirmatory endpoints and 
will therefore be part of the testing procedure in order to control for multiplicity as described 
in section 5.4.  
 
Absolute change from baseline in 6 minute walking distance and in SGRQ total score after 
24-weeks treatment 
6 minute walking distance (6MWD) 
The 6 minute walking distance (6MWD) is captured as part of the 6 minute walk test (6MWT) 
(See general description of 6MWT under Further Secondary Efficacy Analyses). Absolute 
change from baseline in 6 minute walking distance, will be summarized by treatment group 
and visit. The key secondary endpoint, absolute change from baseline after 24 weeks of 
treatment, will be analysed as described below. 


 
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St Georges Respiratory Questionnaire (SGRQ) 
The St Georges Respiratory Questionnaire (SGRQ) is a respiratory specific questionnaire. 
The symptoms component with 3-month symptoms recall is used. The three domain scores, 
Symptoms, Activity, and Impacts and the Total score will be calculated.  Scores are 
expressed as a percentage of overall impairment where 100 represents worst possible health 
status and 0 indicates best possible health status. The standard scoring algorithms will be 
applied, as described in the St George’s Respiratory Questionnaire Manual Version 2.3, 
June 2009. 
The three derived domain scores and total score, and the corresponding changes from 
baseline will be summarised by treatment group and visit. Individual item responses will only 
be listed. The key secondary efficacy endpoint, Change from baseline in SGRQ total score 
after 24-weeks of treatment will be analysed as described below. 
 
Analysis of change from baseline after 24 weeks of treatment in 6 minute walking distance 
(6MWD) and Total SGRQ 
Absolute change from baseline in 6MWD and in SGRQ will be analyzed using the same 
ANCOVA model as for (A-a)DO2, including all data irrespective of adherence to treatment 
regimens as the main approach, and the results from these analyses will be part of the 
procedures to control for multiple testing (see section 5.4). 
 
Sensitivity analyses for absolute change from baseline in 6MWD and SGRQ will be done 
using similar approaches as those used for the sensitivity analyses for (A-a)DO2, but will be 
limited to:  
 
Mixed model for repeated measurements (MMRM),  
 
ANCOVA after multiple imputation,  
 
ANCOVA completer analysis 
 
ANCOVA based on the per protocol set (PPS). 
 
Mean profiles for 6MWD and SGRQ over time will be provided.  
 
Time to WLL during 24-weeks treatment  
Kaplan-Meier plots will be used to assess time to WLL (time from randomisation to 
documentation of fulfilment of criterion for requiring WLL) and treatment comparisons 
corresponding to those made for primary endpoint, will be analysed by a logrank test 
adjusting for the randomisation strata (WLL). Subjects who fulfil the criteria for rescue 
treatment (i.e., worsening of aPAP based on symptoms, reduced exercise capacity and/or 
findings of hypoxemia or desaturation according to the Investigator’s judgement), will be 
counted as if WLL was conducted at the date of fulfilment of rescue treatment criteria. In this 
analysis, subjects withdrawing from the trial will be handled as censored at time of 
discontinuation, and subjects who reach week 24 and have not needed WLL will be censored 
at time point for Visit at week 24. Survival estimates for time to WLL will be tabulated for 
subjects in each group who require WLL, by relevant time points, along with 95% Cis. 
 
Sensitivity analyses for time to WLL will be carried out as follows: 
 
 
Any subject withdrawing from trial before week 24 and before fulfilling criteria for WLL 
will be handled as having WLL the day after discontinuation date. This is done to 


 
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evaluate the impact of missing data and censoring due withdrawals. The same 
analyses as planned above will be conducted in order to evaluate the robustness of 
results with regards to the handling of censoring. 
 
A Cox regression will be applied where the hazard ratio and its 95% confidence 
interval will be estimated, while including adjustment for treatment, Japan vs other 
countries and WLL (stratification). The analysis will be done using the same approach 
for handling censoring as done in the main analysis. 
 
Further Secondary Efficacy Analyses 
The further secondary efficacy endpoints will be statistically analysed, although the analyses 
will be considered supportive rather than confirmatory, and will therefore not be part of the 
testing procedures implemented for primary and key secondary efficacy endpoints to control 
for multiplicity.  
All data will be tabulated using summary statistics including levels at each visit and change 
from baseline for continuous data, and counts and shifts including percentage of subjects 
within categories for frequency data. Tables will be based on all observed data applicable to 
the FAS population. 
Number of WLLs over time 
A Generalized Linear Model, based on the negative binomial distribution, is planned for 
analysis using the number of WLLs as the dependent variable and will include treatment 
group and the stratification factor of whether or not a WLL was conducted within 2 months 
prior to the Baseline (according to protocol version 4.0 and later versions), or whether or not 
WLL was conducted between the screening visit and the randomization visit (according to 
protocol versions before version 4.0), and country (Japan vs. all others) as fixed effects. The 
analysis will be adjusted for each subject’s length of follow-up in the trial. The rate ratio (each 
active dose group: placebo) will be derived from the model along with the 95% 2-sided 
Confidence Intervals. Model adjusted mean rates for each treatment group will be derived. In 
this analysis each lung lavaged contributes as an event in the count per subject, regardless 
of whether both lungs are lavaged on different days or on the same day. Events with the date 
of criteria met in the double-blind period will be counted as being conducted in the double-
blind period. 
6 minute walking test (6MWT) 
Each item related to the six minutes walk test (6MWT) will be summarized by visit. 
Summaries will include distance and duration of walk during the test, the pre and post walk 
Borg CR10, the derived change in dyspnoea score (post walk Borg CR10 score – pre walk 
Borg CR10 score), the SpO2 at start and the worst SpO2 during the walk, blood oxygen 
desaturation derived as (SpO2 at start – Worst SpO2 during the walk). Change from baseline 
after 24 weeks of treatment in; blood oxygen desaturation, difference in pre- to post-test 
dyspnoea score and distance and duration of walk will in addition be summarized separately 
including categorical variables corresponding to improved tolerance to exercise (derived as 
increase in distance walked ≥50 m (compared to baseline) or desaturation <4 percentage 
points on the 6MWT, respectively), see below. 
CT scan 
CT scans will be centrally evaluated by two independent and blinded assessors at the 24 
weeks treatment visit where change in relation to the baseline assessment will be graded as: 
Improved, Worsened, No change, Data missing or Impossible to evaluate. This evaluation, 
as well as the Ground-Glass Opacification (GGO) score for each anatomical area (upper, 
middle and lower), (graded as: no GGO, less than 5%, 5-24%, 25-49%, 50-74%, 75% or 
more GGO) will be summarized in frequency tables by treatment group including proportion 


 
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of subjects reaching each grade. The number of subjects with, and without, improvements 
will be analyzed (see, below). 
 
Continuous endpoints  
The following continuous endpoints will be analysed using the same main model (ANCOVA) 
as applied for primary endpoint, including all collected data irrespective of adherence to 
treatment regimens. 
 
Absolute change in VC (% predicted), haemoglobin corrected DLCO (% predicted), 
FEV1 (% predicted), and FVC (% predicted), and relative change in PaO2 from 
baseline after 24 weeks of treatment. 
 
Change from baseline in pre and post-exercise dyspnoea scores and cough scores 
(severity and frequency VAS scores) after 24-weeks treatment.  
 
Categorical Endpoints 
Number of subjects classifed as having improvements in parameters, as defined below, will 
be summarised by visit in freqency tables, including cumulative counts. Logistic regression 
models will be applied to statistically analyse if proportion of subjects having improvements 
differ between treatment groups according to the same groups as applied for analyses of 
primary and key secondary endpoints. The logistic regressions will include the same 
covariates as for main analysis of primary endpoint, although with the baseline covariates 
corresponding to each respective endpoint. The complement in these analyses, subjects not 
reaching improvements according to the categorisations, will be based on the total number of 
subjects applicable to the FAS population.  
 
Number of subjects with >5 mmHg/>0.67 kPa and number of subjects with 
>10 mmHg/>1.33 kPa improvement in (A-a)DO2 after 24-weeks treatment  
 
Number of subjects with >5 percentage points and number of subjects with 
>10 percentage points improvement in VC (% predicted) after after 24-weeks 
treatment 
 
Number of subjects with >10 percentage points improvement in DLCO (% predicted) 
after 24-weeks treatment  
 
Number of subjects with >10 percentage points improvement in FEV1 (% predicted) 
after 24-weeks treatment 
 
Number of subjects with >10 percentage points improvement in FVC (% predicted) 
after 24-weeks treatment  
 
Number of subjects with >10% relative improvement in PaO2 after 24-weeks 
treatment 
 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m or desaturation <4 percentage points on the 6MWT) compared to baseline 
after 24-weeks treatment 
 
Number of subjects with improved CT score after 24-weeks treatment  
 
5.3.8 
Exploratory Efficacy Analyses 
Exploratory secondary efficacy endpoints will only be summarised descriptively by visit and 
treatment group unless otherwise specified below. 


