Clinical trial NCT03421743
Conditions: Mycobacterium Infections, Nontuberculous
Sponsor: Savara Inc.
Start date: 2018-03-01; Completion date: 2020-01-13
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The trial is an open-label, non-controlled, multicenter, pilot clinical trial of inhaled molgramostim (recombinant human granulocyte-macrophage colony stimulating factor; rhGM-CSF) in subjects with persistent pulmonary non-tuberculous mycobacterial (NTM) infection. Participants will be treated for 24-weeks with inhaled molgramostim and followed up for 12-weeks after end of treatment. The primary aim of the trial is to investigate the efficacy of inhaled molgramostim on NTM sputum culture conversion to negative.

Detailed description:
The study will comprise a Screening Visit, a Baseline Visit, a 24-week treatment period and a 12-week follow-up period. 30 adult participants with a history of chronic NTM infection with at least 2 positive cultures in the prior 2 years, of which at least one is within the last 6 months prior to Screening, will be considered for enrollment. Participants should provide a positive NTM sputum culture at Screening to be eligible.

Two subgroups of participants will be recruited:

* Group 1: Participants who remain sputum culture positive while currently on a multidrug NTM guideline based antimycobacterial regimen, which has been ongoing for at least 6 months prior to the Baseline Visit.
* Group 2: Participants who remain sputum culture positive but have either stopped a multidrug NTM guideline based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance, or never started such treatment.

The treatment period will consist of 14 trial visits (Screening \[within 10 weeks of Baseline\], Baseline, and every 4 weeks to Week 48 \[visits at Weeks 28, 36 and 44 included telephone contact, others included clinic visits\]) and a Follow-up visit 12 weeks after the end of treatment.

At the Baseline visit, eligible participants will start treatment with molgramostim nebulizer solution, 300 μg, administered by inhalation using an eFlow Nebulizer System. At each visit, sputum samples will be collected for staining and microscopy, and microbiological culture. In addition, clinical assessments including body weight, patient reported outcomes, and diffusion capacity of the lung for carbon monoxide (DLCO) will be conducted at each clinic visit. Spirometry will be assessed at Baseline, and at Weeks 12, 24, 32, 40 and 48. A 6-minute walk test (6-MWT) will be conducted at Baseline, at Weeks 12, 24, 48 and at the 12-week Follow-up visit. Safety laboratory samples will be collected at Screening, Baseline and at Weeks 4, 12, 24, 32, 40, 48 and at the 12-week Follow-up visit. Anti-GM-CSF antibodies will be assessed at Baseline, at Week 4, 12, 24, 32, 48, and at the 12-week Follow-up visit.

Arms: arm 1: Inhaled molgramostim administered in participants who remain sputum culture positive while currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 6 months prior to the Baseline Visit arm 2: Inhaled molgramostim administered in participants who remain sputum culture positive but have stopped a multidrug NTM guideline-based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance, or who never started such treatment
Interventions: intervention 1: Inhaled molgramostim intervention 2: Antimycobacterial regimen
Intervention descriptions: intervention 1: 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation intervention 2: Multidrug NTM guideline-based antimycobacterial regimen

Protocol documents:
Prot_000.pdf: 
 
SAV008-01 
An open-label, non-controlled, multicentre, pilot 
clinical trial of inhaled molgramostim in subjects with 
antibiotic-resistant non-tuberculosis mycobacterial 
(NTM) infection 
 
NCT03421743 
 
Clinical Trial Protocol 
Version 4.0 
04 October 2018 


Savara Pharmaceuticals 
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04-Oct-2018 
Confidential 
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1. 
TITLE PAGE 
 
 
 
MOLGRAMOSTIM NEBULIZER SOLUTION 
 
CLINICAL TRIAL PROTOCOL 
 
SAV008-01 
 
An Open-label, Non-controlled, Multicentre, Pilot Clinical Trial of Inhaled 
Molgramostim in Subjects with Antibiotic-resistant Non-tuberculosis 
Mycobacterial (NTM) Infection 
 
OPTIMA  
 
Product Name: 
Molgramostim Nebulizer Solution 
(Molgradex®) 300 µg 
Indication: 
Treatment-resistant pulmonary NTM 
infection  
Phase: 
IIA 
EudraCT No. 
2017-003374-14 
Sponsor: 
Savara ApS 
Slotsmarken 17, 2 t.v. 
2970 Hørsholm 
Denmark  
Date of Protocol: 
04-Oct-2018 
Version: 
4.0 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Savara ApS 
Name of Investigational Product: 
Molgramostim nebulizer solution (Molgradex®) 
Name of Active Ingredient: 
Molgramostim (recombinant human GM-CSF) 
Title of Study:  
An open-label, non-controlled, multicenter, pilot clinical trial of inhaled molgramostim in subjects 
with antibiotic-resistant non-tuberculosis mycobacterial (NTM) infection 
Study center(s): A sufficient number of centers located in Australia and United Kingdom 
International Coordinating Investigator:  Grant Waterer. Royal Perth Hospital, Australia 
Studied period (years):  
Estimated date first subject screened: Q1 2018 
Estimated date last subject completed (48 weeks treatment 
period): Q4 2019 
Estimated date last subject completed (follow-up period): Q1 
2020 
Phase of development:  
IIA 
Objectives:  
Primary: 
• 
To investigate efficacy of inhaled molgramostim on NTM sputum culture conversion to 
negative. 
Secondary: 
• 
To investigate efficacy of inhaled molgramostim on NTM sputum smear conversion to 
negative 
• 
To investigate efficacy of inhaled molgramostim on reduction of NTM bacterial load in 
sputum 
• 
To investigate efficacy of inhaled molgramostim on exercise capacity 
• 
To investigate efficacy of inhaled molgramostim on Patient Reported Outcomes  
• 
To investigate safety of inhaled molgramostim in subjects with NTM infection 
Methodology:  
A Screening Visit will be conducted up to 10 weeks prior to the Baseline Visit to determine 
eligibility. Adult subjects with a history of chronic pulmonary NTM infection with at least 2 positive 
cultures in the prior two years, of which at least one is within the last 6 months prior to Screening, 
will be considered for enrollment. Subjects should provide a positive sputum culture at Screening to 
be eligible.  


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Two subgroups of subjects will be recruited: 
• 
Group 1: Subjects who remain sputum culture positive while currently on a multidrug 
NTM guideline based antimycobacterial regimen, which has been ongoing for at least 6 
months prior to the Baseline Visit 
• 
Group 2: Subjects who remain sputum culture positive but have stopped a multidrug 
NTM guideline based antimycobacterial regimen at least 28 days prior to Screening due 
to lack of response or intolerance, or who never started such treatment. 
The study will include 30 subjects.  The treatment period will consist of 14 trial visits (Screening, 
Baseline, and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 [visits at Weeks 28, 36 and 44 
will include telephone contact, others will include clinic visits]) and a follow-up visit 12 weeks after 
end of treatment. At the Baseline Visit, eligible subjects will start treatment with inhaled 
molgramostim. At each visit, sputum samples for staining and microscopy, and microbiological 
culture will be collected. If required, induced sputum may be obtained according to local standards. 
Subjects will be asked to collect two additional sputum samples, preferably on the consecutive days 
after the clinic visit. For the visits at Weeks 28, 36 and 44 all three samples will be collected at home. 
In addition, clinical assessments including body weight, patient reported outcomes, and diffusing 
capacity of the lung for carbon monoxide (DLCO) will be conducted at each clinic visit. A computed 
tomography (CT) scan will be conducted at Baseline if not performed within 6 months prior to 
Baseline. In case of a drop in DLCO of at least 20% at two consecutive visits the CT scan may be 
repeated. A CT scan can be performed after 48 weeks of treatment if this is a part of the local routine 
clinical practice. Spirometry will be assessed at Baseline, and at Weeks 12, 24, 32, 40 and 48. A 6-
minute walk test (6MWT) will be conducted at Baseline, at Weeks 12, 24, 48 and at the 12-week 
follow-up visit. Safety laboratory assessments will be assessed at Screening, Baseline and at Weeks 4, 
12, 24, 32, 40, 48 and at the 12-week follow-up visit. Anti-GM-CSF antibodies will be assessed at 
Baseline, at Week 4, 12, 24, 32, 48 and at the 12-week follow-up visit. For subjects having a chest X-
ray during the study period as part of the routine local clinical practice, the results from the X-ray will 
be recorded. Participating subjects will be encouraged to contact the clinic between visits if they 
experience adverse events (AE), worsening of their condition or have any other concerns. 
Treatment with inhaled molgramostim will be given at a dosage of 300 µg once daily for 48 weeks. A 
data review was conducted after the first 6 subjects had completed 12 weeks of treatment. If safety 
concerns or poor tolerability were identified in this review, the review committee might decide on less 
frequent dosing for subsequent subjects in the study. The safety review concluded that there were no 
safety issues of significant concern and the dose was unchanged. In order to obtain more robust 
treatment responses, it was decided to extend the treatment duration to 48 weeks. If needed, 
unscheduled visits will be conducted at investigator’s discretion. 
During the study, subjects in Group 1 will continue use of antimycobacterial treatment. All changes in 
antimycobacterial treatment will be recorded, including reasons for each change. In case of worsening 
of NTM pulmonary disease, antimycobacterial treatment may be added or a dosage increase of 
antimycobacterial treatment may be applied as rescue treatment, according to investigator’s 
discretion. 
Number of subjects (planned):  
30 subjects will be included. No formal sample size calculation was done as this is an initial pilot 
study. 


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Diagnosis and main criteria for inclusion: 
Inclusion Criteria:  
1. History of chronic pulmonary infection with M. avium complex (MAC) or M. abscessus 
(defined as at least 2 documented positive sputum cultures in the prior 2 years, of which at 
least one was obtained in the 6 months prior to Screening). 
2. Subject fulfills one of the following criteria: 
o Subjects who remain sputum culture positive while currently on a multidrug NTM 
guideline based antimycobacterial regimen, which has been ongoing for at least 6 
months prior to the Baseline Visit 
o Subjects who remain sputum culture positive but have either stopped a multidrug 
NTM guideline based antimycobacterial regimen at least 28 days prior to Screening 
due to lack of response or intolerance, or never started such treatment.  
3. Ability to produce at least 2 mL of sputum or be willing to undergo an induction that 
produces at least 2 mL of sputum for clinical evaluation. 
4. Female or male ≥18 years of age. 
5. Females who have been post-menopausal for more than 1 year or females of childbearing 
potential after a confirmed menstrual period using a highly efficient method of contraception 
(i.e. a method with less than 1% failure rate such as combined hormonal contraception, 
progesterone-only hormonal contraception, intrauterine device, intrauterine hormone- 
releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence1), during 
and until thirty (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. 
6. Males agreeing to use condoms during and until thirty (30) days after last dose of medication, 
or males having a female partner who is using adequate contraception as described above. 
7. Willing and able to provide signed informed consent. 
8. 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. 
1 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
Exclusion criteria: 
1. Subjects diagnosed with cystic fibrosis. 
2. Prior therapy with inhaled or systemic GM-CSF. 
3. Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to Screening. 
4. Concurrent disease with a life expectancy of less than 6 months. 
5. History of, or present, myeloproliferative disease, leukemia or other hematological 
malignancy. 
6. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring 


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chemotherapy or radiation therapy within one year prior to Screening or anticipated during 
the study period. 
7. Active allergic bronchopulmonary mycosis or connective tissue disease, inflammatory bowel 
disease or other autoimmune disorder requiring therapy associated with significant 
immunosuppression, such as systemic corticosteroids at a dose equivalent of 10 mg/day or 
more of prednisolone, within 3 months prior to Screening or anticipated during the study 
period. 
8. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening. 
9. HIV infection or other disease associated with significant immunodeficiency. 
10. History of lung transplantation. 
11. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to 
Screening. 
12. Treatment with any investigational medicinal product within 3 months of Screening. 
13. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product 
14. Any other serious medical condition which in the opinion of the investigator would make the 
subject unsuitable for the trial 
 
Investigational product, dosage and mode of administration:  
Investigational Medicinal Product (IMP): Molgramostim nebulizer solution 
Active Substance: Molgramostim, recombinant human Granulocyte Macrophage Colony Stimulating 
Factor (rhGM-CSF) 
Pharmaceutical form: Nebulizer solution  
Route of administration: Inhalation 
Inhalation device: PARI eFlow (PARI Pharma GmbH) 
 
 
Duration of treatment:  
Treatment will be given for 48 weeks. 
 
 
Reference therapy, dosage and mode of administration:  
Not applicable 
 
 
 


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Efficacy: 
Primary Endpoint: 
• 
Sputum culture conversion defined as at least three consecutive negative sputum samples 
during the treatment period. 
Secondary Endpoints: 
• 
Sputum smear conversion defined as at least three consecutive negative acid-fast bacilli 
(AFB) stained sputum smears on microscopy during the treatment period in subjects who 
were smear positive at Baseline. 
• 
Durability of sputum culture conversion (defined as conversion at or before Week 48 and 
culture still negative at 12-weeks follow-up). 
• 
Durability of sputum smear conversion (defined as conversion at or before Week 48 and 
smear still negative at 12-weeks follow-up). 
• 
Change in semi-quantitative grade of number of NTM on microscopy of AFB stained sputum 
smears from Baseline to Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 12-week 
follow-up.   
• 
Change in semi-quantitative grade of sputum cultures from Baseline to Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48 and 12-week follow-up. 
• 
Change in symptom scores (assessed using Lower Respiratory Tract Infections – Visual 
Analogue Scale (LRTI-VAS) and Quality of Life Questionnaire– Bronchiectasis (QOL-B) 
from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week follow-up. 
• 
Change in Global Rating of Health (GRH) from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 
40, 48 and 12-week follow-up. 
• 
Change in body weight from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week 
follow-up. 
• 
Change in 6-minute walk distance (6MWD), oxygen desaturation and Borg CR10 scores 
during a 6MWT from Baseline to Week 12, 24, 48 and 12-week follow-up. 
Safety: 
• 
Number of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), severe 
AEs and AEs leading to treatment discontinuation during the trial period. 
• 
Change in white blood cell counts (WBC) and differentials in blood from Baseline to Weeks 
4, 12, 24, 32, 40, 48 and 12-week follow-up. 
• 
Change in DLCO from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week 
follow-up. 
• 
Change in forced expiratory volume in 1 second (FEV1) (% predicted) and forced vital 
capacity (FVC) (% predicted) from Baseline to Weeks 12, 24, 32, 40 and 48. 
Development of anti-GM-CSF antibodies at Week 4, 12, 24, 32, 48 and at 12-week follow-up. 
 


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Methods of Assessment 
Microbiological characterization and quantification – Sputum culture will be done to confirm growth 
or absence of growth of NTM. In addition, a semi-quantitative assessment of bacterial load will be 
conducted. 
AFB staining (fluorescence and/or Ziehl–Neelsen [ZN] stain) will be used to identify NTM in sputum 
and conduct a semi-quantitative assessment of bacterial load (graded as 0, occasional, 1+, 2+, 3+). 
Smears will also be fixated on slides and all slides will be submitted to a central laboratory for a 
second assessment. 
Identification to NTM species level will be conducted on positive samples using established methods.  
Routine bacteriology and fungal culture will be done on sputum samples. 
Functional tests – A 6MWT test will be performed in accordance with European Respiratory 
Society/American Thoracic Society (ERS/ATS) guidance (2014). Borg CR10 scale will be used to 
assess dyspnea before and after the test. 
Patient Reported Outcomes – clinical symptoms will be assessed using Lower Respiratory Tract 
Infections – Visual Analogue Score (LRTI-VAS), grading symptoms of dyspnea, fatigue, cough, 
pain, and sputum, Quality of Life Questionnaire– Bronchiectasis (QOL-B); and GRH which assesses 
global health as “excellent, good, fair or poor”. 
Radiology – if a chest X-ray or CT scan is done, information on the results will be collected. 
Safety laboratory testing – A central laboratory will be used for analysis of hematology, clinical 
chemistry, and urinalysis. 
Anti-GM-CSF antibodies – A central laboratory will be used for analysis of anti-GM-CSF antibodies  
Pulmonary function testing – DLCO and spirometry will be done using local equipment. Percent of 
predicted values will be calculated centrally using standard equations. 
Electrocardiogram (ECG) – ECG will be done using local equipment. No central overreading will be 
done. 
Statistical methods: 
Each subgroup (Group 1 and Group 2) will be analyzed separately. Data will be presented 
descriptively and using 95% confidence intervals. Statistical summaries comparing post-treatment 
values with Baseline will be conducted for selected endpoints. For the primary endpoint, (sputum 
culture conversion rates), the number of patients who convert to negative out of the number per group 
will be presented with 95% exact binomial confidence intervals. 
As this is an exploratory study no adjustments for multiplicity will be done. Further details of all 
analyses will be given in the statistical analysis plan.  
On the basis of the poor historical success rates of current standard therapy, a 30% response rate for 
the primary endpoint would be considered clinically relevant. 


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3. 
TRIAL FLOW CHART 
Table 1: 
Study Schedule of Assessments 
Visit number 
V1 
V2 
V3  
V4 
V5  
V6 
V7 
V8 
V9h 
V10 
V11h 
V12 
V13 
V14 
V15  
UV  
 
Screen
ing 
Base-
line 
Week 4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
TC 
Week 
32 
Week 
36 
TC 
Week 
40 
 
Week 
44 
TC 
Week 
48 
12-Week 
F-up 
Unscheduled 
visita 
Day 
 
< 10 
wks 
after 
V1 
28 
days 
after 
V2 
56 
days 
after 
V2 
84 
days 
after 
V2 
112 
days 
after 
V2 
140 
days 
after  
V2 
168 
days 
after 
V2 
196 
days 
after 
V2 
224  
days 
after 
V2 
252 
days 
after 
V2 
280 
days 
after 
V2 
308 
days 
after 
V2 
336 
days 
after 
V2 
84 days 
after 
V14 
 
Window 
 
 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 Days 
± 7 Days 
Informed 
consent 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and body 
measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
(X) 
Prior and 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
and 
contraceptive 
check 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
X 
X 
(X) 
Physical Exam 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
(X) 
Vital signs 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
(X) 


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Visit number 
V1 
V2 
V3  
V4 
V5  
V6 
V7 
V8 
V9h 
V10 
V11h 
V12 
V13 
V14 
V15  
UV  
 
Screen
ing 
Base-
line 
Week 4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
TC 
Week 
32 
Week 
36 
TC 
Week 
40 
 
Week 
44 
TC 
Week 
48 
12-Week 
F-up 
Unscheduled 
visita 
Day 
 
< 10 
wks 
after 
V1 
28 
days 
after 
V2 
56 
days 
after 
V2 
84 
days 
after 
V2 
112 
days 
after 
V2 
140 
days 
after  
V2 
168 
days 
after 
V2 
196 
days 
after 
V2 
224  
days 
after 
V2 
252 
days 
after 
V2 
280 
days 
after 
V2 
308 
days 
after 
V2 
336 
days 
after 
V2 
84 days 
after 
V14 
 
Window 
 
 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 Days 
± 7 Days 
DLCO 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
(X) 
Spirometry 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
6MWTb  
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Collection of 
Sputum 
sample 
Xc 
Xc 
Xc 
Xc 
Xc  
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc  
(X) 
Laboratory 
Safety 
sampling 
X 
Xd 
Xd 
 
Xd  
 
 
X d 
 
X d 
 
X d 
 
X  
X 
(X) 
Sample for 
anti-GM-CSF 
 
Xd 
Xd 
 
Xd 
 
 
Xd 
 
Xd 
 
 
 
X 
X 
(X) 
ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
(X) 
Chest X-raye 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
(X) 
(X) 
(X) 
CTf 
 
X  
 
 
 
 
 
 
 
 
 
 
 
(X) 
 
(X) 
Questionnaires 
QOL-B, LRTI-
VAS, GRH 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
(X) 
Subject diary 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Trial drug 
administration 
training  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
Trial drug 
dosing at the 
site 
 
 Xg 
Xg 
 
Xg 
 
 
Xg 
 
Xg 
 
Xg 
 
 
 
(X) 


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Visit number 
V1 
V2 
V3  
V4 
V5  
V6 
V7 
V8 
V9h 
V10 
V11h 
V12 
V13 
V14 
V15  
UV  
 
Screen
ing 
Base-
line 
Week 4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
TC 
Week 
32 
Week 
36 
TC 
Week 
40 
 
Week 
44 
TC 
Week 
48 
12-Week 
F-up 
Unscheduled 
visita 
Day 
 
< 10 
wks 
after 
V1 
28 
days 
after 
V2 
56 
days 
after 
V2 
84 
days 
after 
V2 
112 
days 
after 
V2 
140 
days 
after  
V2 
168 
days 
after 
V2 
196 
days 
after 
V2 
224  
days 
after 
V2 
252 
days 
after 
V2 
280 
days 
after 
V2 
308 
days 
after 
V2 
336 
days 
after 
V2 
84 days 
after 
V14 
 
Window 
 
 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 
Days 
± 7 Days 
± 7 Days 
Dispense trial 
drug 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
 
 
 
(X) 
Return of used 
trial drug 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
(X) 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
(X) 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: 6MWT= 6-minute walk test; AE=adverse event; CT= Computed tomography; DLCO= Diffusion capacity of the lung for carbon monoxide; ECG= electrocardiogram; GM-
CSF=granulocyte macrophage colony stimulating factor; GRH=Global rating of health; LRTI-VAS= lower respiratory tract infection-visual analogue scale; QoL-B= Quality of Life- Bronchiectasis 
a Procedures marked with brackets should be performed as necessary. 
b 6MWT includes assessment of SpO2 and Borg CR10 score for dyspnea before, during (SpO2) and after (Borg) the test. 
c Three samples, preferably on consecutive days, will be collected. All samples collected at V9, V11 and V13 will home collected. 
d Sample to be taken before dosing at the site.  
e A chest X-ray not a study requirement. But if subjects have a chest X-ray during the study period as part of the local routine clinical practice, the results from the X-ray will be recorded. 
f A CT scan performed up to 6 months prior to the Baseline visit is accepted. A CT scan can be performed at V14 if this is a part of the local routine clinical practice. 
g Trial drug dosing should be performed after blood sampling. 
h Visit 9 and 11 can be scheduled as a site visit if deemed necessary by the investigator. Procedures in brackets should be performed if visit 9 or 11 is performed as a site visit.


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4. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
TRIAL FLOW CHART ................................................................................................8 
4. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................16 
6. 
INTRODUCTION ......................................................................................................19 
6.1. 
Background .................................................................................................................19 
6.2. 
Trial Rationale ............................................................................................................23 
6.3. 
Potential Risks and Benefits .......................................................................................25 
7. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................27 
7.1. 
Primary Objective .......................................................................................................27 
7.2. 
Secondary Objectives .................................................................................................27 
7.3. 
Endpoints ....................................................................................................................27 
7.3.1. 
Efficacy Endpoints ......................................................................................................27 
7.3.1.1. 
Primary Efficacy Endpoint: ........................................................................................27 
7.3.1.2. 
Secondary Efficacy Endpoints: ...................................................................................27 
7.3.2. 
Safety Endpoints .........................................................................................................28 
8. 
INVESTIGATIONAL PLAN .....................................................................................29 
8.1. 
Overall Trial Design ...................................................................................................29 
8.1.1. 
Trial Period .................................................................................................................31 
8.1.2. 
End of Trial .................................................................................................................31 
8.1.3. 
Trial completion ..........................................................................................................31 
8.2. 
Number of Subjects ....................................................................................................31 
8.3. 
Treatment Assignment ................................................................................................31 
8.4. 
Dose Adjustment Criteria ...........................................................................................32 
8.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................32 
8.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................32 
8.5. 
Criteria for Study Termination ...................................................................................32 


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9. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................33 
9.1. 
Subject Inclusion Criteria ...........................................................................................33 
9.2. 
Subject Exclusion Criteria ..........................................................................................34 
9.3. 
Subject Withdrawal Criteria .......................................................................................35 
9.3.1. 
Discontinuation from Trial Treatment ........................................................................35 
9.3.2. 
Withdrawal from the Trial ..........................................................................................35 
10. 
TREATMENT OF SUBJECTS ..................................................................................36 
10.1. 
Description of Study Drug ..........................................................................................36 
10.2. 
Prohibited Medications ...............................................................................................36 
10.3. 
Treatment Compliance ................................................................................................36 
10.4. 
Randomization and Blinding ......................................................................................36 
10.5. 
Subject Identification List ...........................................................................................36 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37 
11.1. 
Study Drug ..................................................................................................................37 
11.2. 
Study Drug Packaging and Labeling ..........................................................................37 
11.3. 
Study Drug Storage .....................................................................................................37 
11.4. 
Study Drug Preparation ..............................................................................................37 
11.5. 
Administration ............................................................................................................37 
11.6. 
Study Drug Accountability .........................................................................................38 
11.7. 
Study Drug Handling and Disposal ............................................................................38 
12. 
ASSESSMENTS .........................................................................................................39 
12.1. 
Informed consent ........................................................................................................39 
12.2. 
Collection of Sputum Samples for Microbiological Characterization and 
Quantification .............................................................................................................39 
12.3. 
Prior and Concomitant Medication .............................................................................40 
12.4. 
6-Minute Walk Test (6MWT) ....................................................................................40 
12.5. 
Patient Reported Outcomes ........................................................................................41 
12.5.1. 
Lower Respiratory Tract Infections – Visual Analogue Score ...................................41 
12.5.2. 
Quality of Life Questionnaire– Bronchiectasis (QOL-B) ..........................................41 
12.5.3. 
Global Rating of Health (GRH) ..................................................................................41 
12.6. 
Subject Diary ..............................................................................................................41 
12.7. 
Adverse Events ...........................................................................................................41 
12.8. 
Demographic/Medical History/Body Measurements .................................................42 


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12.9. 
Physical Examination .................................................................................................42 
12.10. 
Vital Signs ..................................................................................................................42 
12.11. 
Electrocardiogram (ECG) ...........................................................................................43 
12.12. 
Radiology ....................................................................................................................43 
12.12.1. 
CT Scan ......................................................................................................................43 
12.12.2. 
Chest X ray (only if conducted as part of the local routine clinical practice) ............43 
12.13. 
Pulmonary Function Tests ..........................................................................................43 
12.13.1. 
DLCO .........................................................................................................................43 
12.13.2. 
Spirometry ..................................................................................................................43 
12.14. 
Laboratory Assessments .............................................................................................43 
12.14.1. 
Levels of Anti-GM-CSF Antibodies ..........................................................................44 
12.14.2. 
Laboratory Safety Assessments ..................................................................................44 
12.14.2.1. Blood Hematology ......................................................................................................44 
12.14.2.2. Blood Chemistry .........................................................................................................44 
12.14.2.3. Urinalysis ....................................................................................................................44 
12.14.2.4. Pregnancy Screen ........................................................................................................44 
12.15. 
Adverse and Serious Adverse Events .........................................................................45 
12.15.1. 
Definition of Adverse Events .....................................................................................45 
12.15.1.1. Adverse Event (AE) ....................................................................................................45 
12.15.1.2. Serious Adverse Event (SAE) ....................................................................................45 
12.15.1.3. Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................45 
12.16. 
Recording Adverse Events .........................................................................................46 
12.17. 
Reporting Adverse Events ..........................................................................................48 
12.17.1. 
Reporting of Serious Adverse Events .........................................................................48 
12.17.2. 
SUSAR Reporting Procedure .....................................................................................49 
12.17.3. 
Adverse Events of Special Interest .............................................................................50 
12.17.4. 
Precautions/Overdose .................................................................................................50 
12.17.5. 
Pregnancy ...................................................................................................................50 
12.17.6. 
Safety Management Plan ............................................................................................50 
13. 
STATISTICS ..............................................................................................................51 
13.1. 
Primary Endpoint ........................................................................................................51 
13.2. 
Secondary Endpoints ..................................................................................................51 
13.3. 
Safety Endpoints .........................................................................................................52 


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13.4. 
General ........................................................................................................................52 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................53 
14.1. 
Access to Source Data and Documentation ................................................................53 
14.2. 
Subject Records and Source Data ...............................................................................53 
14.3. 
Study Monitoring ........................................................................................................53 
14.4. 
Audits and Inspections ................................................................................................54 
14.5. 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) ..................54 
15. 
ETHICS ......................................................................................................................55 
15.1. 
Ethics Review .............................................................................................................55 
15.2. 
Ethical Conduct of the Study ......................................................................................55 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................56 
16.1. 
Data Management .......................................................................................................56 
16.1.1. 
Protocol Deviations ....................................................................................................56 
16.2. 
Inspection of Records .................................................................................................56 
16.3. 
Retention of Records ..................................................................................................56 
17. 
FINANCE AND INSURANCE .................................................................................57 
18. 
TRIAL ORGANIZATION .........................................................................................58 
19. 
PUBLICATION POLICY ..........................................................................................59 
20. 
LIST OF REFERENCES ............................................................................................60 
21. 
APPENDICES ............................................................................................................63 
APPENDIX 1. RATIONALE FOR AMENDMENTS AND LIST OF REVISIONS ................64 
APPENDIX 2. SIGNATURE PAGE ..........................................................................................69 
APPENDIX 3. TRIAL ORGANIZATION .................................................................................70 
APPENDIX 4. QUESTIONNAIRES ..........................................................................................71 
4.1 
Borg CR10 Scale ........................................................................................................71 
4.2 
Quality of Life Questionnaire – Bronchiectasis .........................................................72 
4.3 
 Lower Respiratory Tract Infections –Visual Analogue Scale – for use in 
non-CF Bronchiectasis ................................................................................................76 
 


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LIST OF TABLES 
Table 1: 
Study Schedule of Assessments....................................................................................8 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................16 
Table 3: 
Investigational Product ...............................................................................................36 
Table 4: 
Table of Revisions ......................................................................................................64 
  
  


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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
6MWT 
6 Minute Walk Test 
6MWD 
6 Minute Walk Distance 
aPAP 
Autoimmune Pulmonary Alveolar Proteinosis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AFB 
Acid Fast Bacilli 
anti-GM-CSF 
Antibodies Towards Granulocyte Macrophage Colony 
Stimulating Factor 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area Under the Concentration Versus Time Curve 
BAL 
Bronchial Alveolar Lavage 
CA 
Competent Authority 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CT 
Computer Tomography 
CTR 
Clinical Trial Report 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EFD 
Embryo Fetal Development 
EVF 
Erythrocyte Volume Fraction 
eGFR 
Estimated Glomerular Filtration Rate 


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Abbreviation or Specialist Term 
Explanation 
ERS 
European Respiratory Society 
FEV1 
Forced Expiratory Volume in One Second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
GMP 
Good Manufacturing Practice 
GRH 
Global Rating of Health 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonization 
ICMJE 
International Committee of Medical Journal Editors  
IEC 
Independent Ethics Committee 
IDSA 
Infectious Diseases Society of America 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LSLV 
Last Subject Last Visit 
LRTI-VAS 
Lower Respiratory Tract Infections – Visual Analogue Scale 
MAD 
Multiple Ascending Dose 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NK 
Natural Killer Cells 
NOAEL 
No Observed Adverse Effect Level 
NTM 
Non -Tuberculosis Mycobacteria 
NTM-PD 
Non -Tuberculosis Mycobacteria Pulmonary Disease 
PCR 
Polymerase Chain Reaction 
PCV 
Packed Cell Volume 
PCV/EVF 
Packed Cell Volume (PCV) Or Erythrocyte Volume Fraction 
(EVF) Also known as Hematocrit 
PT 
Preferred Term 


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Abbreviation or Specialist Term 
Explanation 
PT-INR 
Prothrombin Time International Normalized Ratio 
QoL-B 
Quality of Life- Bronchiectasis 
RBC 
Red Blood Cells 
RDW 
Red Blood Cell Distribution Width 
rhGM-CSF 
Recombinant Human Granulocyte Macrophage Colony 
Stimulating Factor 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Blood Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
tmax 
Time of Maximum Plasma Concentration 
VC 
Vital Capacity 
WBC 
White Blood Cells 
WHO 
World Health Organization 
ZN 
Ziehl–Neelsen stain 
 
 


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6. 
INTRODUCTION 
6.1. 
Background  
Non-tuberculosis mycobacterial (NTM) infection  
Pulmonary disease due to NTM is an increasing problem in the USA and most western countries.  
Over the last three decades an increasing incidence of pulmonary NTM isolation has been 
observed [Wassilew 2016, Stout 2016] and NTM are now recognized to be a major cause of 
chronic lung disease. Non-tuberculosis mycobacteria cause progressive lung destruction resulting 
in a variety of symptoms including cough, breathlessness and weight loss.   
Incidence rates of NTM pulmonary disease (NTM-PD), show wide geographic variation. In 
Queensland, Australia with compulsory reporting of NTM-PD, the prevalence in the general 
population was 15.1 per 100,000 in 2010 [Thomson 2015]. In Europe prevalences ranging from 
0.2 to 2.9 per 100,000 have been reported [Wassilew 2016] and across the USA prevalences 
range from 1 to 10 per 100,000 [Stout 2016]. In Ontario, Canada the annual prevalence of 
disease was reported as 9.8 per 100,000 [Marras 2013]. Disease frequency increases markedly 
with age [Winthrop 2011]; the prevalence in the over 65 age group was reported as 47 per 
100,000 in 2007, an increase from 20 per 100,000 in 1997 (corresponding to an 8.2% yearly 
increase) [Adjemian 2012]. In Germany, the highest prevalence rates were observed among 
patients >50 years of age, in particular among those ≥80 years of age (9.4 and 9.6 per 100,000 
for men and women respectively) [Ringhausen 2016]. In the USA, consistent with findings in 
Germany, disease frequency increased markedly with age, with prevalence of 15, 30 and 57 per 
100,000 observed in age groups ≥60 years, aged 70-79 years and ≥ 80 years respectively 
[Prevots 2010]. Studies of patients with bronchiectasis in the USA suggest almost two-thirds 
have NTM-PD [Aksamit 2017], suggesting rates are likely to be in the order of per 200-300 per 
100,000 in the over 65 age group.  Several factors may contribute to the emergence of NTM-PD, 
including an aging population with chronic lung diseases, advances in microbiological 
techniques and radiological diagnostics that have improved the identification of pulmonary 
abnormalities [Wassilew 2016, Stout 2016]. 
Although over 160 species of NTM cause human disease, the most in common the USA are M. 
avium and M. intracellulare, and, in a few regions, M. kansasii.  M. abscessus is also a problem 
in the USA as it is a much more aggressive infection than other NTM with worse patient 
outcomes and requiring intravenous and oral therapy.  While NTM are nothing like as contagious 
as tuberculosis, they are transmissible from human to human, [Aitken 2012] and in the case of 
M. abscessus this may be the major route of acquisition [Bryant 2016]. 
Successfully treating NTM disease is a major problem for clinicians and patients.  Antibiotic 
options for NTM are poor [Griffith 2007, Griffith 2016]. The standard regime for NTM (avium, 
intracellulare and kansasii) is a 3-drug regimen of a macrolide (clarithromycin or azithromycin), 
a rifamycin (usually rifampicin) and ethambutol. In clinical trials, it is usual for more than half of 
patients to describe significant side effects of therapy, with up to a quarter being intolerant of 
therapy [Griffith 2007, Aksamit 2017, Rawson 2016]. For this reason, the intention to treat cure 
rates in clinical trials are usually no more than 50%.  Clinical experience is that ‘normal’ practice 
outside of clinical trials is much worse than this. [Rawson 2016] Typical side effects are severe 