 
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Double-blind treatment period 
Absolute change from baseline in Blood Gas and Lung Function Tests 
Absolute change from baseline of (A-a)DO2, VC (% predicted), DLCO (% predicted), FEV1 (% 
predicted), FVC (% predicted), and relative change from baseline of  PaO2 after 4 and 12-
weeks treatment will be summarised by visit according to description in previous sections.  
Time period during which the (A-a)DO2 level is maintained below Baseline minus 10mmHg 
This time period will be defined as the difference between the date of the visit where the (A-
a)DO2 level first reaches below the baseline level minus 10 mmHg and the date of the first 
visit where the where the (A-a)DO2 level first reaches above the baseline level minus 
10mmHg. For subjects never reaching the first threshold before ending the double-blind 
treatment period, the time period will be set to zero, and for subjects never reaching the 
second treshold, the time period will be set to the duration between the visit where the first 
treshold it reached and the last visiti of the double-blind treatment period. This time period, in 
days, will be summarised descriptively. 
Number of subjects with improved tolerance to exercise 
Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m 
(compared to baseline) or desaturation <4 percentage points on the 6MWT, respectively) 
after 4 and 12-weeks treatment will be summarised by visit according to description in 
previous sections. 
Time period during which the improvement in tolerance to exercise is maintained   
The time period during which the improvement in tolerance to exercise is maintained will be 
defined as the difference between the date of the visit where subjects are for the first time 
classified as having improvement in tolerence to exercise, defined as increase in distance 
walked ≥50 m (compared to baseline), and the date of the first visit where the increase in 
distance walked is above ≥50 m compared to baseline on the 6MWT. This time period, in 
days, will be summarised descriptively. 
Dyspnoea score and cough scores 
Change from baseline in dyspnoea score and cough scores (severity and frequency) after 4 
and 12-weeks treatment wil be summarised as described in previous sections for 24 weeks 
of treatment.   
Number of subjects with improved QoL (change of ≥4 units on the SGRQ The St Georges 
Respiratory Questionnaire (SGRQ) was described under Key secondary efficacy endpoints. 
The three derived domain scores and total score, and the corresponding changes from 
baseline will be summarised by visit. Individual item responses will be listed.  
Subjects who have an improvement of more than 4 units from baseline on the SGRQ total 
score will be counted by visit and treatment group. The number of subjects with improvement 
of more than 4 units from baseline on the SGRQ total score will be summarised in the way 
that other categorical data are summarised. 
Number of subjects with ‘no problems’ in EQ-5D after 4, 12, and 24-weeks treatment 
The EuroQol-5D (EQ-5D) will be used to measure health outcome in terms of mobility,self 
care, usual activities, pain/discomfort, anxiety/depression. The 5 level instrument (EQ-5D-5L) 
which uses a 5-point scale (no problems, slight problems, moderate problems, severe 
problems, and extreme problems) will be used in the local language. A VAS-scale is also 
included in the EQ-5D questionnaire. Each dimension/item score and the number of subjects 
in each state will be summarised by visit including the corresponding change from baseline. 


 
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Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
23 (45) 
Number of subjects where each item on the EQ-5D are scored with the highest outcome, 
indicating no problems, will likewise be counted by visit and treatment group. The number of 
subjects with each item, scored as “no problems” on EQ-5D will be summarised in the way 
that other categorical data are summarised.  
Change in serum concentration of possible biomarkers 
The possible biomarkers KL-6, CEA, SP-A, SP-B , SP-C, SP-D, Cyfra 21-1 and LDH will be 
summarised by visit after 4, 12, and 24-weeks treatment including both observed values and 
change from baseline.  
Levels of anti-drug antibodies (anti-GM-CSF, anti-Polyethylene glycol (anti-PEG) and anti-
recombinant Human Albumin (anti-rHA)  
Number of subjects with and without measured anti-drug antibodies (positive/negative), 
number of subjects with neutralising antibodies where tested, actual anti-drug antibody titers, 
and any titer increase or decrease >2 or >4 fold over baseline titer, will be summarised by 
visit using standard descriptive summary statistics.  
Sampling for anti-drug antibodies in France is more frequent than for the other countries, 
thus additional summaries only including data collected in France will be prepared.  
Similar summaries will be done for double-blind treatment period and the Follow-up period. 
Change in serum concentration of GM-CSF post first dose of trial drug and after 4-weeks 
treatment 
Pre and 2h post dose serum concentration of GM-CSF, and the corresponding changes (2h 
post dose measurement – pre dose measurement) will be summarised for first dose of trial 
drug and after 4 weeks of treatment.    
In US sites, additional sampling is done 12 and 24 weeks after randomization, and at week 
12 during follow-up, including pre and 2h post dose. These US sampling data will be 
summarised separately, in the same way as described above.  
For sites in Japan additional sampling is done, including pre-dose and samples at 1, 2, 4 and 
8 hours post dose. These sampling profiles for Japan will be summarised separately. If 
applicable (sufficient number of samples have GM-CSF concentrations above LLOQ) 
standard PK parameters will be derived and evaluated, and the results will be provided in a 
separate PK-report. 
Number of subjects in need for oxygen supplement therapy 
Number of subjects in need for oxygen supplement therapy, will be summarised by visit 
during 24-weeks treatment. The number of subjects in need for oxygen supplement therapy 
will be defined based on actual use of oxygen supplementation as recorded in concomitant 
therapy. Oxygen therapy will be summarised separately according to start and stop date of 
therapy, in the same way that other concomitant medication is presented. Proportion of 
subjects with supplemental oxygen therapy will be compared between treatment groups 
using a logistic regression model including treatment, baseline use of supplemental oxygen 
therapy, strata, and Japan vs Other countries.   
The distribution of DSS at Screening and at Week 24 
Shift tables will be produced for observed DSS scores at Screening/Baseline vs Week 24, 
displaying both the visit distributions and the shifts between visits. Similar shift tables will also 
be produced displaying number of subjects with a DSS score of 1 or 2, vs number of subjects 
not reaching a DSS score of 1 or 2.  
Follow-up period  


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
24 (45) 
The following endpoints related to visits in the follow-up period will be summarised, both by 
randomised treatment during the double-blind treatment period and in total, in the same way 
that the corresponding endpoints during the double-blind treatment period is summarised.  
 
Number of subjects requiring WLL, or other treatment for aPAP and number of 
treatment courses required during 24 and 48-weeks follow-up   
 
Time to WLL, or other treatment for aPAP during 24 and 48 weeks follow-up   
 
Absolute change from baseline in (A-a)DO2 and VC (% predicted), DLCO 
(% predicted), FEV1 (% predicted), FVC (% predicted), and relative change from 
baseline of PaO2 after 12, 24, 36 and 48-weeks follow-up 
 
Number of subjects with improved tolerance to exercise (increase in distance walked 
≥50 m (compared to baseline) or desaturation <4 percentage points on the 6MWT, 
respectively) after 12, 24, 36 and 48-weeks follow-up 
 
Levels of anti-drug antibodies (anti-GM-CSF, anti-Polyethylene glycol (anti-PEG) and 
anti-recombinant Human Albumin (anti-rHA)) after 12 and 24 weeks follow-up 
 
The distribution of DSS after 24 and 48-weeks follow-up 
 
The percentage of subjects with DSS 1 or 2 after 24 and 48-weeks follow-up 
In addition to the above endpoints described in the protocol, (A-a)DO2 values collected during 
the follow-up period will be summarised only including values assessed based on arterial 
blood gas samples, excluding capillary samples. 
5.3.9 
Exposure to Treatment 
Exposure to treatment 
DB period: exposure will be calculated as the number of days from the date of the first dose 
(as recorded in Trial Drug part of CRF) to the date of Visit 8 or until date of discontinuation of 
double-blind Treatment, whichever occurs first. 
FU period: exposure for patients enrolled under protocol versions 1 through 3 will be 
calculated from start and stop dates in the Concomitant Medication part of the CRF. 
Exposure for patients enrolled under protocol versions 4 through 5 will be calculated from the 
date of Visit 8 to the date of Visit 11 or until discontinnuation of treatment. 
Duration of exposure will be summarized/tabulated by treatment group using descriptive 
statistics, including the number and proportion of subjects exposed in defined intervals (at 
least one day to 4 weeks; more than 4 to 8 weeks; more than 8 to 12 weeks; more than 12 to 
16 weeks; more than 16 to 20 weeks, and more than 20 to 24 weeks in the DB period, and 
similarly but in 4-weekly intervals in the FU period).  
Exposure as defined above will also be listed by site and subject (including information on 
premature withdrawal from trial/discontinuation of treatment where relevant). 
Compliance 
Compliance will be calculated as the total number of empty vials returned divided by the total 
number of days in the trial.  
Compliance will be summarized/tabulated by treatment group using descriptive statistics, 
including the number and proportion of subjects in defined compliance intervals (90% or 
more; 80% or more; 70% or more; 50 to 69%; 49% or less). Compliance will also be listed by 
site and subject (including information on premature withdrawal from trial/discontinuation of 
treatment where relevant). 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
25 (45) 
Additional data that will only be listed include: answer to CRF question ‘Medication taken 
according to instruction’ and nebulizer tracking data (not part of the CRF and only available 
in a subgroup of subjects). 
Rescue medication 
Administration of any rescue medication, the type of, reason for, and the corresponding start 
time and time period of rescue medication will be listed separately. 
5.3.10 
Concomitant Medication 
Concomitant medication and concomitant therapy will be summarised as number of subjects 
being treated with each type of medication/therapy classified according to Anatomical 
Therapeutic Chemical (ATC) level 3 and WHO Drug Dictionary preferred term. The safety set 
will be used for these presentations. 
The medications will be divided between those ongoing before baseline (start and end date 
before baseline) or as ongoing after baseline (starting before or after baseline, and stop date, 
or still ongoing, after baseline). Listing of concomitant medication will include all medications 
including an indicator of above defined time intervals.  
If the start date of a concomitant medication is missing, it will be assumed that the 
medication started before treatment. If the date is partially missing, the year and month, if 
available, will be used to decide whether the medication started before baseline or after 
baseline. In summary tables, each subject is only counted once for each drug. 
The safety set will be used for these presentations.  
5.3.11 
Adverse Events  
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
system and tabulated by System Organ Class (SOC) and by Preferred Term (PT). 
A summary table will be presented with No. of subjects with AEs, No. of subjects with serious 
AEs, No. of subjects with severe AEs, No. of subjects with ADRs (probable or possible), 
Number of subjects with at least one AE leading to discontinuation, and also the number of 
AEs, severe AEs, serious AEs, ADRs (where a certain AE is only counted once within each 
subject on a preferred term level). 
The total number of subjects with at least one AE and the number of AEs will be derived and 
summarised by SOC and PT. 
Similar tables will be created for serious adverse events. 
AEs will also be tabulated by severity (mild, moderate and severe) and relationship to 
treatment (probable, possible, unlikely or not applicable). Adverse events occurring or 
worsening after first treatment will be included in summary tables. Any AEs reported before 
first treatment will only be included in listings.  
In listings of AEs the relative day counted from first administration of IMP (Day 1) will be 
presented together with the relative day from the latest administration of IMP (the actual 
dates will also be included).  
5.3.12 
Other Safety Assessments 
Any safety assessments described in this section will be summarised in a similar manner for 
the double-blind and follow-up period, if applicable. 
Vital Signs 
For vital signs parameters (systolic and diastolic blood pressure, heart rate, respiratory rate 
and oral body temperature) summary statistics will be produced for observed values by visit. 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
26 (45) 
In addition, the difference from baseline to each visit at which they were assessed will be 
derived and presented. 
Shift tables that show the number of subjects that changed from normal, abnormal (not 
clinically significant) or abnormal (clinically significant) at baseline to the state at each post-
baseline time of assessment will be presented. 
Clinical Laboratory Measurements 
Clinical laboratory measurements will be assessed at screening, baseline and each visit 
during the double-blind treatment and follow-up period.  
 