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nausea, vomiting, diarrhea, peripheral neuropathy, hepatitis, skin rashes, blood dyscrasias, visual 
loss and hearing loss.  Treatment is usually for a minimum of 18 months, or at least 1 year after 
the last positive sputum culture (which is rarely in the first 6 months of therapy) [Griffith 2007]. 
Follow up studies of clinical trials in NTM show that within 3-years up to half of patients have 
disease recurrence.  This is a mixture of reactivation of prior disease and acquisition of new 
NTM from the environment [Lam 2006]. Non-tuberculosis mycobacteria do progressively 
acquire drug-resistance, including to rifampicin, amikacin, macrolides and quinolones [Cowman 
2016, Zhao 2014, Heidarieh 2016].  The presence of macrolide resistance is well established to 
be associated with worse patient outcomes [Griffith 2016].  For this reason, subsequent episodes 
of disease become progressively harder to treat and some means of preventing disease after 
apparent cure is desperately required [Griffith 2016].   
Investigational Medicinal Product (IMP) 
The IMP, Molgramostim nebulizer solution, is developed by Savara Pharmaceuticals. The drug 
substance molgramostim (rhGM-CSF) is produced in E. coli and has the same amino acid 
sequence as the native protein but is not glycosylated. Another rhGM-CSF product, 
sargramostim, which is produced in S. cerevisiae slightly differs from native GM-CSF by having 
one amino acid difference in position 23 and is glycosylated. Production of molgramostim in 
bacteria circumvents the variability in the molecular weight seen in sargramostim. The 
formulation currently under development is intended for inhalation use.  
No rhGM-CSF products have been approved for respiratory disease therapy or for inhalation use 
in any indication. Two rhGM-CSF products for systemic use have been approved, E.coli derived 
molgramostim (Leucomax®) and yeast-derived sargramostim (Leukine®), largely for use 
following chemotherapy and/or bone marrow transplantation to reduce the risks of neutropenia 
such as infection, or in case of graft failure after bone marrow transplantation. Published clinical 
studies of relevance to the development of molgramostim nebulizer solution in which 
investigational or commercially available rhGM-CSF products have been administered are 
summarized and discussed in the Investigator’s Brochure (IB). 
Pre-clinical studies in cynomolgus monkeys show that molgramostim is deposited in the lungs 
after inhalation. The small fraction of the inhaled dose that is absorbed systemically causes 
increases in stem cell proliferation, resulting in increased number of monocytes, eosinophils and 
neutrophils in the circulation; similar to the known effects after intravenous (IV) administration 
of rhGM-CSF.  
Toxicity of inhaled molgramostim nebulizer solution was investigated in cynomolgus monkeys, 
as this is the most relevant animal species for safety evaluation. After inhalation of 
molgramostim nebulizer solution, rhGM-CSF is deposited in the lungs. Local effects in the lungs 
are characterised by accumulation of inflammatory cells, mostly macrophages, accompanied by 
an increased cellularity in the lymphoid tissue that is associated with the respiratory tract and 
minimal to mild exudation of red blood cells into the alveoli. The infiltration of inflammatory 
cells was not associated with any signs of inflammation or impaired lung function, and it is 
interpreted as an exaggerated pharmacological effect of molgramostim. Its severity was graded 
slight at the 10 μg/kg/day dose level and moderate above this level. Duration of treatment did not 
affect the severity of this finding. Reduced severity of the lung and tracheobronchial changes 
following 4 weeks off dose in recovery animals suggests partial resolution of the changes. 


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Bronchopneumonia was found in one monkey treated with 42 µg/kg/day and in one treated with 
127 µg/kg/day, both from the same study, which employed a bronchoalveolar lavage (BAL) 
procedure before treatment. Since bronchopneumonia is a well-known sequela of BAL and 
because no bronchopneumonia was reported from any animal in studies that did not include this 
pre-treatment procedure, it was concluded that the bronchopneumonia was not directly related to 
molgramostim nebulizer solution. 
The No Observed Adverse Effect Level (NOAEL) across all inhalation toxicity studies was 
based on the chronic (26-week) inhalation toxicity study and was set at the 40 μg/kg/day nominal 
dose level.  NOAELs from other toxicity studies than the 26-week study was either at the same 
nominal dose level (i.e. the 13-week study) or at a higher nominal dose level (i.e. the 6-week 
study). 
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.  
An embryo-fetal developmental (EFD) toxicity study with molgramostim nebulizer solution has 
been conducted in rabbits, which show a similar pharmacological response as humans or 
monkeys, although at a lower potency. The EFD study revealed increases in post implantation 
loss, decreases in the number of live implants, effects on sex ratio and a slight increase in the 
incidence of major malformations in fetuses at the highest dose (150 µg/kg/day), consistent with 
findings from other rhGM-CSF products. Studies in sexually mature monkeys have shown that 
molgramostim has no effect on male and female reproductive organs.  
Further details are available in the Investigator’s Brochure (IB). 
The first clinical study with molgramostim nebulizer solution has been completed (MOL-001). 
This was a phase I study to investigate the effects of molgramostim nebulizer solution in healthy 
adult subjects. The study was a randomized, 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 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 time of maximum plasma concentration (tmax) of 2 hours after inhalation of molgramostim 
nebulizer solution, however, at picogram levels 50-100 times lower than has been observed after 
similar doses of sargramostim administered intravenously. Total systemic exposure (AUClast) 
increased with dose ranging between 13 and 138 pg•h/mL and maximum measurable plasma 
concentrations (Cmax) ranged between 9.1 and 41 pg/mL (Cmax was similar for the 300 and 600 
μg dose levels). In the MAD part, despite the short half-life of approximately 4 hours where GM-
CSF levels returned to 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 


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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 nebulizer solution a slight increase in total WBC and differential counts 
(primarily within normal reference ranges) was observed in a dose-dependent manner. Two 
subjects had adverse events (AEs) concerning WBC differential counts that were considered 
related to GM-CSF (eosinophilia and white blood cell count increased).  
The most common AE was cough, reported for 21/30 (70%) subjects receiving molgramostim 
nebulizer solution and 8/12 (67%) receiving placebo. The AEs considered treatment-related 
reported by two or more (>5%) subjects receiving molgramostim nebulizer 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 was no development of anti-drug 
antibodies up to 28 days after last dose. There were no serious adverse events (SAEs), severe 
AEs, dose-limiting toxicity, or other remarkable findings of clinical concern from review of 
clinical safety data.  
Further details are available in the Investigator’s Brochure (IB). 
Two clinical studies with molgramostim nebulizer solution are currently ongoing. Study MOL-
PAP-002 is a pivotal clinical trial in autoimmune pulmonary alveolar proteinosis (aPAP) being 
conducted in Europe, Japan, Israel, Russia, Turkey, South Korea, and Australia. This trial is a 
randomized, double-blind, placebo-controlled trial, planned to enroll 90 patients with aPAP. 
Treatment is given for 24 weeks and consists of daily administration of molgramostim nebulizer 
solution 300 µg, alternating cycles of molgramostim nebulizer solution 300 µg daily for 7 days 
and placebo daily for 7 days or daily administration of placebo. After the double-blind period, 
there is a 24- to 48-week follow-up period, during which open-label treatment with 
molgramostim nebulizer solution is given. Three reviews of unblinded safety data by an 
independent data safety monitoring board (DSMB) have been conducted, including 10, 38 and 
59 randomized patients, respectively. Data reviewed comprised adverse events, safety laboratory 
data, vital signs and pulmonary function tests from up to 60 weeks of treatment. No safety 
signals of concern were identified and the DSMB recommended that the trial could continue as 
planned.  
Further details are available in the IB. 
 
 
 


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6.2. 
Trial Rationale 
As NTM are inherently resistant to antibiotics treatment is difficult, typically requiring at least 
three antibiotics for a minimum of 18 months. Discontinuation of treatment due to adverse drug 
effects is frequent (10–30%), and the overall treatment success rate is only 40–60%. The 
treatment success rate is higher (70–85%) in patients with non-cavitary nodular bronchiectatic 
lung disease than in those with cavitary lung disease. Even after successful completion of 
antibiotic therapy, microbiological recurrence (predominantly due to reinfection rather than 
relapse) is relatively common (30–50%), especially in patients with nodular bronchiectatic lung 
disease [Stout 2016]. Thus, new treatments are urgently required. The current study is a pilot 
study in subjects who have not responded to multidrug NTM guideline based antimycobacterial 
regimens in the past for reasons of lack of efficacy, inability to tolerate the drug regimen, or did 
not want to take it. Response to further NTM treatments in this subgroup would be not expected.   
Due to their thick cell wall and resistance to normal extracellular defense mechanisms, 
successful killing of mycobacteria requires phagocytosis by macrophage. The macrophages then 
recruit additional help in the form of T-lymphocytes and Natural Killer (NK) cells, which in turn 
activate the macrophage so that it develops sufficient lysosomal activity to neutralize the bacteria 
[Awuh 2017]. At the same time mycobacteria have developed a variety of strategies to not only 
survive within macrophages, but to feed off their lipid-rich environments, multiply and 
ultimately lyse the host cell and spread further within the host.  In NTM disease the fundamental 
problem is failure of this macrophage containment and neutralization [Awuh 2017].   
While many immune defects have been described in patients with NTM including genetic 
abnormalities in interferon-gamma, interleukin-12 and their receptors, anti-cytokine antibodies 
including anti-GM-CSF and deficient response to interferon-gamma, none have consistently 
been identified in patient cohorts [Stout 2016]. It is therefore likely that there are a variety of 
host defects that predispose patients to NTM disease with a common end pathway being 
impaired macrophage function. 
An ideal new therapy would 1) reverse the primary problem of deficient macrophage killing 
capacity, 2) not have the capacity to generate resistance and 3) preferably act synergistically with 
existing antibiotic approaches to allow either less antibiotics, lower doses that may be better 
tolerated, or both, and prevent reinfection in vulnerable hosts. 
GM-CSF is a glycoprotein secreted by macrophages, T cells, mast cells, NK cells, endothelial 
cells and fibroblasts in response to a variety of inflammatory cytokines including tumor necrosis 
factor alpha, interleukin-1 and interleukin-12 [Fleetwood 2005]. Activation of the GM-CSF 
receptor stimulates at least three pathways – JAK-STAT, MAPK and PI3K [Fleetwood 2005]  
and has been used extensively in oncology due to its ability to stimulate stem cells to produce 
granulocytes (neutrophils, eosinophils, and basophils) and monocytes.  In the lung GM-CSF 
increases the number of macrophages with smaller increases in the number of neutrophils, 
basophils and eosinophils [Rose 1992]. Unlike macrophage colony stimulating factor (M-CSF), 
GM-CSF also increases the activation of macrophages, resulting in greater phagocytic and 
cytotoxic activity [Fleetwood 2005]. The pivotal role of macrophages as the effector cell in 
immunity to mycobacteria has long been established [Martino 2008]. 
There is substantive animal in-vivo and human in-vitro data supporting GM-CSF as a therapy for 
NTM infection as both a sole agent and as a potentiator of antibiotic therapy.  GM-CSF alone is 


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sufficient for inhibition of mycobacterial growth in mouse macrophages, demonstrating the key 
“end effector” function of GM-CSF [Rothchild 2014].  Also, GM-CSF as mono-therapy has been 
shown to be capable of controlling NTM infection in animal models and human macrophage cell 
lines [Onyeji 1995, Bermudez 1994]. GM-CSF potentiates the effect of antibiotics against NTM, 
probably through increasing intra-macrophage concentrations of antibiotics which are dependent 
on active transport into the cell [Onyeji 1995, Bermudez 1994]. Furthermore the antibiotic-
potentiating effect of GM-CSF has been shown in Leishmaniasis [Almeida 1999] and 
Pseudomonal infection [Choudhary 2015]. 
Clinical data demonstrating successful treatment of NTM disease with rhGM-CSF are also 
available.  During the AIDS epidemic, the administration of parenteral rhGM-CSF was reported 
to control systemic NTM infection resistant to antibiotic therapy and increase anti-mycobacterial 
acitivity [de Silva 2007, Kemper 1998, Kedzierska 2000].  Two cases of adult patients with 
cystic fibrosis and M. abscessus disease non responsive to conventional antibiotic therapy for 
more than 12 months have been reported to respond to rhGM-CSF. [Moser 2005].  Supportive 
data from interferon gamma, which acts through the GM-CSF pathway, are also available. A 
published case report of inhaled interferon-gamma in a patient with drug resistant M. avium 
infection demonstrated microbiological cure within 7 months and a reduction in sputum counts 
within 2 months [Hallstrand 2004]. A second case of M. avium with no improvement after 3-
years of 3-drug therapy showed reduced levels of NTM in sputum during two 5-week courses of 
inhaled interferon gamma and became smear negative during the third course [Chatte 1995]. 
Intramuscular interferon gamma was given for up to 6 months as adjuvant to antimycobacterial 
multidrug therapy in a placebo-controlled study in 32 patients with atypical mycobacterial 
infections, mainly MAC. Interferon gamma showed trends of improvements in clinical, 
radiological and microbiological parameters over placebo [Milanes-Virelles 2008]. As GM-CSF 
is the most potent effector of macrophages induced by interferon gamma, a similar marked and 
rapid improvement in disease may be expected. 
Clinical data have also shown that rhGM-CSF is well tolerated when inhaled.  Given that anti-
GM-CSF therapies have been trialed for asthma, chronic obstructive pulmonary disease (COPD) 
and autoimmune diseases there is some theoretical risk these may be exacerbated or precipitated.  
However as previously noted there is minimal systemic absorption of rhGM-CSF from inhalation 
and as below there are no current reports of adverse effects. In animal studies as well as in the 
human phase I study there were no significant adverse effects including no increase in airways 
reactivity.  Clinical experience in using inhaled molgramostim in the setting of alveolar 
proteinosis has so far recorded no serious adverse drug reactions in more than 60 patients 
enrolled through the current clinical development program. Lastly there are very limited reported 
side effects of inhaled rhGM-CSF despite case reports and small studies detailing its 
effectiveness in close to 100 patients in the setting of alveolar proteinosis. 
In the current study, the patient population are adult subjects with persistent pulmonary NTM 
infection as evidenced by at least two positive sputum cultures in the prior two years, one of 
which within the 6 months prior to Screening, and a positive culture at Screening. A population 
of treatment-resistant, treatment-intolerant, or never treated patients was selected as these are the 
patients who are currently not well-treated with current standard multidrug antimycobacterial 
regimens. In order to obtain pilot data on the possible scenarios where the medical need is 
considered to be the highest, (i.e. subjects who can tolerate standard antimycobacterial treatment 
but remain NTM positive despite continued treatment, or subjects who are not treated because 


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they have given up on treatment, could not tolerate treatment or did not want to start treatment) 
subjects will be stratified into two groups as follows: 
• Group 1: Subjects who remain sputum culture positive while currently on a multidrug 
NTM guideline based antimycobacterial regimen, which has been ongoing for at least 6 
months prior to the Baseline Visit. 
• Group 2: Subjects who remain sputum culture positive but have either stopped a 
multidrug NTM guideline based antimycobacterial regimen at least 28 days prior to 
Screening due to lack of response or intolerance, or never started such treatment. 
Although there are very successful case reports of the use of GM-CSF in patients with cystic 
fibrosis, these patients will be excluded as these patients, unlike the normal setting of NTM 
infection, typically have multiple pathogens identified at the time of NTM isolation. 
In this trial, molgramostim will be administered via inhalation using PARI eFlow nebulizer 
system (PARI Pharma GmbH, Germany) which is consistent with the pivotal study in aPAP 
(MOL-PAP-002).  The dose of 300 µg once daily is the same dose as currently being used in the 
pivotal study in aPAP (MOL-PAP-002). A data review was conducted after the first 6 subjects 
had completed 12 weeks of treatment. If safety concerns or poor tolerability were identified in 
this review, the review committee might decide on less frequent dosing for subsequent subjects 
in the study.  The review was conducted on 16 September 2018 and concluded that there were no 
safety issues of significant concern and the dose was unchanged. In order to obtain more robust 
treatment responses it was decided to extend the treatment duration to 48 weeks. 
6.3. 
Potential Risks and Benefits 
Although the clinical case report data is extremely encouraging, the true response rate to GM-
CSF in NTM infection is unknown. This pilot study is intended to gather the detailed data 
relevant to planning of the further phase II program, to be conducted in the more formal setting 
of a randomized, double-blind clinical trial. 
As outlined above, pulmonary NTM disease is now a major problem and is increasing, treatment 
is poorly tolerated, is often ineffective and even successful therapy is associated with recurrence 
rates of 50% within 3 years. Patients urgently need better therapies. 
As the majority of inhalational use of rhGM-CSF has been in the context of PAP, where patients 
have pre-existing anti-GM-CSF antibodies, it cannot be excluded that there will be more adverse 
effects in the treatment of NTM infection due to higher local and systemic exposure. The safety 
monitoring in the study has been selected to address these aspects. 
To ensure adequate subject safety in this pilot study, a data review was conducted by a review 
committee (the lead investigators and sponsor representatives) after the first 6 subjects had 
completed 12 weeks treatment as outlined above. This might result in reduced dosing frequency 
if there were safety concerns or poor tolerability. Overall, the safety profile was concluded to be 
acceptable and the committee endorsed continuation of the trial using the same dose, and 
extension of the treatment duration to 48 weeks. Recruitment beyond the 6 first subjects was not 
stopped during the review period. If needed, unscheduled visits will be conducted at 
investigator’s discretion.  