Haematology includes: Haemoglobin, Red Blood Cell Count (RBC), Red Blood Cell 
Distribution Width (RDW), Haematocrit (PCV/EVF), Mean cell volume (MCV), Mean cell 
haemoglobin (MCH), Mean cell haemoglobin concentration (MCHC), Platelet count, White 
cell count, and white cell differential absolute count and percentage: Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils, and Prothrombin Time International 
Normalised Ratio (PT-INR).  
 
Clinical Chemistry includes: Aspartate Aminotransferase (AST), Alanine Aminotransferase 
(ALT), Gamma Glutamyl Transpeptidase (GGT), Alkaline Phosphatase, Bilirubin, Urea, 
Creatinine, Potassium, Sodium, Calcium, Chloride, Phosphate, Total protein, Albumin, LDH, 
C-Reactive Protein (CRP), and Glucose (non-fasting). 
 
Specifically for France, Urinalysis includes: Dipstick measuring for proteinuria, haematuria, 
glucosuria and nitrite; and microalbuminuria test. 
 
For all laboratory parameters, summary statistics will be produced for observed values by 
visit. In addition, the difference from baseline to each visit at which they were assessed will 
be derived and presented. The number of normal, abnormal and clinically significant 
observations will be tabulated for each treatment group by visit, and in corresponding shift 
tables from baseline to each following visit. Abnormal values will be flagged in listings.  
For laboratory values which are below the limit of quantification, the value corresponding to 
the limit of quantification will be used when summarising data (e.g. if the result is <0.5 then 
the value 0.5 will be used in the statistical analysis). 
 
ECG 
Electrocardiogram parameters (heart rate, QRS, PR and QT intervals) will be summarised, 
together with changes from Baseline. Corrected QT will be calculated using Fridericia’s 
formula (QTcF) and summarised, together with changes from Baseline.  
Overall interpretation of ECG, normal, abnormal not clinically significant or clinically 
significant abnormalities will be tabulated by visit and data will be presented in shift tables, 
where data before baseline is cross-tabulated versus data at later assessments.  
Physical Examination 
Any abnormal findings in physical examination are reported as medical history or adverse 
events. Overall interpretation of whether any abnormalities where observed (Yes/No) will be 
presented in shift tables where data before baseline is cross-tabulated versus data at later 
assessments. 
CT Scan 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
27 (45) 
Occurrence of adverse findings at week 24 compared to Baseline (Yes/No) will be 
summarised. Description of any adverse findings will be listed. 
5.4 
Level of Significance, Multiple Comparisons and Multiplicity 
For all significance tests, exact p-values (to four decimal places) will be calculated and 
quoted.  
 
There are two dose regimens and one primary efficacy parameter, and three key secondary 
efficacy parameters, which are intended to support conclusions based on the primary 
parameter. For these analyses type-1 error rate will be controlled as described below. In 
addition, sensitivity analyses and several other endpoints will be considered as supportive 
and descriptive, and no adjustments for multiplicity will be made for these analyses. 
 
Two sets of comparisons (for the primary and key secondary endpoints) will be carried out. 
The first will be of once daily dosing vs. placebo, and the second will be of intermittent dosing 
vs. placebo. In order to account for multiplicity, an overall hierarchical testing procedure will 
be applied in the steps between primary and secondary endpoints, while a Hochberg 
procedure will be applied among the secondary endpoints. An overall significance level of 
0.05 will be applied.   
 
The first step will be the test of once daily dosing vs. placebo for the primary endpoint. If the 
null hypothesis is rejected, then once daily dosing vs. placebo will be tested for the three key 
secondary endpoints using a Truncated Hochberg procedure (applying a truncation factor of 
0.75). If at least one null hypothesis is rejected among the key secondary endpoints, then the 
hierarchical testing will proceed with comparing intermittent dosing vs. placebo for the 
primary endpoint based on a significance level depending on the number of successes in 
previous step, as applicable to the truncation factor used. Last, if the null hypothesis is 
rejected for the comparison of primary endpoint in intermittent dosing vs placebo, then the 
key secondary endpoints will be compared for intermittent dosing vs placebo using the 
regular Hochberg and based on an overall significance level corresponding to the previous 
step. The truncated Hochberg procedure using a truncation factor of 0.75 among the tests in 
the family of secondary tests between Molgramostim OD and Placebo, implies ordered alpha 
levels of 0.0417, 0.0229, 0.0167, while preserving alpha 0.05 for the first test between 
Molgramostim Int. and Placebo if all null hypotheses are rejected, and 0.0083 and 0.0042 if 
only two or one of the ordered hypotheses are rejected, respectively. The steps of the testing 
procedure applied to account for multiple testing among the primary and key secondary 
endpoints are illustrated in figure 2.     
 
All of the analyses will be tabulated separately (irrespective of statistical significance), 
although an overview of the results of the steps in the testing procedure will be also 
tabulated. 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
28 (45) 
Figure 2 
Overview of Analyses for Primary and Key secondary endpoints 
 
Results from analyses denoted “Main analysis” will be part of testing procedures where adjustments to control for 
multiple testing will be implemented. 
 MI – Multiple imputation,  
 
5.5 
Adjustment for Covariates 
In all analyses of ‘change from baseline’, the corresponding baseline value of the parameter 
being analysed will be included in an analysis of covariance (ANCOVA) model. The WLL 
(stratification) will be included in all analysis models. For endpoints analysed by a mixed 
model for repeated measurements (MMRM), baseline will be included as a covariate in the 
model. Geographical region (as defined for subgroups), unique country or centre will not be 
adjusted for in the statistical analyses, instead adjustment will be made for Japan vs all other 
countries in all parametric analyses. 
Primary Endpoint 
Change from baseline of  
(A-a)DO2 after 24-weeks  
Main analysis 
 ANCOVA (FAS) 
Sensitivity analyses 
 MMRM (FAS) 
 ANCOVA MI (FAS) 
 ANCOVA Tipping Point (FAS) 
 ANCOVA Worst case (FAS) 
 ANCOVA (Completer) 
 ANCOVA (PPS)  
Endpoint / Analysis 
OD Molg. 
Vs 
Placebo 
Int. Molg. 
Vs 
Placebo 
OD Molg. 
Vs 
Placebo 
Int. Molg. 
Vs 
Placebo 
OD Molg. 
Vs 
Placebo 
Int. Molg. 
Vs 
Placebo 
Int. Molg. 
Vs 
Placebo 
Truncated 
Hochberg 
Hochberg 
procedure 
OD Molg. 
Vs 
Placebo 
Key Secondary Endpoints 
 
EP 1) Change from baseline in 6MWD 
after 24-weeks   
  Main Analysis 
 ANCOVA (FAS) 
  Sensitivity analyses 
 MMRM (FAS) 
 ANCOVA MI (FAS) 
 ANCOVA (Completer) 
 ANCOVA (PPS)  
 
EP 2) Change from baseline in SGRQ 
total score after 24-weeks  
  Main Analysis 
 ANCOVA (FAS) 
  Sensitivity analyses 
 MMRM (FAS) 
 ANCOVA MI (FAS) 
 ANCOVA (Completer) 
 ANCOVA (PPS)  
 
EP 3) Time to WLL during 24-weeks  
  Main Analysis 
 Logrank test (FAS) 
  Sensitivity analyses 
 Cox regression (FAS) 
 Logrank test (PPS) 
 Logrank test change in censoring (FAS) 
  
 Hierarchical testing procedure 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
29 (45) 
5.6 
Handling of Dropouts and Missing Data 
Different approaches will be applied for evaluation of impact of missing data on the results for 
primary and key secondary endpoints, each is described in previous sections.  
5.7 
Multicentre Studies 
Summary statistics will be presented for the whole population. For baseline demographics 
and disease characteristics, primary endpoint, and key secondary endpoints, summary 
statistics will also be presented by geographical region. The results for the primary and key 
secondary endpoints will be presented graphically as well as in tables. Centre will not be 
included as a stratification factor in either the randomisation procedure or data analysis. All 
subject listings will be sorted by centre. 
5.8 
Examination of Subgroups 
For the primary endpoint, key secondary efficacy endpoints, and AEs summary statistics will 
be presented by subgroups. In addition to subgroups by region, as stated in protocol, 
summary statistics of observed data, during the double-blind treatment period, will be 
prepared for subgroups defined by age, sex, aPAP severity, aPAP duration since diagnosis 
and WLL conducted previously, for the assessments as described in Table 2. 
 