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The trial will be conducted in compliance with the protocol, all applicable 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.  
Overall, there is a good chance for study subjects to gain improvement from their condition 
through participation in the study and the study will, if successful, be an important step on the 
path to an approved treatment for pulmonary NTM infection.  


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7. 
TRIAL OBJECTIVES AND PURPOSE 
7.1. 
Primary Objective 
The primary objective is: 
• To investigate efficacy of inhaled molgramostim on NTM sputum culture conversion to 
negative. 
7.2. 
Secondary Objectives 
The secondary objectives are: 
• To investigate efficacy of inhaled molgramostim on NTM sputum smear conversion to 
negative. 
• To investigate efficacy of inhaled molgramostim on reduction of NTM bacterial load in 
sputum. 
• To investigate efficacy of inhaled molgramostim on exercise capacity. 
• To investigate efficacy of inhaled molgramostim on Patient Reported Outcomes. 
• To investigate safety of inhaled molgramostim in subjects with NTM infection. 
7.3. 
Endpoints 
7.3.1. 
Efficacy Endpoints 
7.3.1.1. 
Primary Efficacy Endpoint: 
• Sputum culture conversion defined as at least three consecutive negative sputum samples 
during the treatment period. 
7.3.1.2. 
Secondary Efficacy Endpoints: 
• Sputum smear conversion defined as at least three consecutive negative AFB stained 
sputum smears on microscopy during the treatment period in subjects who were smear 
positive at Baseline. 
• Durability of sputum culture conversion (defined as conversion at or before Week 48 and 
culture still negative at 12-weeks follow-up). 
• Durability of sputum smear conversion (defined as conversion at or before Week 48 and 
smear still negative at 12-weeks follow-up). 
• Change in semi-quantitative grade of number of NTM on microscopy of AFB stained 
sputum smears from Baseline to Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 12-
week follow-up.   
• Change in semi-quantitative grade of sputum cultures from Baseline to Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48 and 12-week follow-up. 


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• Change in symptom scores (assessed using Lower Respiratory Tract Infections – Visual 
Analogue Scale (LRTI-VAS) and Quality of Life Questionnaire– Bronchiectasis (QOL-
B) from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week follow-up. 
• Change in Global Rating of Health (GRH) from Baseline to Weeks 4, 8, 12, 16, 20, 24, 
32, 40, 48 and 12-week follow-up. 
• Change in body weight from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-
week follow-up. 
• Change in 6MWD, oxygen desaturation and Borg CR10 scores during a 6MWT from 
Baseline to Week 12, 24, 48 and 12-week follow-up. 
7.3.2. 
Safety Endpoints 
• Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment discontinuation 
during the trial period. 
• Change in WBC and differentials in blood from Baseline to Weeks 4, 12 24, 32, 40, 48 
and 12-week follow-up. 
• Change in DLCO from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and at 12-week 
follow-up. 
• Change in forced expiratory volume in 1 second (FEV1) (% predicted) and forced vital 
capacity (FVC) (% predicted) from Baseline to Weeks 12, 24, 32, 40 and 48. 
• Development of anti GM-CSF antibodies at Week 4, 12, 24, 32, 48 and at 12-week 
follow-up. 
 


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8. 
INVESTIGATIONAL PLAN 
8.1. 
Overall Trial Design 
This is an open-label, non-controlled, multicenter, pilot clinical trial of inhaled molgramostim in 
subjects with persistent pulmonary NTM infection.  
The primary objective is to investigate efficacy of inhaled molgramostim on NTM sputum 
culture conversion to negative. The primary endpoint is sputum culture conversion defined as at 
least three consecutive negative sputum samples during the treatment period.  
Secondary objectives are to investigate the efficacy of inhaled molgramostim on NTM sputum 
smear conversion to negative, on reduction of NTM bacterial load in sputum and on Patient 
Reported Outcomes, exercise capacity as well as evaluation of the safety of inhaled 
molgramostim in these subjects.  
Secondary efficacy endpoints and the safety endpoints are detailed in Section 7.3. 
The study will comprise a Screening Visit, Baseline Visit, a 48-week treatment period and a 12-
week follow up period. The Screening Visit (Visit 1) will be conducted up to 10 weeks prior to 
the Baseline Visit (Visit 2) to determine eligibility. Adult subjects with a history of chronic NTM 
infection with at least 2 positive cultures in the prior two years, of which at least one is within the 
last 6 months prior to Screening, will be considered for enrollment. Subjects should provide a 
positive NTM sputum culture at Screening to be eligible.  
Two subgroups of subjects will be recruited: 
• Group 1: Subjects who remain sputum culture positive while currently on a multidrug 
NTM guideline based antimycobacterial regimen, which has been ongoing for at least 
6 months prior to the Baseline Visit. 
• Group 2: Subjects who remain sputum culture positive but have either stopped a 
multidrug NTM guideline based antimycobacterial regimen at least 28 days prior to 
Screening due to lack of response or intolerance, or never started such treatment. 
The study will include 30 subjects.  
The treatment period will consist of 14 trial visits (Screening, Baseline, and at Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, and 48; Visits 1-14) and a follow-up visit (Visit 15) 12 weeks after 
end of treatment. The visits at Weeks 28, 36 and 44 (Visits 9, 11 and 13) will include a telephone 
contact, all other visits will include a clinic visit. 
At the Baseline Visit (Visit 2), eligible subjects will start treatment with inhaled molgramostim 
administered via the PARI eFlow nebulizer.  
At each visit (Visits 1-15), sputum samples for staining and microscopy, and microbiological 
culture will be collected. If required, induced sputum may be obtained according to local 
standards. On the days of clinic visits (Visits 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 15), subjects will 
be asked to collect two additional sputum samples at home, preferably on the consecutive days 
after the site visit. On the days of the telephone contact visits (Visits 9, 11 and 13), three sputum 
samples will be collected at home, preferably on consecutive days. 


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Any AEs will also be collected at Baseline and all subsequent visits (Visits 2-15), At all clinic 
visits a pregnancy test/contraceptive check will be conducted, changes in concomitant 
medication, measurement of body weight and an assessment of DLCO will be performed. A 
computed tomography (CT) scan will be conducted at Baseline (Visit 2) if not performed within 
6 months prior to Baseline. If DLCO drops by at least 20% at two consecutive visits the CT scan 
may be repeated. A CT scan can be performed after 48 weeks of treatment if this is a part of the local 
routine clinical practice. 
A physical examination and an electrocardiogram (ECG) will be performed at Screening and 
Weeks 24 and 48 (Visits 1, 8 and 14) and vital signs will be collected at Screening, Baseline, and 
Weeks 4, 12 24, 32, 40 and 48 (Visits 1, 2, 3, 5, 8, 10, 12 and 14). Spirometry will be conducted 
at Baseline and at Weeks 12, 24, 32, 40 and 48 (Visits 2, 5, 8, 10, 12 and 14). A 6MWT will be 
conducted at Baseline, at Weeks 12, 24 and 48 and at the 12-week follow-up visit (Visits 2, 5, 8, 
14 and 15). Blood samples for safety laboratory testing will be taken at Screening, Baseline, and 
at Weeks 4, 12, 24, 32, 40, 48 and at the 12-week follow-up visit (Visits 1, 2, 3, 5, 8, 10, 12, 14, 
15). Anti-GM-CSF will be assessed at Baseline, at Week 4, 12, 24, 32, 48 and at the 12-week 
follow-up visit (Visits 2, 3, 5, 8, 10, 14 and 15). Patient reported outcomes (QoL-B, LRTI-VAS 
and GRH) will be assessed at Baseline and at all post Baseline clinic visits (Visits 2, 3, 4, 5, 6, 7, 
8, 10, 12, 14 and 15). For subjects having a chest X-ray during the study period as part of the 
routine local clinical practice, the results from the X-ray will be recorded.  
Participating subjects will be encouraged to contact the clinic between visits if they experience 
adverse events (AEs), worsening of their condition or have any other concerns. If needed, 
unscheduled visits will be conducted at investigator’s discretion. 
A schedule of study assessments is available in Table 1 . 
Treatment with inhaled molgramostim will be given at a dosage of 300 µg once daily for 48 
weeks. All subjects in the trial initially consented to 24 weeks of treatment. All enrolled subjects 
continuing with 48 weeks of treatment will re-consent and follow the visits schedule as described 
above.  
Subjects that do not wish to continue to 48 weeks of treatment will end treatment after 24 weeks 
(visit 8) and will attend the follow-up visit 12-weeks later as per the visit schedule outlined in 
Protocol Version 2.0 or 3.0.  
Subjects who complete the initial 24-week treatment period prior to the approval of Protocol 
Version 4.0 will proceed to the 12 week follow up as per the visit schedule in Protocol Version 
2.0 or 3.0.  Once Protocol Version 4.0 is approved they will be asked to re consent and re-initiate 
treatment.  This will occur at the next trial visit or at an unscheduled visit. These subjects will not 
receive the whole 48-week treatment.  The will receive treatment for an additional 24 weeks 
minus the number of weeks that they have been in follow up.   
Subjects that do not wish to re consent and re initiate treatment will stay in follow up and attend 
the follow-up visit as per the visit schedule outlined in Protocol Version 2.0 or 3.0.  
At Baseline and at Weeks 4, 12, 24, 32 and 40 (Visits 2, 3, 5, 8, 10 and 12), dosing will take 
place in the clinic after blood sampling. A data review was conducted after the first 6 subjects 
had completed 12 weeks of treatment. If safety concerns or poor tolerability were identified in 
this review, the review committee might decide on less frequent dosing for subsequent subjects 


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in the study. The review was conducted on 16 September 2018 and concluded that there were no 
safety issues of significant concern and the dose was unchanged. In order to obtain more robust 
treatment responses it was decided to extend the treatment duration from 24 to 48 weeks. Any 
changes to the conduct of the study such as change of dose, dose regimen or duration will be 
documented in a protocol amendment. 
During the study, subjects in Group 1 will continue use of antimycobacterial treatment. All 
changes in antimycobacterial treatment will be recorded, including reasons for each change. In 
case of worsening of NTM pulmonary disease, antimycobacterial treatment may be added or a 
dosage increase of antimycobacterial treatment may be applied as rescue treatment, according to 
investigator’s discretion. 
8.1.1. 
Trial Period 
Estimated date first subject screened: Q1 2018 
Estimated date last subject completed (24 weeks treatment period): Q4 2019 
Estimated date last subject completed (follow-up period): Q1 2020 
The duration of trial participation for each subject is approximately 60 to 70 weeks: 
• Screening period for the subjects is up to 10 weeks  
• Treatment period up to 48 weeks (+/- 7 days) 
• Follow-up for 12 weeks (+/- 7 days) 
8.1.2. 
End of Trial 
The end of the trial is defined as the last subject’s last visit (LSLV). 
8.1.3. 
Trial completion  
Trial completion is defined as the date of the Clinical Trial Report (CTR). 
8.2. 
Number of Subjects 
It is planned that 30 subjects will be enrolled. No formal sample size calculation was done as this 
is an initial pilot study. 
8.3. 
Treatment Assignment 
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 101 at each site. 
At the Baseline visit, all subjects found to be eligible according to the inclusion/exclusion criteria 
will be classified into the following treatment groups by a central electronic data capture system: 


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• Group 1: Subjects who remain sputum culture positive while currently on a multidrug 
NTM guideline based antimycobacterial regimen, which has been ongoing for at least 
6 months prior to the Baseline Visit. 
• Group 2: Subjects who remain sputum culture positive but have either stopped a 
multidrug NTM guideline based antimycobacterial regimen at least 28 days prior to 
Screening due to lack of response or intolerance, or never started such treatment. 
Patients successfully assigned to a subgroup will then start treatment with open-label 
molgramostim nebulizer solution.  
8.4. 
Dose Adjustment Criteria 
A data review was conducted by a safety review committee comprised of the lead investigators 
and sponsor representatives after the first 6 subjects had completed 12 weeks of treatment. If 
safety concerns or poor tolerability were identified in this review, the review committee might 
decide on less frequent dosing for subsequent subjects in the study. The review concluded that no 
dose adjustment was required. Any changes to the conduct of the study such as change of dose 
regimen will be documented in a protocol amendment. 
Subjects who experience poor tolerability to treatment (i.e. unacceptable respiratory or 
gastrointestinal symptoms, the nature of which may be assumed to be reversible) may reduce the 
dose. Prior to dose reduction, the Sponsor medical monitor must be consulted. 
8.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
No prespecified safety criteria have been defined for the safety review committee. 
8.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
Not applicable. 
8.5. 
Criteria for Study Termination 
The investigator or the sponsor may terminate this trial prematurely for any reasonable cause. 
The Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) and Competent 
Authorities (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 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. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subject fulfilling all inclusion and none of the exclusion criteria can be enrolled in the trial. An 
enrolled subject is defined as a subject receiving treatment with the trial IMP. 
9.1. 
Subject Inclusion Criteria 
1. History of chronic pulmonary infection with MAC or M. abscessus (defined as at least 2 
documented positive sputum cultures in the prior 2 years, of which at least one was 
obtained in the 6 months prior to Screening). 
2. Subject fulfills one of the following criteria: 
o Subjects who remain sputum culture positive while currently on a multidrug NTM 
guideline based antimycobacterial regimen, which has been ongoing for at least 6 
months prior to the Baseline Visit 
o Subjects who remain sputum culture positive but have either stopped a multidrug 
NTM guideline based antimycobacterial regimen at least 28 days prior to 
Screening due to lack of response or intolerance, or never started such treatment.  
3. Ability to produce at least 2 mL of sputum or be willing to undergo an induction that 
produces at least 2 mL of sputum for clinical evaluation. 
4. Female or male ≥18 years of age. 
5. Females who have been post-menopausal for more than 1 year or females of childbearing 
potential after a confirmed menstrual period using a highly efficient method of 
contraception (i.e. a method with less than 1% failure rate such as combined hormonal 
contraception, progesterone-only hormonal contraception, intrauterine device, 
intrauterine hormone- releasing system, bilateral tubal occlusion, vasectomized partner, 
sexual abstinence1), during and until thirty (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. 
6. Males agreeing to use condoms during and until thirty (30) days after last dose of 
medication, or males having a female partner who is using adequate contraception as 
described above. 
7. Willing and able to provide signed informed consent. 
 
1 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
 


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8. 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 
9.2. 
Subject Exclusion Criteria 
1. Subjects diagnosed with cystic fibrosis. 
2. Prior therapy with inhaled or systemic GM-CSF. 
3. Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to 
Screening. 
4. Concurrent disease with a life expectancy of less than 6 months. 
5. History of, or present, myeloproliferative disease, leukemia or other hematological 
malignancy. 
6. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring 
chemotherapy or radiation therapy within one year prior to Screening or anticipated 
during the study period. 
7. Active allergic bronchopulmonary mycosis or connective tissue disease, inflammatory 
bowel disease or other autoimmune disorder requiring therapy associated with significant 
immunosuppression, such as systemic corticosteroids at a dose equivalent of 10 mg/day 
or more of prednisolone, within 3 months prior to Screening or anticipated during the 
study period. 
8. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening. 
9. HIV infection or other disease associated with significant immunodeficiency. 
10. History of lung transplantation. 
11. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior 
to Screening. 
12. Treatment with any investigational medicinal product within 3 months of Screening. 
13. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product 
14. Any other serious medical condition which in the opinion of the investigator would make 
the subject unsuitable for the trial. 
 
 
 
 
 
 


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9.3. 
Subject Withdrawal Criteria 
9.3.1. 
Discontinuation from Trial Treatment 
Subjects may be discontinued from treatment and assessments at any time, if deemed necessary 
by the investigator.  
Potential reasons for discontinuation of treatment are:  
• Lack of efficacy/worsening of disease  
• Unacceptable AE 
• Serious hypersensitivity reaction 
• Pregnancy 
Those who discontinue treatment will not automatically be withdrawn from the trial but will be 
encouraged to continue to follow the same visit schedule. For example: if treatment is 
discontinued at Week 4 (Visit 3) the subject will be encouraged to attend the remaining visits.  
The reason and date the subject is discontinued from treatment will be documented in the 
electronic case report form (eCRF).  
9.3.2. 
Withdrawal from the Trial 
Subjects are free to discontinue their participation in the trial at any time. Withdrawal from the 
trial will not affect or prejudice the subject’s further care or treatment. Potential reasons for 
withdrawal of subjects from the trial are:  
• Screening failure 
• The decision of a subject to withdraw from the trial (including if the subject withdraws 
informed consent)  
• Unacceptable treatment response 
• Unacceptable adverse event 
• Subject is lost to Follow-up 
• Other reason(s) (e,g incorrect enrollment) 
The reason and date the subject is withdrawn from the trial will be documented in the eCRF (e.g. 
lost to follow-up, consent withdrawn, 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 48 if withdrawn during the treatment period).  
All AEs should be followed-up according to Section 12.15.  
If a subject is withdrawn from the trial, all data collected until the time of withdrawal will be 
used in the data presentations unless consent to use the data was withdrawn by the subject.  