Table 2: Subgroup Analyses  
  
Age Groups 
Sex 
aPAP severity 
aPAP 
diagnosis 
Previous WLL 
  
</≥ 65 
M/F 
DSS 2/3/4/5 
</≥ 6m 
Y/N 
Subject Disposition 
+ 
+ 
+ 
+ 
+ 
Exposure 
+ 
+ 
+ 
+ 
+ 
Efficacy 
  
  
  
  
  
(A-a)DO2   
+ 
+ 
+ 
+ 
+ 
6MWD 
+ 
+ 
+ 
+ 
+ 
SGRQ total score 
+ 
+ 
+ 
+ 
+ 
Time to WLL  
+ 
+ 
+ 
+ 
+ 
FVC  
+ 
DLCO  
  
  
+ 
  
  
KL-6 
+ 
Safety 
  
  
  
  
  
AEs (SOC/PT) 
+ 
+ 
 
Furthermore, estimated differences with corresponding 95% Cis will be presented for the 
efficacy endpoints split by the subgroups in forest plots. The estimated differences and the 
95% Cis will be calculated by applying the general ANCOVA.  
5.9 
Interim Analysis  
Analyses will be conducted when all subjects have completed the double-blind treatment 
period, before all subjects have completed the open-label follow-up period. This does not 
constitute a statistical interim analysis. 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
30 (45) 
5.10 
Data Monitoring 
An independent DSMB comprised of pulmonologists from lung centres who are experts in 
interstitial lung disease, and in conducting clinical studies were appointed and assigned for 
safety surveillance of the trial. The DSMB members were not investigators in the study. All 
members of the DSMB were unblinded to the treatment received by the subject and the 
subject identification.  
 
All study team members remained blinded. Unblinded safety and tolerability data listings for 
the DSMB review were provided by a statistician from TFS who is independent of the study. 
 
All details of the procedures related to independent unblinding, delivery and review of data 
are described in the DSMB Charter, V4.0, dated 18 Sep 2018. 
6 
REFERENCES 
[1] Jones P, Spencer S, Adie S. The St George’s Respiratory Questionnaire Manual; Version 
2.3; June 2009; St George’s Hospital Medical School; London, UK 
[2] Panel on Handling Missing Data in Clinical Trials; National Research Council. The 
Prevention and Treatment of Missing Data in Clinical Trials; 2010; The National Academies 
Press, Washington DC 
 


 
 
APPENDIX 1 
Data from subjects screened (SCR) but not randomised in the study will only be presented in listings of inclusion/exclusion evaluations and the 
number of subjects will be included in the subject disposition. 
Tables, Figures and Listings to be Produced for the Clinical Study Report (Section 14 and 16 according to ICH E3) 
In general, data will be summarised in the same way for the DB and FU period, although will depend on the availability of data in each period. 
Summaries of efficacy data during the FU period will include data collected during the DB period, while relevant safety output reported at FU 
may contain data collected during both periods and/or and or data only collected during the FU period. Columns below, SCR (Screened), DB-
FAS, DB-PPS, DB-SAF, FU-FAS, FU-MOL INT and FU-SAF indicate the combination of period and population that the corresponding output 
will be based on. Treatment groups will be abbrevaiated as ‘MOL OD’ (Molgramostim Once Daily), ‘MOL INT’ (Molgramostim Intermittently) and 
‘PBO’ (Placebo) for output based on the DB period. For output based on FU period, the abbreaviations ‘MOL OD/MOL FU’, ‘MOL INT/MOL FU’ 
and ‘PBO/MOL FU’ will be used for the corresponding randomised treatment groups followed by molgramostim in FU period. The final 
numbering of output may change in the CSR. 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
 
 
14.1 DEMOGRAPHIC DATA 
 
 
 
 
 
 
 
Table 
14.1.1 
Subject Disposition Analysis Sets and Reason for Exclusions 
X 
 
 
 
 
 
X 
Table 
14.1.2 
Subject Disposition Analysis Sets and Reason for Exclusions by Age Group 
X 
 
 
 
 
 
 
Table 
14.1.3 
Subject Disposition Analysis Sets and Reason for Exclusions by Sex  
X 
 
 
 
 
 
 
Table 
14.1.4 
Subject Disposition Analysis Sets and Reason for Exclusions by aPAP severity 
X 
 
 
 
 
 
 
Table 
14.1.5 
Subject Disposition Analysis Sets and Reason for Exclusions by aPAP diagnosis 
X 
 
 
 
 
 
 
Table 
14.1.6 
Subject Disposition Analysis Sets and Reason for Exclusions by previous WLL 
X 
 
 
 
 
 
 
Table 
14.1.7 
Subject Discontinuation     
 
X 
X 
X 
X 
X 
X 
Table 
14.1.8 
Number of Subjects by Visit 
 
X 
X 
X 
X 
X 
X 
Table 
14.1.9 
Demographics: Age Sex and Race     
 
X 
X 
X 
X 
X 
X 
Table 
14.1.10 
Demographics: Age Sex and Race by Region 
 
X 
X 
X 
 
 
 
Table 
14.1.11 
Demographics: Weight Height and BMI     
 
X 
X 
X 
X 
X 
X 
Table 
14.1.12 
Demographics: Weight Height and BMI by Region  
 
X 
X 
X 
 
 
 
Table 
14.1.13 
aPAP history    
 
X 
X 
X 
X 
X 
X 
Table 
14.1.14 
aPAP history by Region 
 
X 
X 
X 
 
 
 
Table 
14.1.15 
Medical history   
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
32 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
 
 
14.2 EFFICACY DATA 
 
 
 
 
 
 
 
 
 
Primary Endpoint 
 
 
 
 
 
 
 
Table 
14.2.1.1 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment  
 
X 
X 
 
 
 
 
Figure 
14.2.1.2 
Mean profiles of (A-a)DO2 over time 
 
X 
  
  
  
  
 
Figure 
14.2.1.3 
Mean change profiles of (A-a)DO2 over time 
 
X 
  
  
  
  
 
Table 
14.2.1.4 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 while on treatment by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.1.5 
Analysis of primary endpoint change from baseline in (A-a)DO2 after 24 weeks (ANCOVA)  
 
X 
 
 
 
 
 
Table 
14.2.1.6 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2  after 24 weeks (MMRM)  
 
X 
 
 
 
 
 
Table 
14.2.1.7 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2 after 24 weeks (ANCOVA) multiple imputation analysis  
 
X 
 
 
 
 
 
Table 
14.2.1.8 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2 after 24 weeks (ANCOVA) multiple imputation of 
measurements following WLL   
 
X 
 
 
 
 
 
Table 
14.2.1.9 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2 after 24 weeks (ANCOVA) tipping point analysis  
 
X 
 
 
 
  
 
Table 
14.2.1.10 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2 after 24 weeks (ANCOVA) worst case analysis   
 
X 
 
 
 
 
 
Table 
14.2.1.11 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2  after 24 weeks (ANCOVA) completer analysis  
 
X 
 
 
 
 
 
Table 
14.2.1.12 
Sensitivity analysis for primary endpoint change from baseline in (A-a)DO2  after 24 weeks (ANCOVA)    
 
 
X 
 
 
 
 
Table 
14.2.1.13 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment by Age Group 
 
X 
 
 
 
 
 
Table 
14.2.1.14 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment by Sex 
 
X 
 
 
 
 
 
Table 
14.2.1.15 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment by aPAP severity 
 
X 
 
 
 
 
 
Table 
14.2.1.16 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment by aPAP diagnosis 
 
X 
 
 
 
 
 
Table 
14.2.1.17 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment – by strata 
 
X 
 
 
 
 
 
Figure 
14.2.1.18 
Mean profiles of (A-a)DO2 over time by region 
 
X 
  
  
  
  
 
Table 
14.2.1.19 
Summary of (A-a)DO2 and change from baseline in (A-a)DO2 by visit during 24 weeks treatment – by region 
 
X 
 
 
 
 
 
Figure 
14.2.1.20 
Mean profiles of (A-a)DO2 over time by strata 
 
X 
  
  
  
  
 
Figure 
14.2.1.21 
Forest Plot for analyses of change from baseline in (A-a)DO2, Molgramostim OD vs Placebo by  subgroups   
 
X 
 
 
 
 
 
Figure 
14.2.1.22 
Forest Plot for analyses of change from baseline in (A-a)DO2, Molgramostim Int. vs Placebo by  subgroups   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key Secondary Efficacy Endpoints  
 
 
 
 
 
 
 
Table 
14.2.2.1 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit during 24 weeks treatment 
 
X 
X 
 
 
 
 
Figure 
14.2.2.2 
Mean profiles of six minutes walking distance (6MWD) over time 
 
X 
  
  
  
 
 
Figure 
14.2.2.3 
Mean change profiles of six minutes walking distance (6MWD) over time 
 
X 
  
  
  
 
 
Table 
14.2.2.4 
Analysis of change from baseline in six minutes walking distance (6MWD) after 24 weeks (ANCOVA) 
 
X 
  
  
  
 
 
Table 
14.2.2.5 
Sensitivity analysis of change from baseline in six minutes walking distance (6MWD) after 24 weeks (MMRM) 
 
X 
  
  
  
 
 
Table 
14.2.2.6 
Sensitivity analysis of change from baseline in six minutes walking distance (6MWD) after 24 weeks (ANCOVA) – multiple 
imputation   
 
X 
  
  
  