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Description of Study Drug 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
Molgramostim nebulizer solution 
Dosage Form: 
Nebulizer solution 
Unit Dose 
300 µg 
Route of Administration 
Inhalation using the PARI eFlow nebulizer (PARI Pharma GmbH) 
Physical Description 
Clear, colourless solution containing molgramostim, a recombinant human 
Granulocyte Macrophage Colony Stimulating Factor (rhGM-CSF).  
Excipients are mannitol, polyethylene glycol 4000, Recombumin® Prime, 
disodium phosphate (anhydrous), citric acid (monohydrate), and water for 
injection 
10.2. 
Prohibited Medications 
The following prior medications are not allowed (See exclusion criteria Section 9.2): 
• Treatment with inhaled or systemic GM-CSF 
• Therapy associated with significant immunosuppression such as systemic prednisolone at 
a dose equivalent of 10 mg/day or more within 3 months prior to Screening 
10.3. 
Treatment Compliance 
Subject compliance in the treatment period 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. 
10.4. 
Randomization and Blinding 
Not applicable.  
10.5. 
Subject Identification List 
The investigator will maintain a list of all subjects screened in the trial at the site. This list 
includes each subject's identity, date of enrolment and corresponding subject number so that any 
subject may be identified if required for any reason. 


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11. 
STUDY DRUG MATERIALS AND MANAGEMENT 
11.1. 
Study Drug 
Each vial of molgramostim contains 300 µg molgramostim in 1.2 mL solution (250 µg/mL). 
11.2. 
Study Drug Packaging and Labeling 
All manufacturing and packaging will be performed in accordance with current Good 
Manufacturing Practice (GMP).  
Individual medication kits containing trial medication for four weeks will be supplied in 
adequate amounts at the dispensing visits.   
Labels will comply with local regulations and will be printed in local language. 
11.3. 
Study Drug Storage 
The IMP must be stored at 2-8°C.   
The IMP will be stored at the trial site or the at the site pharmacy as required by local regulations 
and laws for the participating sites. The Investigator will ensure that the IMP will be stored in 
appropriate conditions in a secure location with controlled access. The storage compartment 
must be monitored and the temperature documented. Any deviations in storage temperature must 
be reported to sponsor without delay. In case of a temperature deviation, the IMP must not be 
used until acceptance from the sponsor. 
The IMP kits will be dispensed to the subject at Baseline (Visit 2), and at Weeks 4, 8, 12, 16, 20, 
24, 32 and 40 (Visits 3, 4, 5, 6, 7, 8, 10 and 12) during the treatment period.  
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. 
Subjects will be asked to return used and unused medication at the next clinic visit to check 
compliance. 
11.4. 
Study Drug Preparation 
Not applicable. 
11.5. 
Administration 
The PARI eFlow nebulizer system (PARI Pharma GmbH, Germany) will be used to administer 
the IMP. The eFlow Nebulizer Handset is a single subject use, reusable electronic nebulizer. 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 


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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 at the Baseline visit (Visit 2) under the 
supervision of trial personnel.  
During the treatment period at Weeks 4, 12, 24, 32 and 40 (Visits 3, 5, 8, 10 and 12), subjects 
will be asked not to take their study treatment prior to the clinic visit because blood samples for 
laboratory testing will be taken. At these visits dosing will take place in the clinic after the blood 
samples have been taken. The subject should be instructed to take the last dose the day before the 
48-week visit (Visit 14).  
11.6. 
Study 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.  
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. 
11.7. 
Study Drug Handling and Disposal 
Unused IMP must be returned to supply vendor, or sent for destruction after agreement with the 
Sponsor, but only after the trial and overall drug accountability has been completed. A list of trial 
drug, used, or returned must be prepared and signed by the investigator or designee; an account 
must be given for any discrepancies. 


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12. 
ASSESSMENTS  
The timing of all trial assessments is shown in the Schedule of Procedures in Table 1. 
12.1. 
Informed consent 
All subjects must provide informed consent in accordance with the origins of the Declaration of 
Helsinki and the applicable laws of the country. The written informed consent must be obtained 
before any trial activities are performed, incl. any period for wash-out of concomitant 
medication. 
It is the responsibility of the principal investigator or a sub-investigator to obtain the written 
informed consent from the subject. 
The investigator must explain the nature of the trial, its purpose, the assessments involved, the 
expected duration, the potential risks and benefits involved and any discomfort it may entail and 
provide the subject with a copy of the information sheet and the consent form. Information to a 
subject can be delegated to a nurse, but the investigator must be available for questions and both 
the nurse and the investigator must sign the consent form to document this. 
The subject must be given sufficient time to consider the trial before deciding whether to 
participate. Each subject must be informed that participation in the trial is voluntary and that 
he/she may withdraw from the trial at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician. 
The subject must sign and date the informed consent form before he/she enters the trial (i.e. 
before any trial related activity). The investigator must give a copy of the signed informed 
consent to the subject. The investigator should keep the original. 
If information becomes available that may be relevant to the subject’s willingness to continued 
participation in the trial the subject information sheet will be updated by Savara and approved by 
an IEC/IRB and the Competent authorities. The subject must be informed in a timely manner 
about the updated subject information sheet and written informed consent must be obtained. 
12.2. 
Collection of Sputum Samples for Microbiological Characterization 
and Quantification 
Sputum samples for staining and microscopy, and microbiological culture will be collected at the 
timepoints shown in in Table 1. 
The analysis of the samples will be performed at a specialized mycobacterial laboratory.  
If required, induced sputum may be obtained using local standards.  
On the days of clinic visits (Visits 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 15), subjects will be asked 
to collect two additional sputum samples at home, preferably on the consecutive days after the 
site visit. On the days of the telephone contact visits (Visits 9, 11 and 13), three sputum samples 
will be collected at home, preferably on consecutive days. 
The sputum samples must be refrigerated immediately after sampling. Details regarding the 
collection and handling of sputum samples will be provided in a separate document. 


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AFB staining (fluorescence and /or ZN stain) will be used to identify NTM in sputum and 
conduct a semi-quantitative assessment of bacterial load (graded as 0, occasional, 1+, 2+, 3+). 
Smears will also be fixated on slides and all slides will be submitted to a central laboratory for a 
second assessment. 
Microbiological culture to identify growth of NTM will be conducted using established 
standards. A semi-quantitative assessment of sputum cultures will be performed. Identification to 
NTM species level will be conducted on positive samples using established methods.  
If sufficient sputum volume is obtained, an additional aliquot will be frozen and stored for 
potential post-hoc analysis by quantitative polymerase chain reaction (PCR). Such PCR analysis 
will be performed no later than two years after trial completion. PCR data will not be included in 
the CTR, but reported separately. 
Routine bacteriology and fungal culture will be performed. 
12.3. 
Prior and Concomitant Medication 
The subject’s use of all concomitant medication must be recorded in the eCRF.  
All relevant prior medication should also be recorded. This includes the most recent course of 
antimycobacterial treatment taken within 3 years prior to the screening visit. Other prior 
medication should also be recorded if considered relevant by the investigator. Standard 
information about the medication will be collected including the name of medication, dose, 
frequency, administration route and treatment period.  
Changes to medication not provided as a part of this trial should be kept to a minimum during the 
trial. However, if considered necessary for the subject’s well-being concomitant medication may 
be given at the discretion of the investigator according to local standard care. All changes will be 
recorded, including reasons for each change.  
In case of worsening of NTM pulmonary disease, antimycobacterial treatment may be added or a 
dosage increase of antimycobacterial treatment may be applied as rescue treatment, according to 
investigator’s discretion. 
At each visit the investigator should ask the subject about use of concomitant medication. All 
concomitant medication must be documented in the subject’s medication records and in the 
eCRF. Furthermore, each change in concomitant medication (e.g. new treatment, discontinuation 
of treatment and change in dosage/routine) during the trial must be documented in the same way.  
12.4. 
6-Minute Walk Test (6MWT) 
Exercise capacity will be assessed using the 6MWT at the timepoints shown in Table 1. 
The 6MWT will be performed in accordance with European Respiratory Society/American 
Thoracic Society (ERS/ATS) guidance [Holland 2014] by technicians with documented training 
and experience of performing the 6MWT in accordance with the referred ERS/ATS guidance. 
The 6MWT should be performed twice at each visit in accordance with the ERS/ATS guidelines.  
Data from both tests should be entered in the eCRF. Parameters to be recorded comprise pre and 
post walk dyspnea score using the Borg (CR-10) Dyspnea Score, blood oxygen saturation (SpO2) 


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(%) at start, worst SpO2 (%) during the walk, distance walked (6MWD; m), duration of the walk 
(minutes and seconds), O2 flow rate if applicable, reason for stopping early (if applicable). 
Trial specific instructions will be provided in a separate document. 
If a subject is on long-term oxygen therapy, oxygen should be given at their standard flow rate 
and held constant throughout the test. The tests conducted after Baseline should be performed 
using the same oxygen conditions that were used at Baseline.  
12.5. 
Patient Reported Outcomes 
The following patient reported outcomes will be assessed at the timepoints shown in Table 1. 
A sample of all questionnaires are presented in Appendix 4 . 
• Clinical symptoms will be assessed using Lower Respiratory Tract Infections – Visual 
Analogue Score (LRTI-VAS),  
• Quality of Life Questionnaire– Bronchiectasis (QOL-B), 
• Global Rating of Health (GRH). 
12.5.1. 
Lower Respiratory Tract Infections – Visual Analogue Score 
For each of the clinical symptoms of lower respiratory tract infections (dyspnea, fatigue, cough, 
pain, and sputum) the subject will assess the severity using a 10cm visual analogue scale ranging 
from 0=no symptoms to 10 =worst possible symptoms. The results from visual analogue scores 
will be entered in the eCRF. 
12.5.2. 
Quality of Life Questionnaire– Bronchiectasis (QOL-B) 
The QOL-B questionnaire in the local language will be used to assess subject’s quality of life. 
The results from QOL-B will be entered in the eCRF. 
12.5.3. 
Global Rating of Health (GRH) 
Global Rating of Health will be assessed as an interviewer questionnaire.  Global Rating of 
Health assesses global health as “excellent, good, fair or poor”. The results from GRH will be 
entered in the eCRF 
12.6. 
Subject Diary 
The subject will receive a subject diary at the timepoints shown in Table 1. The subject diary will 
include information about the IMP, the use of the nebulizer and home collection of sputum 
samples. The subject will be asked to record AEs experienced between the visits in the subject 
diary. The subject will also be asked to place the tear-off label from the IMP box in the subject 
diary. 
12.7. 
Adverse Events 
Any AEs will be reported at every visit from Baseline (Visit 2) to the completion of the 12-week 
follow-up (Visit 15). Subjects will be encouraged to contact the clinic in between visits if they 


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experience AEs or have any concerns. For further information of definitions and reporting of 
AEs and SAEs, see Section 12.15.  
12.8. 
Demographic/Medical History/Body Measurements 
The following demographic and body measurement data and medical history will be collected at 
the timepoints shown in Table 1. 
• Date of birth 
• Weight (kg) in indoor clothes 
• Height (cm) without shoes 
• Sex 
• Race (White/Asian/Black/American Indian or Alaska Native/Native Hawaiian or Other 
Pacific Islander)  
• Smoking (Previous/Current/Never) 
• Relevant prior and concurrent disorders 
• Prior and current NTM infections including dates and species  
12.9. 
Physical Examination 
All subjects will undergo a standard physical examination at the timepoints shown in Table 1. 
Complete physical examinations will include at a minimum a review of the subject’s general 
appearance, head, eyes, ears, nose, and throat (HEENT), neck, heart, lungs, abdomen, 
extremities, skin, and general neurological system. Any abnormalities will be recorded in the 
eCRF and assessed as ‘clinically significant’ or ‘not clinically significant’. 
Symptom-oriented or brief physical examinations may be performed as clinically indicated. New 
abnormal clinically significant physical examination findings not present during the baseline 
visits should be recorded as AEs and followed during subsequent visits.  
12.10. 
Vital Signs 
The following vital signs will be assessed at the timepoints shown in Table 1. 
• Resting systolic and diastolic blood pressure (mmHg), after 5 minutes sitting  
• Resting heart rate (beats per minute), after 5 minutes sitting  
• Resting respiration rate (breaths per minute), after 5 minutes sitting  
• Oral body temperature (°C) 
The observed values will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal findings 
will be assessed as ‘clinically significant’ or ‘not clinically significant’. 


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12.11. 
Electrocardiogram (ECG) 
A 12-lead ECG will be assessed using a standard ECG machine according to local procedures at 
the time points shown in Table 1. 
No central overreading will be performed. 
Heart rate, QRS, PR and QT intervals will be recorded from the ECGs. The ECGs will be 
interpreted and signed and dated by the investigator or his/her designee. Results will be classified 
as normal, having a non-clinically significant abnormality, or having a clinically significant 
abnormality. All clinically significant abnormalities will be recorded as AEs. 
12.12. 
Radiology 
12.12.1. 
CT Scan 
If not performed within 6 months prior to Baseline, a CT scan will be performed at the Baseline 
visit (Visit 2). If there is a decrease in DLCO of at least 20% at two consecutive visits the CT 
scan may be repeated and the results recorded. 
12.12.2. 
Chest X ray (only if conducted as part of the local routine clinical practice) 
Chest X-rays are not required for the study but if subjects have a chest X-ray as part of the local 
routine clinical practice during the study period, the reason and the results from the chest X-ray 
will be recorded as normal, having a non-clinically significant abnormality, or having a clinically 
significant abnormality. Clinically significant abnormalities that were not present before the 
study or that worsened during the study (based on medical records) will be recorded as AEs. 
12.13. 
Pulmonary Function Tests 
12.13.1. 
DLCO 
DLCO will be done using local appropriately calibrated equipment by site staff with documented 
training in lung function testing at the time points shown in Table 1. 
The DLCO measurements should be performed in accordance ATS/ERS guidelines [Graham 
2017]. Parameters to be recorded are DLCO (absolute measured) and DLCO (predicted). The 
average of two valid tests will be calculated.   
12.13.2. 
Spirometry 
FEV1 and FVC will be assessed using a local appropriately calibrated spirometer by site staff 
with documented training in lung function tests at the time points shown in Table 1. 
The FEV1 and FVC are measured as 3 valid measurements and the highest value will be entered 
in the eCRF.  
12.14. 
Laboratory Assessments 
Blood samples for laboratory assessment will be taken at the timepoints shown in Table 1. 
The total amount of blood required for sampling is approximately 240 mL with a maximum of 
30 mL for one visit.  


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All blood samples should be taken prior to dosing at the clinic visit.  
12.14.1. 
Levels of Anti-GM-CSF Antibodies 
Analyses for anti-GM-CSF antibodies will be performed at a central laboratory.  
12.14.2. 
Laboratory Safety Assessments 
The laboratory safety analyses (hematology, clinical chemistry and urinalysis) 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. A trial specific 
laboratory manual for sampling, handling, storage and shipment of samples will be provided to 
the site personnel. The manual will be provided to the site before start of the trial.  
The observed values will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal findings 
will be assessed as ‘clinically significant’ or ‘not clinically significant’.  
12.14.2.1. Blood Hematology 
The following parameters will be analyzed: 
Hemoglobin, Red Blood Cell Count (RBC), Red Blood Cell Distribution Width (RDW), 
Hematocrit (PCV/EVF), Mean cell volume (MCV), Mean cell hemoglobin (MCH), Mean cell 
hemoglobin concentration (MCHC), Platelet count, White cell count, and white cell differential 
absolute count: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, and Prothrombin 
Time International Normalized Ratio (PT-INR) 
12.14.2.2. Blood Chemistry 
The following parameters will be analyzed: 
Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma Glutamyl 
Transpeptidase (GGT), Alkaline Phosphatase, Bilirubin, Urea, S-Creatinine, estimated 
glomerular filtration rate (eGFR), Potassium, Sodium, Calcium, Chloride, Phosphate, Total 
protein, Albumin, Lactate dehydrogenase (LDH), C-Reactive Protein (CRP), and Glucose (non-
fasting) 
12.14.2.3. Urinalysis 
The following parameters will be analyzed: 
pH, Glucose, RBCs, WBCs, Protein, and Microalbuminuria. 
12.14.2.4. Pregnancy Screen 
A serum pregnancy test and contraceptive check will be performed for female subjects at the 
timepoint shown in Table 1. 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. 