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
33 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Table 
14.2.2.7 
Sensitivity analysis of change from baseline in six minutes walking distance (6MWD) after 24 weeks (ANCOVA) – completer 
analysis  
 
X 
  
  
  
 
 
Table 
14.2.2.8 
Sensitivity analysis of change from baseline in six minutes walking distance (6MWD) after 24 weeks (ANCOVA)  
 
  
X 
  
  
 
 
Table 
14.2.2.9 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit during 24 weeks treatment by Age 
Group 
 
X 
  
  
  
 
 
Table 
14.2.2.10 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit during 24 weeks treatment by Sex 
 
X 
  
  
  
 
 
Table 
14.2.2.11 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit during 24 weeks treatment by 
aPAP severity 
 
X 
  
  
  
 
 
Table 
14.2.2.12 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit during 24 weeks treatment by 
aPAP diagnosis 
 
X 
  
  
  
 
 
Table 
14.2.2.13 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit and strata during 24 weeks 
treatment  
 
X 
X 
 
 
 
 
Figure 
14.2.2.14 
Mean profiles of six minutes walking distance (6MWD) over time by strata 
 
X 
 
 
 
 
 
Table 
14.2.2.15 
Summary of six minutes walking distance (6MWD) and change from baseline in 6MWD by visit and region during 24 weeks 
treatment   
 
X 
 
 
 
 
 
Figure 
14.2.2.16 
Mean profiles of six minutes walking distance (6MWD) over time by region 
 
X 
 
 
 
 
 
Figure 
14.2.2.17 
Forest Plot for analyses of change from baseline in minutes walking distance (6MWD), Molgramostim OD vs Placebo by 
subgroups   
 
X 
  
  
  
 
 
Figure 
14.2.2.18 
Forest Plot for analyses of change from baseline in minutes walking distance (6MWD), Molgramostim Int. vs Placebo by 
subgroups   
 
X 
  
  
  
 
 
Table 
14.2.2.19 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit during 24 weeks treatment  
 
X 
X 
  
  
 
 
Figure 
14.2.2.20 
Mean profiles of SGRQ total score over time  
 
X 
  
  
  
 
 
Figure 
14.2.2.21 
Mean change profiles of SGRQ total score over time  
 
X 
  
  
  
 
 
Table 
14.2.2.22 
Analysis of change from baseline in SGRQ total score after 24 weeks (ANCOVA) 
 
X 
  
  
  
 
 
Table 
14.2.2.23 
Sensitivity analysis of change from baseline SGRQ total score after 24 weeks (MMRM) 
 
X 
 
 
 
 
 
Table 
14.2.2.24 
Sensitivity analysis of change from baseline in SGRQ total score after 24 weeks (ANCOVA) – multiple imputation   
 
X 
 
 
 
 
 
Table 
14.2.2.25 
Sensitivity analysis of change from baseline in SGRQ total score after 24 weeks (ANCOVA) – completer analysis  
 
X 
 
 
 
 
 
Table 
14.2.2.26 
Sensitivity analysis of change from baseline in SGRQ total score after 24 weeks (ANCOVA)   
 
 
X 
 
 
 
 
Table 
14.2.2.27 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit during 24 weeks treatment by Age Group 
 
X 
 
 
 
 
 
Table 
14.2.2.28 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit during 24 weeks treatment by Sex 
 
X 
 
 
 
 
 
Table 
14.2.2.29 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit during 24 weeks treatment by aPAP severity 
 
X 
 
 
 
 
 
Table 
14.2.2.30 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit during 24 weeks treatment by aPAP diagnosis 
 
X 
 
 
 
 
 
Table 
14.2.2.31 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit and strata during 24 weeks treatment 
 
X 
  
  
  
 
 
Figure 
14.2.2.32 
Mean profiles of SGRQ total score over time by strata  
 
X 
  
  
  
 
 
Table 
14.2.2.33 
Summary of SGRQ total score and change from baseline in SGRQ total score by visit and region during 24 weeks treatment 
 
X 
  
  
  
 
 
Figure 
14.2.2.34 
Mean profiles of SGRQ total score over time by region  
 
X 
  
  
  
 
 
Figure 
14.2.2.35 
Forest Plot for analyses of change from baseline in SGRQ total score, Molgramostim OD vs Placebo by subgroups   
 
X 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
34 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Figure 
14.2.2.36 
Forest Plot for analyses of change from baseline in SGRQ total score, Molgramostim Int. vs Placebo by subgroups   
 
X 
 
 
 
 
 
Table 
14.2.2.37 
Summary of number of subjects in need of WLL during 24-weeks of treatment  
 
X 
X 
 
 
 
 
Table 
14.2.2.38 
Life table summary of time from randomization to need of WLL  
 
X 
 
 
 
 
 
Figure 
14.2.2.39 
Kaplan – Meier plot for time to need of WLL during 24-weeks of treatment   
 
X 
  
  
  
 
 
Table 
14.2.2.40 
Analysis of difference between treatment groups (logrank test) in time to WLL during 24 weeks of treatment   
 
X 
  
  
  
 
 
Table 
14.2.2.41 
Sensitivity analysis of difference between treatment groups (Cox regression) in time to WLL during 24 weeks of treatment 
 
X 
 
 
 
 
 
Table 
14.2.2.42 
Sensitivity analysis of difference between treatment groups (logrank test) in time to WLL during 24 weeks of treatment – 
alternative censoring  
 
X 
 
 
 
 
 
Table 
14.2.2.43 
Sensitivity analysis of difference between treatment groups (logrank test) in time to WLL during 24 weeks of treatment   
 
 
X 
 
 
 
 
Table 
14.2.2.44 
Summary of number of subjects in need of WLL during 24-weeks of treatment by Age Group 
 
X 
 
 
 
 
 
Table 
14.2.2.45 
Summary of number of subjects in need of WLL during 24-weeks of treatment by Sex 
 
X 
 
 
 
 
 
Table 
14.2.2.46 
Summary of number of subjects in need of WLL during 24-weeks of treatment by aPAP severity 
 
X 
 
 
 
 
 
Table 
14.2.2.47 
Summary of number of subjects in need of WLL during 24-weeks of treatment by aPAP diagnosis 
 
X 
 
 
 
 
 
Table 
14.2.2.48 
Summary of number of subjects in need of WLL during 24-weeks of treatment by strata and by visit 
 
X 
 
 
 
 
 
Figure 
14.2.2.49 
Kaplan – Meier plot for time to need of WLL during 24-weeks of treatment by strata   
 
X 
  
  
  
 
 
Table 
14.2.2.50 
Summary of number of subjects in need of WLL during 24-weeks of treatment by region 
 
X 
 
 
 
 
 
Figure 
14.2.2.51 
Kaplan – Meier plot for time to need of WLL during 24-weeks of treatment by region   
 
X 
  
  
  
 
 
Figure 
14.2.2.52 
Forest Plot for analyses of time to WLL , Molgramostim OD vs Placebo by  subgroups   
 
X 
 
 
 
 
 
Figure 
14.2.2.53 
Forest Plot for analyses of time to WLL, Molgramostim Int. vs Placebo by subgroups   
 
X 
 
 
 
 
 
Table 
14.2.2.54 
Overview of statistical hypothesis testing for primary and key secondary efficacy endpoints according to testing procedure  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Further Secondary Efficacy Endpoints 
 
 
 
 
 
 
 
Table 
14.2.3.1 
Summary of VC (% predicted) and change from baseline in VC (% predicted) by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.2 
Analysis of change from baseline in VC (% predicted) after 24 weeks (ANCOVA) 
 
X 
 
 
 
 
 
Table 
14.2.3.3 
Summary of DLCO (% predicted) and change from baseline in DLCO (% predicted) by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.4 
Analysis of change from baseline in DLCO (% predicted) after 24 weeks (ANCOVA) 
 
X 
 
 
 
 
 
Figure 
14.2.3.5 
Summary of DLCO (% predicted) and change from baseline in DLCO (% predicted) by visit during 24 weeks treatment by aPAP 
severity  
 
X 
 
 
 
 
 
Figure 
14.2.3.6 
Forest Plot for analyses change from baseline in DLCO (% predicted) by subgroups   
 
X 
 
 
 
 
 
Table 
14.2.3.7 
Summary of FEV1(% predicted) and change from baseline in FEV1(% predicted by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.8 
Analysis of change from baseline in FEV1(% predicted) after 24 weeks (ANCOVA)   
 
X 
 
 
 
 
 
Table 
14.2.3.9 
Summary of FVC (% predicted) and change from baseline in FVC (% predicted) by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.10 
Analysis of change from baseline in FVC (% predicted) after 24 weeks (ANCOVA)   
 
X 
 
 
 
 
 
Figure 
14.2.3.11 
Summary of FVC (% predicted) and change from baseline in FVC (% predicted) by visit during 24 weeks treatment by aPAP 
severity    
 
X 
 
 
 
 
 
Figure 
14.2.3.12 
Forest Plot for analyses of change from baseline in FVC (% predicted) by subgroups   
 
X 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
35 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Table 
14.2.3.13 
Summary of PaO2 and relative change from baseline in PaO2 by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.14 
Analysis of relative change from baseline in PaO2 after 24 weeks (ANCOVA) 
 
X 
 
 
 
 
 
Table 
14.2.3.15 
Number and % of subjects with >5 mmHg/>0.67 kPa improvement in (A-a)DO2 compared to baseline by visit during 24 weeks 
treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.16 
Analysis of number of subjects with >5 mmHg/>0.67 kPa improvement in (A-a)DO2 compared to baseline after 24 weeks 
treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.17 
Number and % of subjects with >10 mmHg/>1.33 kPa improvement in (A-a)DO2 compared to baseline by visit during 24 weeks 
treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.18 
Analysis of number subjects with >10 mmHg/>1.33 kPa improvement in (A-a)DO2 compared to baseline after 24 weeks 
treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.19 
Number and % of subjects with >5 percentage points improvement in VC (% predicted) compared to baseline by visit during 24 
weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.20 
Analysis of number of subjects with >5 percentage points improvement in VC (% predicted) compared to baseline after 24 weeks 
treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.21 
Number and % of subjects with >10 percentage points improvement in VC (% predicted) compared to baseline by visit during 24 
weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.22 
Analysis of number of subjects with >10 percentage points improvement in VC (% predicted) compared to baseline after 24 
weeks treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.23 
Number and % of subjects with >10 percentage points improvement in DLCO (% predicted) compared to baseline by visit during 
24 weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.24 
Analysis of number of subjects with >10 percentage points improvement in DLCO (% predicted) compared to baseline after 24 
weeks treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.25 
Number and % of subjects with >10 percentage points improvement in FEV1(% predicted) compared to baseline by visit during 24 
weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.26 
Analysis of number of subjects with >10 percentage points improvement in FEV1(% predicted) compared to baseline after 24 
weeks treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.27 
Number and % of subjects with >10 percentage points improvement in FVC (% predicted) compared to baseline by visit during 24 
weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.28 
Analysis of number of subjects with >10 percentage points improvement in FVC (% predicted) compared to baseline after 24 
weeks treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.29 
Number and % of subjects with >10% relative improvement in PaO2 compared to baseline by visit during 24 weeks treatment 
 
X 
 
 
 
 
 
Table 
14.2.3.30 
Analysis of number of subjects with >10% relative improvement in PaO2 compared to baseline after 24 weeks treatment (Logistic 
regression) 
 
X 
 
 
 
 
 
Table 
14.2.3.31 
Summary of change from baseline in SpO2 at start and the worst SpO2 oxygen desaturation and distance of walk during 6 
minutes walk test (6MWT) by visit during 24 weeks treatment   
 
X 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
36 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Table 
14.2.3.32 
Number of subjects with improved tolerance to exercise (increase from baseline in distance walked ≥50 m) by visit during 24 
weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.33 
Analysis of number of subjects with improved tolerance to exercise (increase from baseline in distance walked ≥50 m) after 24 
weeks treatment (Logistic regression)  
 
X 
 
 
 
 
 
Table 
14.2.3.34 
Number of subjects with improved tolerance to exercise (desaturation <4 percentage points on the 6MWT) by visit during 24 
weeks treatment full analysis set 
 
X 
 
 
 
 
 
Table 
14.2.3.35 
Analysis of number of subjects with improved tolerance to exercise (desaturation <4 percentage points on the 6MWT) after 24 
weeks treatment (Logistic regression)  
 
X 
 
 
 
 
 
Table 
14.2.3.36 
Summary of Borg CR10 pre post and corresponding difference in walk  dyspnea score and change from baseline in scores by visit 
during 24 weeks treatment  
 
X 
 
 
 
 
 
Table 
14.2.3.37 
Analysis of change from baseline in  dyspnea score after 24 weeks (ANCOVA) 
 
X 
 
 
 
 
 
Table 
14.2.3.38 
Summary of cough (VAS) scores and change from baseline in cough scores by visit during 24 weeks treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.39 
Analysis of change from baseline in cough (VAS) scores after 24 weeks (ANCOVA) 
 
X 
 
 
 
 
 
Table 
14.2.3.40 
Summary of number of subjects with Improved Worsened or No change in CT score during 24 weeks of treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.41 
Summary of CT Ground-Glass Opacification (GGO) score during 24 weeks of treatment   
 
X 
 
 
 
 
 
Table 
14.2.3.42 
Analysis of number of subjects with Improved CT score compared to baseline after 24 weeks treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table  
14.2.3.43 
Summary of number of WLLs over time  
 
X 
 
 
 
 
 
Table 
14.2.3.44 
Summary of details related to WLLs including reasons for, one or both lungs, and saline volume used.  
 
X 
 
 
 
 
 
Table  
14.2.3.45 
Analysis of number of WLLs over time (negative binomial regression) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Efficacy Endpoints Double-Blind Treatment Period 
 
 
 
 
 
 
 
Table 
14.2.4.1 
Summary of time during which the (A-a)DO2 level is maintained below baseline (A-a)DO2 level -10mmHg  
 
X 
 
 
 
 
 
Table 
14.2.4.2 
Summary of time period during which the improvement in tolerance to exercise is maintained   
 
X 
 
 
 
 
 
Table 
14.2.4.3 
Summary of SGRQ dimension scores and corresponding changes from baseline by visit during 24 weeks of treatment 
 
X 
 
 
 
 
 
Table 
14.2.4.4 
Summary of number of subject with improved QoL score (improvement of at least 4 units on SGRQ total score) during 24 weeks 
of treatment 
 
X 
 
 
 
 
 
Table 
14.2.4.5 
Summary of EQ-5D-5L dimension scores and corresponding shifts from baseline by visit during 24 weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.6 
Summary of Krebs von den Lungen-6 (KL-6) and change from baseline in Krebs von den Lungen-6 (KL-6) by visit during 24 weeks 
of treatment   
 
X 
 
 
 
 
 
Table 
14.2.4.7 
Summary of Krebs von den Lungen-6 (KL-6) and change from baseline in Krebs von den Lungen-6 (KL-6) by visit during 24 weeks 
of treatment by aPAP severity   
 
X 
 
 
 
 
 
Table 
14.2.4.8 
Summary of Carcinoembryonic antigen (CEA) and change from baseline in Carcinoembryonic antigen (CEA) by visit during 24 
weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.9 
Summary of Surfactant Protein A (SP-A) and change from baseline in Surfactant Protein A (SP-A) by visit during 24 weeks of 
treatment   
 
X 
 
 
 
 
 
Table 
14.2.4.10 
Summary of Surfactant Protein A (SP-B) and change from baseline in Surfactant Protein A (SP-B) by visit during 24 weeks of 
 
X 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
37 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
treatment   
Table 
14.2.4.11 
Summary of Surfactant Protein A (SP-C) and change from baseline in Surfactant Protein A (SP-C) by visit during 24 weeks of 
treatment   
 
X 
 
 
 
 
 
Table 
14.2.4.12 
Summary of Surfactant Protein A (SP-D) and change from baseline in Surfactant Protein A (SP-D) by visit during 24 weeks of 
treatment   
 
X 
 
 
 
 
 
Table 
14.2.4.13 
Summary of Cytokeratin 19 Fragment (Cyfra 21-1) and change from baseline in Cytokeratin 19 Fragment (Cyfra 21-1) by visit 
during 24 weeks of treatment   
 
X 
 
 
 
 
 
Table 
14.2.4.14 
Summary of Lactate Dehydrogenase (LDH) and change from baseline in Lactate Dehydrogenase (LDH) by visit during 24 weeks of 
treatment   
 
X 
 
 
 
 
 
Table 
14.2.4.15 
Summary of anti-drug antibodies (anti-GM-CSF, anti-Polyethylene glycol (anti-PEG) and anti-recombinant Human Albumin (anti-
rHA) by visit during 24 weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.16 
Summary of anti-drug antibodies (France only) (anti-GM-CSF, anti-Polyethylene glycol (anti-PEG) and anti-recombinant Human 
Albumin (anti-rHA) by visit during 24 weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.17 
Summary of GM-CSF pre- and post-dose at baseline and after 4-weeks of treatment and change from pre-dose at baseline in GM-
CSF during 24 weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.18 
Summary of GM-CSF at baseline and after 4-weeks of treatment in pre-dose and repeated post dose (in Japan only) during 24 
weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.19 
Summary of GM-CSF pre- and post-dose at baseline, after 4, 12 and 24 weeks of treatment and change from pre-dose at baseline 
in GM-CSF (in US only) during 24 weeks of treatment  
 
X 
 
 
 
 
 
Table 
14.2.4.20 
Summary of number and percentage of subjects in need for oxygen supplement therapy during 24-weeks treatment  
 
X 
 
 
 
 
 
Table  
14.2.4.21 
Analysis of number of subjects in need for oxygen supplement therapy during 24-weeks treatment (Logistic regression) 
 
X 
 
 
 
 
 
Table 
14.2.4.22 
Summary of DSS at Screening and at Week 24  
 
X 
 
 
 
 
 
Table 
14.2.4.23 
Shift tables for DSS at Screening and at Week 24  
 
X 
 
 
 
 
 
Table 
14.2.4.24 
Summary of number and percentage of subjects with DSS 1 or 2 at Screening and at Week 24 
 
X 
 
 
 
 
 
Table 
14.2.4.25 
Shift tables for subjects with DSS 1 or 2 at Screening and at Week 24 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Efficacy Endpoints Follow-Up Period 
 
 
 
 
 
 
 
Table 
14.2.5.1 
Summary of number of subjects in need of WLL or other treatment during 48-weeks follow-up  
 
 
 
 
X 
X 
 
Table 
14.2.5.2 
Summary of number of subjects in need of WLL or other treatment during 48-weeks follow-up by visit and type of treatment   
 
 
 
 
X 
X 
 
Table 
14.2.5.3 
Life table summary of time from start of Follow-up need for WLL or other treatment during Follow-up  
 
 
 
 
X 
X 
 
Figure 
14.2.5.4 
Kaplan – Meier plot for time from start of Follow-up need for WLL or other treatment during Follow-up  
 
 
 
 
X 
X 
 
Table 
14.2.5.5 
Summary of and change from baseline in (A-a)DO2 during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 
Table 
14.2.5.6 
Summary and change from baseline in (A-a)DO2 by visit (including only samples for arterial blood gas) during 48-weeks follow-up 
by visit  
 