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12.15. 
Adverse and Serious Adverse Events 
12.15.1. 
Definition of Adverse Events 
12.15.1.1. Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable 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. 
12.15.1.2. Serious Adverse Event (SAE) 
Any untoward medicinal occurrence or effect that at any dose: 
• Results in death 
• Is life-threatening 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• May jeopardize the subject or may require intervention to prevent one or more of the 
other outcomes listed above (Important Medical Events) 
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 hospitalization did in fact 
take place as a result of it. As a rule, hospitalization is the admission to a hospital with at least 
one overnight stay. 
The presentation of a patient in the emergency room (casualty center, health care center) alone 
without subsequent in-patient admission does not yet fulfill the criterion hospitalization. 
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). 
12.15.1.3. Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is an AE which 
• has a reasonable possibility of causal relationship to an IMP, 


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• 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. 
12.16. 
Recording Adverse Events 
All trial subjects will be carefully monitored for the occurrence of AEs during the trial period 
from Baseline (Visit 2) to the 12-week follow-up visit (Visit 15). The investigator will collect 
AEs using a non-leading question such as “have you experienced any new health problems or 
worsening of existing conditions” as well as reporting events directly observed or spontaneously 
volunteered by subjects. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
All AEs including but not limited to events reported by the subject, or reported in answer to an 
open question by the investigator or member of this team, which fall into any of the above 
definitions must be recorded as an AE in the eCRF and should include the following 
information: 
• Brief description of the event (diagnosis) 
• Start date (and time, if relevant) 
• Stop date (and time, if relevant) (or resolution) 
• Severity 
• Action taken regarding trial drug 
• Opinion on causality 
• Seriousness 
• Outcome 
Severity 
Severity describes the intensity of an event, and will be assessed as: 
Mild 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate 
The AE interferes with daily activity, but the subject is still able to function. Medical 
intervention may be considered. 
Severe 
The AE is incapacitating and requires medical intervention. 


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If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description. 
Causality 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE.  
Causality will be assessed as: 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the IMP, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfil this definition. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the IMP, but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on IMP withdrawal may be lacking or unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal relationship to IMP 
administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
Not applicable 
This assessment can be used e.g. in cases where the subject did not receive any treatment with 
IMP or if the causality cannot be judged because information is insufficient or contradictory. 
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. 
12.17. 
Reporting Adverse Events 
12.17.1. 
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 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 


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Company: Premier Research 
Department: Pharmacovigilance and Device Safety (PVDS) 
 
E-mail: SavaraSafety@premier-research.com 
Fax: +421 2 68203713 
Note: If there is local legislation requiring investigators to report AEs to the 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. 
12.17.2. 
SUSAR Reporting Procedure 
According to national legislation and European directives and guidelines, the sponsor of the 
clinical trial will report all SUSARs to the CA and Ethics Committee in all Member States 
concerned, to the European clinical trials database (Eudravigilance Clinical Trial Module - 
EVTCM), and if applicable, to other regulatory authorities according to local laws and 
regulations.  
The Sponsor shall ensure that all relevant information about SUSARs that are fatal or life-
threatening is recorded and reported as soon as possible to the competent authorities in all the 
Member States concerned, and to 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. 


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12.17.3. 
Adverse Events of Special Interest 
There are currently no AEs of special interest identified due to limited previous experience of 
Savara’s molgramostim. 
12.17.4. 
Precautions/Overdose 
No acute systemic or hypersensitivity reactions have been reported in subjects receiving inhaled 
sargramostim or molgramostim products.  
There is no known antidote to molgramostim. In the event of overdose, symptomatic 
management is indicated. 
Based on information from similar products, overdose may manifest with respiratory symptoms, 
e.g. bronchospasm, wheezing, dyspnea, decreased pulmonary function or cough. 
Hematologic findings such as leukocytosis, eosinophilia and neutrophilia may occur in case of  
systemic exposure. With high systemic doses of similar products, the following symptoms have 
been observed: tachycardia, hypotension, dyspnea, and flu-like symptoms. These symptoms 
abated quickly on symptomatic treatment. More information is available in the IB. 
12.17.5. 
Pregnancy 
Female subjects will be instructed to notify the investigator immediately if they become pregnant 
during the trial. Male subjects will be instructed to notify the investigator immediately if their 
female partner becomes pregnant. Pregnant subjects will be withdrawn from further trial 
treatment. The subjects will also be instructed to report pregnancies discovered after the last 
visit, if they believe that conception occurred during their participation in the trial.  
A pregnancy as such is not an AE, unless there is a possibility that the IMP has interfered with 
the efficiency of any contraceptive measures. However, the investigator should report 
pregnancies according to the procedures and timelines described for reporting of SAEs, Section 
12.17.1. The pregnancy report form should be used instead of the SAE form. 
The pregnant subject or partner will be followed until the end of the pregnancy. Any 
complication during the pregnancy should preferably be reported as an AE. The outcome of the 
pregnancy must be reported on the pregnancy report form. Any spontaneous abortion, stillbirth, 
birth defect/congenital anomaly, death, or other serious infant condition must be reported and 
followed up as an SAE. 
12.17.6. 
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 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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13. 
STATISTICS 
A total of 30 subjects will be included. No formal sample size calculation was done as this is an 
initial pilot study. 
On the basis of the poor historical success rates of current standard therapy, a 30% response rate 
for the primary endpoint would be considered clinically relevant. 
Data will be presented descriptively and using 95% confidence intervals. Statistical analysis 
comparing post-treatment values with Baseline will be conducted for selected endpoints. As this 
is an exploratory study no adjustments for multiplicity will be done. Further details of all 
analyses will be given in the statistical analysis plan.  
13.1. 
Primary Endpoint 
• Sputum culture conversion defined as at least three consecutive negative sputum 
samples during the treatment period. 
The time of culture conversion is defined as the time the first of three consecutive negative 
samples was obtained. 
Sputum culture conversion rates (number of patients who convert to negative out of the number 
per group) will be presented with 95% exact binomial confidence intervals. 
13.2. 
Secondary Endpoints 
All endpoints that are of the form “conversion to negative” will be presented in the same way as 
the primary endpoint.  This includes: 
• Sputum smear conversion defined as at least three consecutive negative AFB stained 
sputum smears on microscopy during the treatment period in subjects that were smear 
positive at Baseline. 
• Durability of sputum culture conversion (defined as conversion at or before Week 48 
and culture still negative at 12-weeks follow-up). 
• Durability of sputum smear conversion (defined as conversion at or before Week 48 
and smear still negative at 12-weeks follow-up). 
Semi-quantitative grading: 
• Change in semi-quantitative grade of number of NTM on microscopy of AFB stained 
sputum smears will be cross-tabulated in 5-by-5 tables of negative, scant, 1+, 2+, or 
3+ comparing Baseline to Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 12-
week follow-up.  The number of patients who decrease over the scale (and proportion 
out of the number per group) will be presented with 95% exact binomial confidence 
intervals. 
• Change in semi-quantitative grade of sputum cultures will be cross-tabulated in a 
similar way comparing Baseline to Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 
and 12-week follow-up.  The number of patients who decrease over the scale (and 


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proportion out of the number per group) will be presented with 95% exact binomial 
confidence intervals. 
 
All endpoints that are of the form “changes in quantitative assessments” will be presented as 
median, min and max at baseline and each assessment visit; and median, min and max change 
from Baseline to each assessment visit.  This includes: 
• Change in symptom scores (assessed using LRTI-VAS and QOL-B) from Baseline to 
Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week follow-up. 
• Change in GRH from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week 
follow-up. 
• Change in body weight from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 
12-week follow-up. 
• Change in 6MWD, oxygen desaturation and Borg CR10 scores during a 6MWT from 
Baseline to Week 12, 24, 48 and 12-week follow-up. 
No “analysis sets” (intention to treat, per protocol, etc.) are being defined.  All subjects will be 
included in the analyses/data presentations (equivalent to the Full Analysis Set). 
Only recorded data will be analyzed/presented and any subjects who have missing data will only 
have observed data reported, with no imputation for missing data. 
No interim analyses are planned. 
Data listings will show all recorded data, separately by Group (as defined above). 
13.3. 
Safety Endpoints 
All AEs will be summarized in total and by Group 1 or Group 2. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by System Organ Class (SOC) and Preferred Term (PT). 
All serious AE and AEs leading to study withdrawal will be listed and individual-subject 
narratives written for all SAEs. 
13.4. 
General 
No “analysis sets” (intention to treat, per protocol, etc.) are being defined.  All subjects will be 
included in the analyses/data presentations (equivalent to the Full Analysis Set). 
Only recorded data will be analyzed/presented and any subjects who have missing data will only 
have observed data reported, with no imputation for missing data. 
No interim analyses are planned. 
Data listings will show all recorded data, separately by Group (as defined above). 
 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Access to Source Data and Documentation  
The investigator should guarantee direct access to source documents for the monitor and auditors 
as well as for inspection by appropriate regulatory agencies, and the IEC/IRB, if required. 
14.2. 
Subject Records and Source Data 
The origin of source data in the trial will be specified for each trial site in a separate document.  
It is the responsibility of the investigator to record essential information in the medical records in 
accordance with national regulations and requirements. The following information should be 
included as a minimum: 
• A statement that the subject is in a clinical trial 
• The identity of the trial e.g. Trial code 
• Subject number 
• That informed consent was obtained and the date 
• Diagnosis 
• Dates of all visits and telephone contacts with the subject during the trial period 
• Any information relating to AEs 
• All treatments and medications prescribed/administered (including dosage) 
• Date of subject withdrawal  
• Subject health service identification number 
The investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness 
of the data recorded in the eCRFs. After each subject visit, the eCRF should be completed in a 
timely manner. Data reported in the eCRF that are derived from source documents should be 
consistent with the source documents or the discrepancies should be explained. Data recorded in 
the eCRFs will be monitored. 
14.3. 
Study Monitoring 
Regular monitoring visits will be performed according to International Conference on 
Harmonization (ICH) GCP. Data will be evaluated for compliance with the protocol and 
accuracy in relation to source documents. In accordance with written standard operating 
procedures (SOP)s, the monitors will verify that the clinical trial is conducted and data are 
generated, documented and reported in compliance with the protocol, GCP and the applicable 
regulatory requirements. 


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14.4. 
Audits and Inspections 
Authorized representatives of Savara, a regulatory authority, an Independent Ethics Committee 
or an Institutional Review Board may visit the site to perform audits or inspections, including 
source data verification.  The purpose of a Savara audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements.  The investigator should contact 
Savara immediately if contacted by a regulatory agency about an inspection. 
14.5. 
Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) 
The investigator must obtain IEC/IRB approval for the investigation.  Initial IEC/IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the investigator and made available for inspection.  
Any modification of the protocol must be documented in a protocol amendment and any 
amendment considered substantial requires approval/favorable opinion by the appropriate 
regulatory authority and IEC/IRB. 
 
 


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15. 
ETHICS 
15.1. 
Ethics Review 
This protocol and any amendments will be submitted to a properly constituted IEC/IRB, in 
accordance with the International Conference on Harmonization (ICH) guidelines, the applicable 
European Directives and local legal requirements, for approval/favorable opinion. An 
approval/favorable opinion must be obtained in writing before the first subject can be recruited. 
15.2. 
Ethical Conduct of the Study 
The trial will be conducted in compliance with the protocol, applicable regulatory requirements, 
GCP and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by 
the World Medical Association. 


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Data Management  
Data management and handling of data will be conducted according to the trial specific Data 
Management Plan with ICH guidelines and standard operating procedures (SOPs). 
An eCRF system, will be used to capture data from the trial. Data entry will be performed by the 
trial site personnel. Validation and data queries will be handled by qualified Contract Research 
Organization (CRO) staff. The data will be subjected to validation according to a data validation 
plan in order to ensure accuracy in the collected eCRF data. 
Changes to the data in the eCRF will be made at the site by delegated trial site personnel. The 
eCRF will have an audit trail with appropriate functionality for data capture, tracking and 
documentation of any queries or changes. Electronic signatures will be used to lock the data and 
identify the person entering or changing the data. Before database closure a reconciliation will be 
performed between the SAEs entered in the safety database and the trial database. After database 
closure, the database will be exported as SAS® data sets. 
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan, will be described in a trial specific Data Management Report. 
16.1.1. 
Protocol Deviations 
The instructions in the protocol must be followed. If deviations occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed. 
Deviations must be documented. In addition, deviations must be accompanied by a description of 
the deviation, the relevant dates (start and stop) and the action taken. Deviation reports must be 
reported in the eCRF and supporting documentation must be kept in the investigator’s file and in 
the trial master file. 
16.2. 
Inspection of Records 
The Investigator agrees to allow the monitor to inspect the drug storage area, study drug stocks, 
drug accountability records, subject charts and study source documents, and other records 
relative to study conduct. 
16.3. 
Retention of Records 
The investigator/institution should maintain essential documents (as defined in ICH E6 GCP, 
Section 8) as required by the applicable regulatory requirement(s). The investigator/institution 
should take measures to prevent accidental or premature destruction of the documents. 
Essential documents should be retained according to applicable regulatory requirements of the 
country(ies) where the product is approved, and/or where the sponsor intends to apply for 
approval. If it becomes necessary for Savara or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 
It is the responsibility of the sponsor to inform the investigator/institution in writing as to when 
the documents no longer need to be retained. 


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17. 
FINANCE AND INSURANCE 
The sponsor must provide insurance or must indemnify (legal and financial coverage) the 
investigator/the institution against claims arising from the trial, except for claims that arise from 
malpractice, negligence or non-compliance with the protocol. 
The compensation to the investigators for work performed under this protocol will be set out in 
separate clinical trial agreements with the investigators. 


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18. 
TRIAL ORGANIZATION 
The telephone numbers and fax numbers of relevant Sponsor staff are listed in the investigator 
site file. 
The title, name, address and contact details of CROs, laboratories and other vendors are listed in 
Appendix 3. 
 


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19. 
PUBLICATION POLICY 
Information about this clinical trial will be publicly registered on the website 
www.clinicaltrials.gov before the first subject enters into the trial. 
A CTR will be prepared according to the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3).    
All information supplied by the sponsor in connection with this trial will remain the sole 
property of the sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the sponsor. 
Savara is committed to data transparency by disclosing information from its research programs 
through presentations at scientific congresses and publication in peer-reviewed journals. Savara 
adheres to the International Committee of Medical Journal Editors (ICMJE) recommendations 
regarding authorship. 
Draft manuscripts for joint publication will be prepared in collaboration between Savara, the 
coordinating Investigator and other Investigators, as appropriate depending on their contribution 
to the trial.  
Investigators participating in this multicenter study may publish data subsets from their 
individual institution only after publication of the primary manuscript. Written permission to 
publish must be obtained from the sponsor in advance. As some of the information regarding the 
IMP and development activities at the sponsor may be of a strictly confidential nature, the 
sponsor must be given a 30-day period to review and approve any publication manuscript prior 
to their submission to journals, meetings or conferences. Such a manuscript should always 
reference the primary publication of the entire study.  
The sponsor undertakes to publish the results in compliance with the joint position of the 
innovative pharmaceutical industry [Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases, available from 
http://clinicaltrials.ifpma.org/clinicaltrials/fileadmin/files/pdfs/EN/November_10_2009] for 
public disclosure of clinical trial results in a free, publicly accessible database, regardless of 
outcome, no later than one year after the medicinal product is first approved and is commercially 
available in any country. 
 