 
 
 
X 
X 
 
Table 
14.2.5.7 
Summary of and change from baseline in VC (% predicted) during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 
Table 
14.2.5.8 
Summary of and change from baseline in DLCO (% predicted) during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
38 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Table 
14.2.5.9 
Summary of and change from baseline in FEV1 (% predicted) during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 
Table 
14.2.5.10 
Summary of and change from baseline in FVC (% predicted) during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 
Table 
14.2.5.11 
Summary of and relative change from baseline of PaO2 during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 
Table 
14.2.5.12 
Summary of number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m) during 48-weeks follow-
up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.13 
Summary of number of subjects with improved tolerance to exercise (desaturation <4 percentage points on the 6MWT) during 
48-weeks follow-up by visit  
 
 
 
 
X 
X 
 
Table 
14.2.5.14 
Summary of Borg CR10 pre post and corresponding difference in walk dyspnoea score and change from baseline in scores during 
48-weeks follow-up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.15 
Summary of cough (VAS) scores and change from baseline in cough scores during 48-weeks follow-up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.16 
Summary of SGRQ dimension scores and corresponding changes from baseline during 48-weeks follow-up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.17 
Summary of EQ-5D-5L dimension scores and corresponding shifts from baseline during 48-weeks follow-up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.18 
Summary of levels of and change from baseline in anti-GM-CSF after 12 and 24 weeks of follow-up by visit  
 
 
 
 
X 
X 
 
Table 
14.2.5.19 
Summary of GM-CSF pre- and post-dose during Follow-up (US only)  
 
 
 
 
X 
X 
 
Table 
14.2.5.20 
Summary of DSS at during 48-weeks follow-up by visit   
 
 
 
 
X 
X 
 
Table 
14.2.5.21 
Shift tables for DSS during 48-weeks follow-up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.22 
Summary of number and percentage of subjects with DSS 1 or 2 during 48-weeks follow-up by visit 
 
 
 
 
X 
X 
 
Table 
14.2.5.23 
Shift tables for subjects with DSS 1 or 2 during 48-weeks follow-up by visit  
 
 
 
 
X 
X 
 
Table 
14.2.5.24 
Summary of details related to WLLs including reasons for, one or both lungs, and saline volume used during 48-weeks follow-up.  
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exposure 
 
 
 
 
 
 
 
Table 
14.2.6.1 
Extent of Exposure 
 
X 
X 
X 
X 
X 
X 
Table 
14.2.6.2 
Extent of Exposure by Age Group 
 
 
 
X 
 
 
 
Table 
14.2.6.3 
Extent of Exposure by Sex 
 
 
 
X 
 
 
 
Table 
14.2.6.4 
Extent of Exposure by by aPAP severity 
 
 
 
X 
 
 
 
Table 
14.2.6.5 
Extent of Exposure by aPAP diagnosis 
 
 
 
X 
 
 
 
Table 
14.2.6.6 
Extent of Exposure by previous WLL 
 
 
 
X 
 
 
 
Table 
14.2.6.7 
Compliance 
 
X 
X 
X 
X 
X 
X 
Table  
14.2.6.8 
Concomitant Medication 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
14.3 SAFETY DATA  
 
 
 
 
 
 
 
 
 
Displays of Adverse Events 
 
 
 
 
 
 
 
Table 
14.3.1.1 
Summary of adverse events during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table 
14.3.1.2 
Adverse events by system organ class and preferred term during 24 weeks of treatment   
 
 
 
X 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
39 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Table 
14.3.1.3 
Adverse events: Number of subjects by severity and relationship to treatment during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table 
14.3.1.4 
Summary of serious adverse events during 24 weeks of treatment 
 
 
 
X 
 
 
 
Table 
14.3.1.5 
Serious adverse events by system organ class and preferred term during 24 weeks of treatment   
 
 
 
X 
 
 
 
Table 
14.3.1.6 
Serious adverse events: Number of subjects by severity and relationship to treatment during 24 weeks of treatment 
 
 
 
X 
 
 
 
Table 
14.3.1.7 
Adverse events by system organ class and preferred term during 24 weeks of treatment by Age Groups 
 
 
 
X 
 
 
 
Table 
14.3.1.8 
Adverse events by system organ class and preferred term during 24 weeks of treatment by Sex 
 
 
 
X 
 
 
 
Table 
14.3.1.9 
Summary of adverse events in total and during 48 weeks of follow-up  
 
 
 
 
 
 
X 
Table 
14.3.1.10 
Adverse events by system organ class and preferred term in total and during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.1.11 
Adverse events: Number of subjects by severity and relationship to treatment total and during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.1.12 
Summary of serious adverse events during total and during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.1.13 
Serious adverse events by system organ class and preferred term total and during 48 weeks of follow-up 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Listings of Deaths Other Serious and Significant Adverse Events 
 
 
 
 
 
 
 
Listing 
14.3.2.1 
List of deaths  
 
 
 
X 
 
 
X 
Listing 
14.3.2.2 
List of other serious adverse events  
 
 
 
X 
 
 
X 
Listing 
14.3.2.3 
List of adverse events leading to treatment and/or trial discontinuation 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Data 
 
 
 
 
 
 
 
Listing 
14.3.4.1 
 Laboratory reference ranges 
X 
 
 
 
 
 
 
Listing 
14.3.4.2 
 Abnormal laboratory Value Listing 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Table 
14.3.5.1 
Summary of haematology laboratory measurements and corresponding changes from baseline by visit during 24 weeks of 
treatment 
 
 
 
X 
 
 
 
Table 
14.3.5.2 
 Shift tables for haematology laboratory measurements from baseline by visit during 24 weeks of treatment 
 
 
 
X 
 
 
 
Table 
14.3.5.3 
Summary of biochemistry laboratory measurements and corresponding changes from baseline by visit during 24 weeks of 
treatment  
 
 
 
X 
 
 
 
Table 
14.3.5.4 
Shift tables for biochemistry laboratory measurements from baseline by visit during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table  
14.2.5.5 
Summary of urinalysis laboratory measurements (France only) by visit during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table 
14.3.5.6 
Summary of haematology laboratory measurements and corresponding changes from baseline by visit during 48 weeks of follow-
up 
 
 
 
 
 
 
X 
Table 
14.3.5.7 
Shift tables for haematology laboratory measurements from baseline by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.5.8 
Summary of biochemistry laboratory measurements and corresponding changes from baseline by visit during 48 weeks of follow-
up 
 
 
 
 
 
 
X 
Table 
14.3.5.9 
Shift tables for biochemistry laboratory measurements from baseline by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.5.10 
Summary of urinalysis laboratory measurements (France only) by visit during 48 weeks of treatment 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
40 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
 
 
Other Safety Data 
 
 
 
 
 
 
 
Table 
14.3.6.1 
 Summary of vital signs and change from baseline in vital signs by visit during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table 
14.3.6.2 
 Shift tables for changes in vital signs from baseline by visit during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table 
14.3.6.3 
 Shift tables for changes in Physical examination from baseline by visit during 24 weeks of treatment  
 
 
 
X 
 
 
 
Table 
14.3.6.4 
 Summary of ECG and change from baseline in ECG by visit during 24 weeks of treatment full analysis set 
 
 
 
X 
 
 
 
Table 
14.3.6.5 
 Shift tables for changes in ECG from baseline by visit during 24 weeks of treatment   
 
 
 
X 
 
 
 
Table 
14.3.6.6 
 Summary of adverse findings in CT at week 24 compared to baseline   
 
 
 
X 
 
 
 
Table 
14.3.6.7 
 Summary of vital signs and change from baseline in vital signs by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.6.8 
 Shift tables for changes in vital signs from baseline by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.6.9 
 Shift tables for changes in Physical examination from baseline by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.6.10 
 Summary of ECG and change from baseline in ECG by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
Table 
14.3.6.11 
 Shift tables for changes in ECG from baseline by visit during 48 weeks of follow-up 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Listing 
16.1.7 
Randomization Scheme 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.2 PATIENT DATA LISTINGS 
 
 
 
 
 
 
 
 
 
Discontinued Patients 
 
 
 
 
 
 
 
Listing 
16.2.1.1 
Discontinued Subjects Reason for Discontinuation 
 
 
 
X 
 
 
X 
Listing 
16.2.1.2 
Visit Dates and Other Important Dates (informed consent rand date study termination) 
 
 
 
X 
 
 
X 
Listing 
16.2.1.3 
Study Termination 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Listing 
16.2.2  
Protocol Deviations  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patients excluded from the efficacy analysis 
 
 
 
 
 
 
 
Listing 
16.2.3.1 
Subjects Excluded from the Efficacy Analysis (Evaluability Reason for Evaluability Classification) 
 
X 
 
 
X 
 
 
Listing 
16.2.3.2 
 Treatment Allocation and Evaluability for All Subjects 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
 
 
 
 
 
 
 
Listing 
16.2.4.1  
Demographic Data 
 
 
 
X 
 
 
X 
Listing 
16.2.4.2 
Medical History 
 
 
 
X 
 
 
X 
Listing 
16.2.4.3 
aPAP History 
 
 
 
X 
 
 
X 
Listing 
16.2.4.4 
Inclusion Criteria Not Met and Exclusion Criteria Met 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance and/or drug concentration data 
 
 
 
 
 
 
 
Listing 
16.2.5.1 
Exposure  
 
 
 
X 
 
 
X 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
41 (45) 
 
 
 
SCR 
DB-
FAS 
DB-
PPS 
DB-
SAF 
FU-
FAS 
FU-
MOL 
INT 
FU-
SAF 
Listing 
16.2.5.2 
Compliance 
 
 
 
X 
 
 
X 
Listing 
16.2.5.3 
Rescue medication 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Individual efficacy response data 
 
 
 
 
 
 
 
Listing 
16.2.6.1 
Individual Efficacy Response Data (A-a)DO2 PaO2 and Lung function tests 
 
X 
 
 
X 
 
 
Listing 
16.2.6.2 
Individual Efficacy Response Data 6MWT 
 
X 
 
 
X 
 
 
Listing 
16.2.6.3 
Individual Efficacy Response Data GM-CSF 
 
X 
 
 
X 
 
 
Listing 
16.2.6.4 
Individual Efficacy Response Data Anti-Drug antibodies 
 
X 
 
 
X 
 
 
Listing 
16.2.6.5 
Individual Efficacy Response Data Biomarkers 
 
X 
 
 
X 
 
 
Listing 
16.2.6.6 
Individual Efficacy Response Data DSS 
 
X 
 
 
X 
 
 
Listing 
16.2.6.7 
Individual Efficacy Response Data Dyspnoea score 
 
X 
 
 
X 
 
 
Listing 
16.2.6.8 
Individual Efficacy Response Data Cough scores 
 
X 
 
 
X 
 
 
Listing 
16.2.6.9 
Individual Efficacy Response Data EQ-5D 
 
X 
 
 
X 
 
 
Listing 
16.2.6.10 
Individual Efficacy Response Data SGRQ 
 
X 
 
 
X 
 
 
Listing 
16.2.6.11 
Individual Efficacy Response Data CT     
 
X 
 
 
X 
 
 
 
 
 Adverse Event listings 
 
 
 
 
 
 
 
Listing 
16.2.7.1 
Adverse Event Listings by Treatment Subject Relative Day or Week 
 
 
 
X 
 
 
X 
Listing 
16.2.7.2 
Adverse Event Listings by System Organ Class Preferred Term Treatment and Subject 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Listing of individual laboratory measurements by patient 
 
 
 
 
 
 
 
Listing 
16.2.8.1 
Listing of Reference Ranges  
X 
 
 
 
 
 
 
Listing 
16.2.8.2 
Listing of Individual Laboratory Measurements by Subject 
 
 
 
X 
 
 
X 
Listing 
16.2.8.3 
Listing of Relevant Comments Regarding Laboratory Values 
 
 
 
X 
 
 
X 
Listing 
16.2.9  
Vital Signs  
 
 
 
X 
 
 
X 
Listing 
16.2.10  
Physical Examination  
 
 
 
X 
 
 
X 
Listing 
16.2.11  
ECG 
 
 
 
X 
 
 
X 
Listing 
16.2.12  
Concomitant Medications and Therapy  
 
 
 
X 
 
 
X 
 
  


 
 
APPENDIX 2. SAMPLE SIZE RECALCULATION MOL-PAP-002 
 
1.1 Introduction 
 
This document describes the results from the pre-planned blinded sample size re-
calculation as described in the Protocol, Final Version 5, dated 01 December 2017 
(Section 12.2). The sample size calculation was planned to be in January 2018, when 
approximately 50 patients would have reached 24 weeks of treatment. 
 
1.2 Methods 
 
The blinded sample size recalculation was conducted for the following three Key 
secondary endpoints according to protocol 
 
 
Change from baseline to week 24 in 6MWD 
 
Change from baseline to week 24 in SGRQ Total Score 
 
Time to WLL 
 
The change from baseline to week 24 in 6MWD [and SGRQ] were analysed in an 
ANCOVA model including WLL (stratification), and baseline 6MWD [SGRQ]. For the 
purposes of the sample size re-estimation process, only data on patients who had 
baseline and week 24 data was used and no imputations were made for missing values. 
 
The minimal clinically important effect sizes for 6MWD and SGRQ in aPAP were 
considered to be in the order of 40-50 m and 7-10 points, respectively. From each 
ANCOVA model, the respective residual variance for 6MWD [and SGRQ] was used to 
calculate sample size based on the effect sizes of 50 m and 10 points, respectively.  
 
The overall (pooled) event rate for WLL was determined including any patients who 
would meet the criteria for WLL any time prior to week 24, but excluding any patients who 
withdraw prior to week 24 where WLL has not been required. WLL rates of 5% (active) 
versus 20% (placebo) at 24 weeks was assumed, and compared to the observed 
(pooled) WLL rate.  
 
All sample size calculations correspond to two group comparisons and were made based 
on a 2-sideded 5% significance level, and 80% and 90% power. The observed SD was 
increased/ decreased with 10% for sensitivity. All sample size calculations were treated 
as independent calculations without considering that the power to reject any hypothesis is 
conditional on first rejecting the null hypothesis for the primary endpoint in a hierarchical 
manner. 
 
If the maximum of these sample size calculations were to be no more than 33 patients 
per group, then no change to the target sample size would be made. Otherwise, the 
sample size would be increased to attain 90% power for at least 2 of the 3 key secondary 
endpoints, subject to the total study size not exceeding 150 patients. 
 
The sample size calculations were done using proc Power in SAS Enterprise Guide 
version 7.12. 
 
 
 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
43 (45) 
1.3 Results from Sample Size Recalculation 
 
The sample size for SGRQ Total Score was based on an analysis of 51 subjects that had 
both a baseline score and a score after 24 weeks of treatment. From the ANCOVA model 
for change from baseline, including adjustment for strata and baseline score, the 
Residual Mean Square Error (MSE) was 101.582, translating to an SD of 10.1. In addition 
to the calculation based on the observed SD, sample sizes were also calculated 
assuming a 10% increase/decrease in SD. 
From Table 1, it can be seen that the number of subjects needed per treatment group 
needs to be at least 23 in order to detect a significant difference between groups of 10 
based on the observed SD with a power of 90%.   
 
Table 1 Recalculated Sample Size to detect a difference of 10 in Total SGRQ 
 
Estimated 
Standard Deviation 
Power 
9.1 
10.1 
11.1 
80% 
15 
18 
21 
90% 
19 
23 
27 
ANCOVA MSE = 101.582 based on 51 subjects with a result at baseline 
and after 24 weeks. 
 
As for SGRQ Total Score the sample size calculation for the 6MWD was based on 51 
subjects having both a baseline measurement and a corresponding measurement after 
24 weeks of treatment. From the ANCOVA including adjustment for baseline and strata 
the estimated residual MSE was 4928.203, corresponding to an SD=70.2. For sensitivity 
the SD was increased/decreased with 10%. As can be seen from Table 2, based on the 
observed SD at least 43 subjects would be needed per treatment group in order to 
detect a difference of 50m between any groups with a power of 90%. 
 
Table 2  Recalculated Sample Size to detect a difference of 50 in 6MWD 
 
Estimated 
Standard Deviation 
Power 
63.2 
70.2 
77.2 
80% 
27 
32 
39 
90% 
35 
43 
52 
ANCOVA MSE = 4928.203 based on 51 subjects with a result at baseline 
and after 24 weeks. 
 
The observed event rate of WLL was low, only 4 events among 78 randomized subjects 
either having WLL and then discontinuing, or subjects still remaining in trial. For the 
calculations it was anticipated the sample size would be calculated assuming 5% of 
subjects on active treatment vs 20% on placebo would have an event. Given these 
assumed event rates, and assuming an exponential distribution of survival times, at least 
47 subjects would be needed to detect a difference between treatment groups using a 
log-rank test, with 80% power, and 63 subjects with 90% power, if these event rates are 
true. Given the low event rate, even though probably slightly underestimated in observed 
subjects, these calculated sample sizes are likely too optimistic. 


 
Statistical Analysis Plan 
Version: Final 1.0 
Date: 2019-04-25 
Sponsor: Savara ApS. 
Study Code: MOL-PAP-002 
EudraCT No.: 2015-003878-33 
 
ST_Form_Statistical Analysis Plan_03 
44 (45) 
 
 
 
1.4 Conclusion 
 
From these sample size calculations it is clear that the two endpoints with highest power 
to detect a clinically relevant difference between treatment groups based on the least 
number of subjects are SGRQ Total Score and 6MWD. Based on the pre-defined 
criterion that the sample size would be increased to attain 90% power for at least 2 of 
the 3 key secondary endpoints, the results indicate that the critical endpoint is the 
6MWD, which would require that the sample size should be increased to at least 
43x3=129 randomised subjects. After reviewing the results from the sample-size 
recalculation it was decided by Savara ApS to increase the sample size to 45x3=135 
randomised subjects. Any subjects already in screening at the time of reaching 135 
randomised subjects may also be randomised, if otherwise eligible for the trial.  


 
 
APPENDIX 3. CONVERSION FACTORS 
For parameters that were reported in the eCRF in more than one unit, the following conversion factors will be applied: 
Parameter 
Reported Unit: 
Converted Unit: 
Conversion Factor: 
(A-a)DO2  
kPa 
mmHg 
Multiply reported result with 7.5 
Absolute DLCO/TLCO (corrected for haemoglobin) * 
mmol/min/kPa 
ml/min/mmHg 
Multiply reported result with 2.987 
Absolute DLCO/TLCO (uncorrected) * 
mmol/min/kPa 
ml/min/mmHg 
Multiply reported result with 2.987 
Haemoglobin value used for correction 
g/L 
g/dL 
Multiply reported result with 0.1 
Haemoglobin value used for correction 
mmol/L 
g/dL 
Multiply reported result with 1.61   
O2 flow rate 
ml/h 
L/min 
Multiply reported result with 0.000017  
PaCO2  
kPa 
mmHg 
Multiply reported result with 7.5 
PaO2 
kPa 
mmHg 
Multiply reported result with 7.5 
Patm 
kPa 
mmHg 
Multiply reported result with 7.5 
 
* https://www.thoracic.org/statements/resources/pft/DLCO.pdf