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20. 
LIST OF REFERENCES 
Aitken ML, Limaye A, Pottinger P, et al. Respiratory outbreak of Mycobacterium abscessus 
subspecies massiliense in a lung transplant and cystic fibrosis center. Am J Respir Crit Care 
Med. 2012;185(2):231-232. 
Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous 
mycobacterial lung disease in U.S. Medicare beneﬁciaries. Am J Respir Crit Care Med,  
2012;185:881–6. 
Aksamit TR, O'Donnell AE, Barker A, et al. Adult Bronchiectasis Patients: A First Look at the 
United States Bronchiectasis Research Registry. Chest. 2017;151(5):982-92. 
Almeida R, D'Oliveira A, Jr., Machado P, et al. Randomized, double-blind study of 
stibogluconate plus human granulocyte macrophage colony-stimulating factor versus 
stibogluconate alone in the treatment of cutaneous Leishmaniasis. J Infect Dis. 
1999;180(5):1735-1737. 
Awuh JA, Flo TH. Molecular basis of mycobacterial survival in macrophages. Cellular and 
molecular life sciences : CMLS. 2017. 
Bermudez LE, Martinelli J, Petrofsky M, Kolonoski P, Young LS. Recombinant granulocyte-
macrophage colony-stimulating factor enhances the effects of antibiotics against Mycobacterium 
avium complex infection in the beige mouse model. J Infect Dis. 1994;169(3):575-580. 
Bryant JM, Grogono DM, Rodriguez-Rincon D, et al. Emergence and spread of a human-
transmissible multidrug-resistant nontuberculous mycobacterium. Science. 2016;354(6313):751-
757 
Chatte G, Panteix G, Perrin-Fayolle M, Pacheco Y. Aerosolized interferon gamma for 
Mycobacterium avium-complex lung disease. Am J Respir Crit Care Med. 1995;152(3):1094-
1096. 
Choudhary GS, Yao X, Wang J, Peng B, Bader RA, Ren D. Human Granulocyte Macrophage 
Colony-Stimulating Factor Enhances Antibiotic Susceptibility of Pseudomonas aeruginosa 
Persister Cells. Sci Rep. 2015;5:17315. 
Cowman S, Burns K, Benson S, Wilson R, Loebinger MR. The antimicrobial susceptibility of 
non-tuberculous mycobacteria. J Infect. 2016;72(3):324-331. 
de Silva TI, Cope A, Goepel J, Greig JM. The use of adjuvant granulocyte-macrophage colony-
stimulating factor in HIV-related disseminated atypical mycobacterial infection. J Infect. 
2007;54(4):e207-210. 
Fleetwood AJ, Cook AD, Hamilton JA. Functions of granulocyte-macrophage colony-
stimulating factor. Crit Rev Immunol. 2005;25(5):405-428. 
Graham B L, Brusasco V, Burgos F et al. 2017 ERS/ATS standards for single-breath carbon 
monoxide uptake in the lung. Eur Respir J 2017; 49: 1600016 


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Griffith DE, Aksamit T, Brown-Elliott BA, et al. An Official ATS/IDSA Statement: Diagnosis, 
Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care 
Med. 2007;175(4):367-416. 
Griffith DE, Aksamit TR. Understanding nontuberculous mycobacterial lung disease: it's been a 
long time coming. F1000Res. 2016;5:2797. 
Hallstrand TS, Ochs HD, Zhu Q, Liles WC. Inhaled IFN-gamma for persistent nontuberculous 
mycobacterial pulmonary disease due to functional IFN-gamma deficiency. Eur Respir J. 
2004;24(3):367-370. 
Heidarieh P, Mirsaeidi M, Hashemzadeh M, et al. In Vitro Antimicrobial Susceptibility of 
Nontuberculous Mycobacteria in Iran. Microb Drug Resist. 2016;22(2):172-178. 
Holland AE, Spruit MA, Troosters T et al. An official European Respiratory Society/American 
Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Resp 
J, 2014;44 (6):1428-1446 
Kedzierska K, Mak J, Mijch A, et al. Granulocyte-macrophage colony-stimulating factor 
augments phagocytosis of Mycobacterium avium complex by human immunodeficiency virus 
type 1-infected monocytes/macrophages in vitro and in vivo. J Infect Dis. 2000;181(1):390-394. 
Kemper CA, Bermudez LE, Deresinski SC. Immunomodulatory treatment of Mycobacterium 
avium complex bacteremia in patients with AIDS by use of recombinant granulocyte-
macrophage colony-stimulating factor. J Infect Dis. 1998;177(4):914-920. 
Lam PK, Griffith DE, Aksamit TR, et al. Factors Related to Response to Intermittent Treatment 
of Mycobacterium avium Complex Lung Disease. Am J Respir Crit Care Med. 2006. 
Marras TK, Mendelson D, Marchand-Austin A, May K, Jamieson FB. Pulmonary 
nontuberculous mycobacterial disease, Ontario, Canada, 1998–2010. Emerg Infect Dis. 2013; 19: 
1889–91. 
Martino A. Mycobacteria and innate cells: critical encounter for immunogenicity. J Biosci. 
2008;33(1):137-144. 
Milanes-Virelles MT, Garcia-Garcia I, Santos-Herrera Y, Valdes-Quintana M, Valenzuela-Silva 
CM, Jimenez-Madrigal G, et al. Adjuvant interferon gamma in patients with pulmonary atypical 
Mycobacteriosis: a randomized, double-blind, placebo-controlled study. BMC Infect Dis. 2008; 8 
(17)  
Moser C, Jensen P, Pressler T, Holby N. Adjunctive treatment with granulocyte-macrophage 
colony simulating factor (GM-CSF) of CF patients with severe Mycobacterium abscessus lung 
infection. The 19th annual north american cystic fibrosis conference; 2005; Baltimore, Maryland. 
Onyeji CO, Nightingale CH, Tessier PR, Nicolau DP, Bow LM. Activities of clarithromycin, 
azithromycin, and ofloxacin in combination with liposomal or unencapsulated granulocyte-
macrophage colony-stimulating factor against intramacrophage Mycobacterium avium-
Mycobacterium intracellulare. J Infect Dis. 1995;172(3):810-816. 
Prevots DR, Shaw PA, Strickland D et al. Non-tuberculous mycobacterial lung disease 
prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med. 2010: 
182 (7): 970-976 


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Rawson TM, Abbara A, Kranzer K, et al. Factors which influence treatment initiation for 
pulmonary non-tuberculous mycobacterium infection in HIV negative patients; a multicentre 
observational study. Respir Med. 2016;120:101-108. 
Ringhausen FC, Wagner D, deRoux A et al. Prevalence of Nontuberculous Mycobacterial 
Pulmonary Disease, Germany, 2009–2014. Emerg Infect Dis, 2016; 22(6): 1102-1105 
Rose RM, Kobzik L, Dushay K, et al. The effect of aerosolized recombinant human granulocyte 
macrophage colony-stimulating factor on lung leukocytes in nonhuman primates. The American 
review of respiratory disease. 1992;146(5 Pt 1):1279-1286. 
Rothchild AC, Jayaraman P, Nunes-Alves C, Behar SM. iNKT cell production of GM-CSF 
controls Mycobacterium tuberculosis. PLoS pathogens. 2014;10(1):e1003805. 
Stout JE, Koh WJ, Yew WW. Update on pulmonary disease due to non-tuberculous 
mycobacteria. Int J Infect Dis. 2016; 45:123-134. 
Thomson R, Donnan E, Unwin S. Nontuberculous Mycobacterial Lung Disease. Time to Get a 
Grip! Ann Am Thorac Soc. 2015;12(10):1425-1427. 
Wassilew N, Hoffmann H, Andrejak C, Lange C (2016). Pulmonary Disease Caused by Non-
Tuberculous Mycobacteria. Respiration. 2016; 91(5): 386-402. 
Winthrop KL, Varley CD, Ory J, Cassidy PM, Hedberg K. Pulmonary disease associated with 
nontuberculous mycobacteria, Oregon, USA. Emerg Infect Dis. 2011;17(9):1760-1761. 
Zhao X, Wang Y, Pang Y. Antimicrobial susceptibility and molecular characterization of 
Mycobacterium intracellulare in China. Infect Genet Evol. 2014;27:332-338 
 


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21. 
APPENDICES 
 


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APPENDIX 1. RATIONALE FOR AMENDMENTS AND LIST OF 
REVISIONS  
Table 4: 
Table of Revisions 
Date 
Version 
Description of Document 
Rationale for changes 
27-Sep-2017 
1.0 
Final Protocol 
 
12-Nov-2017 
2.0 
Amendment 1 to the protocol.  
 
Section 2. Synopsis 
The synopsis was updated with the following: 
 
- 
Study timelines updated to reflect the 
current estimations. 
- 
Inclusion criterion 5 corrected. Double-
blind trial treatment changed to trial 
treatment.  
- 
NTM PCR endpoint and assessments 
removed. 
- 
A semi-quantitative assessment of sputum 
cultures added as an endpoint. 
 
Section 3. Trial Flow Chart 
- 
Subject diary was added. 
 
Section 6.1 Background 
- 
Updated information on ongoing clinical 
trial in PAP including the most recent 
DSMB review. 
 
Section 6.2 Trial Rationale 
- 
Revised some of the background literature 
information to be more informative and 
better aligned with source information.   
 
Section 7.3 Endpoints 
- 
Endpoints updated. NTM PCR endpoint 
removed 
- 
A semi-quantitative assessment of sputum 
cultures added as an endpoint. 
 
Section 8.1 Overall Trial Design 
- 
Text on PCR removed  
 
Section 8.1.1 Trial Period 
- 
Study timelines updated to reflect the 
current estimations. 
 
Section 8.1.3 Trial Completion 
- 
Definition of trial completion added. 
 
 
The protocol was amended on the 12-
Nov-2017 (Amendment 1 to the 
protocol) before the protocol was 
submitted to any CA or IEC.  
Reason for the changes was not 
provided as protocol version 1.0 had 
not been in use. 
Amendment 1 to the protocol is 
considered substantial  
 


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Date 
Version 
Description of Document 
Rationale for changes 
Section 8.2 Number of Subjects 
- 
Text updated to clarify wording. 
 
Section 9 Selection and Withdrawal of Subjects 
- 
Intro text included to specify that the 
subject must fulfil all inclusion and none 
of the exclusion criteria. 
 
Section 9.1 
- 
Inclusion criterion 5 corrected. Double-
blind trial treatment changed to trial 
treatment.  
 
Section 10.5 Subject Identification Lists 
- 
Text updated to specify that the 
investigator must maintain a log of all 
screened subjects. 
 
Section 12.2 Collection of Sputum Samples for 
Microbiological Characterization and 
Quantification 
- 
A semi-quantitative assessment of the 
sputum culture was added. Quantitative 
PCR taken out but described that samples 
will be stored for potential post-hoc 
analysis. 
 
Section 12.6 Subject Diary 
- 
Section on subject diaries was added. 
- 
 
Section 13.2 Secondary Endpoints 
- 
Statistical methods updated to correspond 
with changes in assessments and secondary 
endpoints. 
 
Section 12.13.1 DLCO 
- 
Calculation of DLCO clarified 
 
Section 13.2 Secondary Endpoints 
- 
Endpoints updated. NTM PCR endpoint 
removed 
- 
A semi-quantitative assessment of sputum 
cultures added as an endpoint. 
 
Section 20 List of References 
- 
Some references taken out in line with 
revisions to Section 6.2. 
 
22-Aug-2018 
3.0 
Amendment 2 to the protocol.  
 
Section 2. Synopsis 
The synopsis was updated with the following: 
- 
Number of collected sputum samples 
Amendment 2 to the protocol is 
considered substantial 
The rational for the changes is the 
following  
 


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Date 
Version 
Description of Document 
Rationale for changes 
changed to 3 samples at all visits. 
- 
Definition of sexual abstinence added to 
inclusion criterion 5 
- 
Anti-drug-antibodies change to Anti-GM-
CSF-antibodies under assessments. 
- 
Flow chart updated to reflect that 3 sputum 
samples will be collected at each visit 
 
Section 8.1 Overall Trial Design 
- 
Number of collected sputum samples 
changed to 3 samples at all visits. 
 
Section 9.1 Subject Inclusion Criteria 
- 
Definition of sexual abstinence added to 
the inclusion criterion 5 
 
Section 11.5 Administration 
- 
Text updated to clarify that study treatment 
should not be taken prior to visit 3 and 5.  
 
Section 12.2 
- 
Number of collected sputum samples 
changed to 3 samples at all visits. 
 
Section 12.14.1 
- 
Text changed from Anti-drug-antibodies to 
Anti-GM-CSF 
 
Spelling and formatting errors and was  
The number of sputum samples pr. 
visit is increased to strength the 
validity and robustness of the 
microbiological assessments. 
 
Definition of sexual abstinence was 
added after a request from the 
competent authority in UK (MHRA). 
 
Anti-drug-antibodies was changed to 
anti-GM-CSF to specify the actual 
analysis performed. 
 
Text in section 11.5 wrongly stated 
that blood sampling should be done 
before IMP dosing at visit 3 and 4. 
 
 
 
 
  
26-Sep-2018 
4.0 
Section 2. Synopsis 
The synopsis was updated with the following: 
- 
Study period dates were revised to reflect 
the longer treatment duration 
- 
Additional visits at 4-week intervals: 32, 
36, 40, 44, 48. The visits at Weeks 32, 40 
and 48 will include a clinic visit and the 
visits at Weeks 28, 36 and 44 will include 
telephone contact 
- 
Details of visits at which each assessment 
was performed was revised 
- 
Update on safety review provided 
- 
One grading changed from scant to 
occasional to align with the naming at 
laboratory 
- 
Safety laboratory sample added at the 12-
weeks follow-up visit. 
- 
Duration of treatment was prolonged to 48 
weeks 
- 
Study endpoints were revised to allow for 
data from the additional visits and 
assessments 
 
Section 3.0. Trial Flow Chart 
Treatment period is to be extended 
by 24 weeks to a total of 48 weeks 
 
Protocol wording updated to reflect 
that the safety review meeting has 
taken place.  
 
Dose modifications allowed after 
sponsor approval in case of 
intolerance in order to maintain 
subjects on treatment if deemed 
feasible by the investigator. 
 
CT scan added at visit 14. CT scans 
should only be performed if this is 
already a part of local standard at the 
site. 
 
Safety laboratory sampling added at 
the 12-week follow-up visit in order 
to assess the laboratory parameters 


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Date 
Version 
Description of Document 
Rationale for changes 
- 
Revised to detail additional visits and 
assessments 
- 
CT scan added as an optional procedure at 
V14 
- 
Safety laboratory sample added at the 12-
weeks follow-up visit.  
 
Section 6.2. Trial Rationale 
- 
The treatment duration was revised and 
update on the safety review was provided 
 
Section 7.3. Endpoints 
- 
Study endpoints were revised to allow for 
data from the additional visits and 
assessments 
 
Section 8.1. Overall Trial Design 
- 
Additional visits at 4-week intervals: 32, 
36, 40, 44, 48. The visits at Weeks 32, 40 
and 48 will include a clinic visit and the 
visits at Weeks 28, 36 and 44 will include 
telephone contact 
- 
Details of visits at which each assessment 
was performed was revised 
- 
Duration of treatment was revised 
- 
Update on the safety review was provided 
 
Section 8.1.1. Trial Period 
- 
Dates were revised to reflect the longer 
treatment duration 
 
Section 8.4 
- 
Update from the safety was provided 
- 
Dose reductions allowed in case of poor 
tolerability 
 
Section 9.3.2. Withdrawal from the Trial 
- 
Revised required assessments to those 
conducted at Week 48 
 
Section 11.3 Study Drug Storage 
- 
Revised in line with additional visits and 
extended treatment duration 
 
Section 11.5 Administration 
- 
Revised in line with additional visits and 
extended treatment duration 
 
Section 12.2 Collection of Sputum Samples for 
Microbiological Characterization and 
Quantification 
- 
Revised in line with additional visits and 
extended treatment duration. Detailed three 
samples are to be collected at home for the 
after 12-weeks off IMP treatment.   
 
 
 
 
 
 
 
 
 
 
 
 
 


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Date 
Version 
Description of Document 
Rationale for changes 
telephone contact visits  
- 
One grading changed from scant to 
occasional to align with the naming at 
laboratory 
 
Section 12.7 Adverse Events 
- 
Revised in line with additional visits and 
extended treatment duration.  
 
Section 12.14 Laboratory Assessments 
- 
Revised total volume of blood to 240 mL 
due to additional visits and extended 
treatment duration.  
 
Section 12.16 Adverse Events 
- 
Revised in line with additional visits and 
extended treatment duration.  
 
Section 13 Statistics 
- 
Study endpoints were revised to allow for 
data from the additional visits and 
assessments 
- 
One grading changed from scant to 
occasional to align with the naming at 
laboratory 
 


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


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APPENDIX 3.  TRIAL ORGANIZATION 
 
Central Laboratory (Safety Laboratory Analysis): 
Name: BARC Global Central Laboratory 
Address: Industriepark Zwijnaarde 3, 9052 Ghent, Belgium 
Phone: +32 9 329 23 29 
 
Reference Laboratory (Anti-GM-CSF analysis): 
Name: IPM Biotech GmbH 
Address: Lademannbogen 10, 22339 Hamburg,  
Phone:  +49 40 5267790 
 
Reference Laboratory (Microbiology analysis Australia): 
Name: Sullivan Nicolaides Pathology 
Address: 24 Hurworth St, Bowen Hills, QLD 4006 
Phone number: +61 07 3377 8666 
 
Reference Laboratory (Microbiology analysis UK): 
Name: Royal Brompton Hospital 
Address:  Sydney St, Chelsea, London SW3 6NP, UK 
Phone number: +44 20 7352 8121 
 
CRO (Submissions, Monitoring, Data Management and Statistics): 
Name: Southern Star Research  
Address: Level 1, 1 Merriwa Street, Gordon NSW 2072, Australia. Postal: PO Box 52, Gordon 
NSW 2072 Australia 
Phone: +61 2 9011 6266 
 
Manufacturing: 
Name: Miltenyi Biotec GmBH 
Address: Robert-Koch-Straße 1, 17166 Teterow, Germany 
Phone: +49 2204 8306-0 
 
Packaging/labelling of IMP: 
Name: KLIFO A/S 
Address: Smedeland 36, 2600 Glostrup 
Phone: +45 44 22 29 00 
 
Pharmacovigilance 
Name: Premier Research 
Address: 1st Floor, Rubra 2, Mulberry Business Park, Wokingham, RG41 2GY, UK 
Phone: +44 118 936 4000 
 


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APPENDIX 4. QUESTIONNAIRES 
4.1 
Borg CR10 Scale 
 
 
 


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4.2 
Quality of Life Questionnaire – Bronchiectasis 
 
 


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4.3 
 
Lower Respiratory Tract Infections –Visual Analogue Scale – for 
use in non-CF Bronchiectasis 
 
 
 
 
 
 

SAP_001.pdf: 
 
SAV008-01 
An open-label, non-controlled, multicentre, pilot 
clinical trial of inhaled molgramostim in subjects with 
antibiotic-resistant non-tuberculosis mycobacterial 
(NTM) infection 
 
NCT03421743 
 
Statistical Analysis Plan 
Version 1.0 
19 February 2020 


Protocol Number: SAV008-01 
 
 19 February 2020 
Document status: SAP Version 1.0 (FINAL) 
 
BM S01-A, v2.0 
Statistical Analysis Plan 
Effective:  18/JAN/2018 
CONFIDENTIAL 
Page 1 of 33
 
 
 
STATISTICAL ANALYSIS PLAN 
An Open-label, Non-controlled, Multicentre, Pilot Clinical Trial of Inhaled 
Molgramostim in Subjects with Antibiotic-resistant Non-tuberculosis 
Mycobacterial (NTM) Infection 
 
Protocol No.: SAV008-01 
Product Code: Molgramostim Nebulizer Solution (Molgradex®) 300 µg 
 
PREPARED FOR:   Savara ApS 
 
Slotsmarken 17, 2 t.v. 
 
2970 Hørsholm 
 
Denmark 
 
PREPARED BY:       Southern Star Research 
 
Level 1, 1 Merriwa St 
 
Gordon, NSW, 2072  
 
Australia  
 
DATE OF ISSUE:     19 February 2020  
 
 
VERSION/STATUS: Version 1.0 (FINAL) 
 
 
      VERSION DATE:      19 February 2020 
 
      AUTHOR:         Dr Elisa Young 
 
 
 
 
 
 




Protocol Number: SAV008-01 
 
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Document status: SAP Version 1.0 (FINAL) 
 
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Table of contents 
 
1. 
INTRODUCTION .................................................................................................................... 5 
2. 
PROJECT OVERVIEW ............................................................................................................ 5 
2.1 
Study Design ............................................................................................................................. 5 
2.2 
Objectives ................................................................................................................................. 7 
 
Primary objective .............................................................................................................. 7 
 
Secondary objective(s) ..................................................................................................... 7 
2.3 
Sample Size ............................................................................................................................... 7 
2.4 
Treatment Assignment and Randomisation ............................................................................. 7 
3. 
STATISTICAL CONSIDERATIONS ........................................................................................... 8 
3.1 
Analytical Approach .................................................................................................................. 8 
3.2 
Data Capture............................................................................................................................. 8 
 
Database ........................................................................................................................... 8 
 
Third Party Data ................................................................................................................ 9 
3.3 
Statistical Programming ......................................................................................................... 10 
 
CDISC .............................................................................................................................. 10 
 
Study Terminology .......................................................................................................... 11 
 
Baseline .......................................................................................................................... 12 
 
Change from Baseline ..................................................................................................... 12 
 
Listings, Tables and Figures ............................................................................................ 12 
4. 
ANALYSIS SETS ................................................................................................................... 12 
4.1 
Analysis Set Descriptions ........................................................................................................ 12 
 
Full Analysis Set (FAS) ..................................................................................................... 12 
5. 
PROTOCOL DEVIATIONS..................................................................................................... 12 
6. 
SUBJECT DISPOSITION ........................................................................................................ 13 
7. 
DEMOGRAPHIC AND BASELINE INFORMATION ................................................................ 13 
7.1 
Demographics ......................................................................................................................... 13 
 
Definition of variables .................................................................................................... 13 
 
Biostatistical methods .................................................................................................... 13 
7.2 
Baseline Characteristics .......................................................................................................... 14 
7.3 
Medical history ....................................................................................................................... 14 
7.4 
Pregnancy Test ....................................................................................................................... 14 
7.5 
Eligibility ................................................................................................................................. 14 
7.6 
Disease specific Medical History ............................................................................................ 14 
 
Definition of variables .................................................................................................... 14 
 
Biostatistical methods .................................................................................................... 14 
7.7 
NTM Sampling ........................................................................................................................ 14 
8. 
TREATMENT EXPOSURE ..................................................................................................... 15 
 
Definition of variables .................................................................................................... 15 
 
Biostatistical methods .................................................................................................... 15 
9. 
EFFICACY ............................................................................................................................ 16 
9.1 
Endpoints ................................................................................................................................ 16 
 
Primary Efficacy Endpoint: ............................................................................................. 16 
 
Secondary Efficacy Endpoints: ........................................................................................ 16 
9.2 
Variables ................................................................................................................................. 16 
 
Primary Endpoint Variables ............................................................................................ 16 


Protocol Number: SAV008-01 
 
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Document status: SAP Version 1.0 (FINAL) 
 
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Secondary Endpoint Variables ........................................................................................ 17 
9.3 
Biostatistical methods ............................................................................................................ 17 
 
Primary Endpoint ............................................................................................................ 17 
 
Secondary Endpoints ...................................................................................................... 18 
10. 
SAFETY ............................................................................................................................ 20 
10.1 
Safety Endpoints ..................................................................................................................... 20 
10.2 
Adverse Events ....................................................................................................................... 20 
 
Definition of variables .................................................................................................... 20 
 
Biostatistical methods .................................................................................................... 21 
10.3 
Deaths ..................................................................................................................................... 21 
10.4 
Prior and Concomitant Medication ........................................................................................ 21 
10.5 
Laboratory .............................................................................................................................. 22 
 
Definition of variables .................................................................................................... 22 
 
Biostatistical methods .................................................................................................... 22 
10.6 
Vital Signs ............................................................................................................................... 23 
 
Definition of variables .................................................................................................... 23 
 
Biostatistical methods .................................................................................................... 23 
10.7 
Body Measurements .............................................................................................................. 23 
 
Definition of variables .................................................................................................... 23 
 
Biostatistical methods .................................................................................................... 23 
10.8 
Physical Examination .............................................................................................................. 23 
 
Definition of variables .................................................................................................... 23 
 
Biostatistical methods .................................................................................................... 23 
10.9 
12-lead ECG ............................................................................................................................ 24 
 
Definition of variables .................................................................................................... 24 
 
Biostatistical methods .................................................................................................... 24 
10.10 
Pulmonary Function Tests .................................................................................................. 24 
 DLCO ............................................................................................................................... 24 
 Spirometry ...................................................................................................................... 24 
10.11 
Radiology ............................................................................................................................ 24 
 CT Scan............................................................................................................................ 24 
 Chest X-Ray ..................................................................................................................... 24 
10.12 
Pregnancy Test ................................................................................................................... 24 
11. 
IMMUNOGENICITY ......................................................................................................... 25 
11.1 
Definition of variables ............................................................................................................ 25 
11.2 
Biostatistical methods ............................................................................................................ 25 
12. 
HANDLING OF MISSING DATA........................................................................................ 25 
13. 
CHANGES TO THE PLANNED ANALYSIS .......................................................................... 25 
13.1 
Interim Analysis ...................................................................................................................... 25 
14. 
INTERIM AND FINAL ANALYSIS ...................................................................................... 25 
15. 
SOFTWARE ..................................................................................................................... 25 
16. 
REFERENCES ................................................................................................................... 26 
17. 
Appendix 1: QOL-B Scoring Manual ............................................................................... 27 
 


Protocol Number: SAV008-01 
 
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Document status: SAP Version 1.0 (FINAL) 
 
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1. INTRODUCTION 
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of 
the data from the SAV008-01 study. 
 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. In addition, post hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any 
post hoc, or unplanned, exploratory analyses performed will be clearly identified as such in 
the final CSR. 
2. PROJECT OVERVIEW 
2.1 Study Design 
This is an open-label, non-controlled, multicentre, pilot clinical trial of inhaled molgramostim in 
subjects with persistent pulmonary NTM infection. 
 
The study will comprise a Screening Visit, Baseline Visit, a 48-week treatment period and a 
12-week follow up period. The Screening Visit (Visit 1) will be conducted up to 10 weeks prior 
to the Baseline Visit (Visit 2) to determine eligibility. Adult subjects with a history of chronic 
NTM infection with at least 2 positive cultures in the prior two years, of which at least one is 
within the last 6 months prior to Screening, will be considered for enrolment. Subjects should 
provide a positive NTM sputum culture at Screening to be eligible. 
 
The study will include 30 subjects. 
 
The treatment period will consist of 14 trial visits (Screening, Baseline, and at Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, and 48; Visits 1-14) and a follow-up visit (Visit 15) 12 weeks 
after end of treatment. The visits at Weeks 28, 36 and 44 (Visits 9, 11 and 13) will include a 
telephone contact, all other visits will include a clinic visit. 
 
At the Baseline Visit (Visit 2), eligible subjects will start treatment with inhaled molgramostim 
administered via the PARI eFlow nebulizer. 
 
At each visit (Visits 1-15), sputum samples for staining and microscopy, and microbiological 
culture will be collected. If required, induced sputum may be obtained according to local 
standards. On the days of clinic visits (Visits 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 15), subjects 
will be asked to collect two additional sputum samples at home, preferably on the consecutive 
days after the site visit (At the commencement of the study, only 1 sample was required for 
Visits 2 to 7, with the additional sampling added in protocol amendment(s)). On the days of 
the telephone contact visits (Visits 9, 11 and 13), three sputum samples will be collected at 
home, preferably on consecutive days. 
 
Any AEs will also be collected at Baseline and all subsequent visits (Visits 2-15), At all clinic 
visits a pregnancy test/contraceptive check will be conducted, changes in concomitant 
medication, measurement of body weight and an assessment of DLCO will be performed. A 
computed tomography (CT) scan will be conducted at Baseline (Visit 2) if not performed 
within 6 months prior to Baseline. If DLCO drops by at least 20% at two consecutive visits the 
CT scan may be repeated. A CT scan can be performed after 48 weeks of treatment if this is 
a part of the local routine clinical practice. 
 
A physical examination and an electrocardiogram (ECG) will be performed at Screening and 
Weeks 24 and 48 (Visits 1, 8 and 14) and vital signs will be collected at Screening, Baseline, 
and Weeks 4, 12 24, 32, 40 and 48 (Visits 1, 2, 3, 5, 8, 10, 12 and 14). Spirometry will be 
conducted at Baseline and at Weeks 12, 24, 32, 40 and 48 (Visits 2, 5, 8, 10, 12 and 14). A 


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6MWT will be conducted at Baseline, at Weeks 12, 24 and 48 and at the 12-week follow-up 
visit (Visits 2, 5, 8, 14 and 15). Blood samples for safety laboratory testing will be taken at 
Screening, Baseline, and at Weeks 4, 12, 24, 32, 40, 48 and at the 12-week follow-up visit 
(Visits 1, 2, 3, 5, 8, 10, 12, 14, 15). Anti-GM-CSF will be assessed at Baseline, at Week 4, 12, 
24, 32, 48 and at the 12-week follow-up visit (Visits 2, 3, 5, 8, 10, 14 and 15). Subject 
reported outcomes (QoL-B, LRTI-VAS and GRH) will be assessed at Baseline and at all post 
Baseline clinic visits (Visits 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 15). For subjects having a chest 
X-ray during the study period as part of the routine local clinical practice, the results from the 
X-ray will be recorded. 
 
Participating subjects will be encouraged to contact the clinic between visits if they 
experience adverse events (AEs), worsening of their condition or have any other concerns. If 
needed, unscheduled visits will be conducted at investigator’s discretion. 
 
Treatment with inhaled molgramostim will be given at a dosage of 300 μg once daily for 48 
weeks. All subjects in the trial initially consented to 24 weeks of treatment. All enrolled 
subjects continuing with 48 weeks of treatment will re-consent and follow the visits schedule 
as described above. 
 
Subjects that do not wish to continue to 48 weeks of treatment will end treatment after 24 
weeks (visit 8) and will attend the follow-up visit 12-weeks later as per the visit schedule 
outlined in Protocol Version 2.0 or 3.0. 
 
Subjects who complete the initial 24-week treatment period prior to the approval of Protocol 
Version 4.0 will proceed to the 12-week follow up as per the visit schedule in Protocol Version 
2.0 or 3.0. Once Protocol Version 4.0 is approved they will be asked to re consent and re-
initiate treatment. This will occur at the next trial visit or at an unscheduled visit. These 
subjects will not receive the whole 48-week treatment. The will receive treatment for an 
additional 24 weeks minus the number of weeks that they have been in follow up. 
 
Subjects that do not wish to re consent and re initiate treatment will stay in follow up and 
attend the follow-up visit as per the visit schedule outlined in Protocol Version 2.0 or 3.0. 
 
At Baseline and at Weeks 4, 12, 24, 32 and 40 (Visits 2, 3, 5, 8, 10 and 12), dosing will take 
place in the clinic after blood sampling. A data review was conducted after the first 6 subjects 
had completed 12 weeks of treatment. If safety concerns or poor tolerability were identified in 
this review, the review committee might decide on less frequent dosing for subsequent 
subjects in the study. The review was conducted on 16 September 2018 and concluded that 
there were no safety issues of significant concern and the dose was unchanged. In order to 
obtain more robust treatment responses it was decided to extend the treatment duration from 
24 to 48 weeks. Any changes to the conduct of the study such as change of dose, dose 
regimen or duration will be documented in a protocol amendment. 
 
During the study, subjects in Group 1 will continue use of antimycobacterial treatment. All 
changes in antimycobacterial treatment will be recorded, including reasons for each change. 
In case of worsening of NTM pulmonary disease, antimycobacterial treatment may be added 
or a dosage increase of antimycobacterial treatment may be applied as rescue treatment, 
according to investigator’s discretion. 
 
 


Protocol Number: SAV008-01 
 
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2.2 Objectives 
 Primary objective 
The primary objective is: 
• To investigate efficacy of inhaled molgramostim on NTM sputum culture conversion to 
negative.  
 Secondary objective(s) 
The secondary objectives are: 
• To investigate efficacy of inhaled molgramostim on NTM sputum smear conversion to 
negative. 
• To investigate efficacy of inhaled molgramostim on reduction of NTM bacterial load in 
sputum. 
• To investigate efficacy of inhaled molgramostim on exercise capacity. 
• To investigate efficacy of inhaled molgramostim on Subject Reported Outcomes. 
• To investigate safety of inhaled molgramostim in subjects with NTM infection.  
2.3 Sample Size 
It was planned that 30 subjects will be enrolled. No formal sample size calculation was done 
as this is an initial pilot study. 
2.4 Treatment Assignment and Randomisation 
At the Baseline visit, all subjects found to be eligible according to the inclusion/exclusion 
criteria will be classified into the following treatment groups: 
 
• Group 1:  Subjects who remain sputum culture positive while currently on a 
multidrug NTM guideline based antimycobacterial regimen, which has 
been ongoing for at least 6 months prior to the Baseline Visit. 
• Group 2:  Subjects who remain sputum culture positive but have either stopped a 
multidrug NTM guideline based antimycobacterial regimen at least 28 
days prior to Screening due to lack of response or intolerance, or never 
started such treatment. 
 
Subjects successfully assigned to a subgroup will then start treatment with open-label 
molgramostim nebulizer solution. 


Protocol Number: SAV008-01 
 
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Document status: SAP Version 1.0 (FINAL) 
 
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3. STATISTICAL CONSIDERATIONS 
3.1 Analytical Approach 
Data analysis will be performed according to Southern Star Research’s Standard Operating 
Procedures (SOPs). 
 
The general analytical approach for all endpoints will be descriptive in nature.  All summaries 
will present the data by treatment group as well as by all subjects combined.  
 
Unless otherwise stated, the following statistical approaches will be taken: 
 
Continuous variables:   
Descriptive statistics will include the number of non-missing 
values, mean, standard deviation (SD), median, minimum, and 
maximum.  The minimum and maximum values will be 
presented to the same number of decimal places as recorded in 
the eCRF; mean, median, and SD will be presented to one more 
decimal place than the raw data. 
 
Categorical variables:   
Descriptive statistics will include frequency counts and 
percentages per category.  Percentages will be rounded to 
one decimal place, with the denominator being the number of 
subjects in the relevant population with non-missing data. 
 
Multiplicity:   
As this is an exploratory study no adjustments for multiplicity will 
be applied. 
 
Confidence intervals (CIs):   CIs will be two-sided and will use 95% confidence levels.  Any 
analyses requiring significance testing will use a two-sided test 
at the 5% significance level. 
 
Unscheduled Visits 
Unscheduled visits will be excluded from summary tables. 
 
3.2 Data Capture 
 Database 
The primary method of data collection is via the study database, developed within the chosen 
Electronic Data Capture (EDC) platform, IBM Clinical Development. The database has been 
designed based on the final protocol, the system/core configuration, electronic Case Report 
Form (eCRF) specifications and/or mock eCRF and consistency check specifications. 
 
Data will be entered directly into the EDC system.  
 
Site-collected data will be entered directly from source notes at the site and will be verified by 
Clinical Research Associates (CRAs) to ensure data integrity.  
 
This study also includes subject reported outcomes collected through ePRO entry within the 
EDC. 
 
Refer to the Data Management Plan for further details. 
 
 


Protocol Number: SAV008-01 
 
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Document status: SAP Version 1.0 (FINAL) 
 
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 Third Party Data 
 Safety Laboratory 
Central safety laboratory data will be received from BARC Global Central Laboratory as 
specified in the BARC Data Transfer Specification. Data transfers are being processed on a 
monthly basis throughout the study, with each transfer being reconciled against the CRF 
data.  
 
The final data transfer will be incorporated into the End of Study analysis once the final 
transfer has been received, reconciled and any issues are considered resolved. 
 
No conversion of laboratory data will be performed. 
 Anti-GM-CSF 
Anti-GM-CSF data will be received from Bioagilytix Europe GMBH as specified in the 
Bioagilytix Data Transfer Specification. Two data transfers will take place.  The first transfer 
will occur following analysis of samples up to Visit 5 for the first six subjects and the second 
transfer will occur at End of Study.  
 
The End of Study data transfer will be incorporated into the End of Study analysis once the 
transfer has been received, reconciled and any issues are considered resolved. 
 Microbiology Analysis (Australia) 
Microbiology analysis of samples from Australian sites will be analysed and reported by 
Sullivan Nicolaides Pathology (SNP) as specified in the SNP Data Transfer Specification. 
Data transfers are being processed on a monthly basis throughout the study, with each 
transfer being reconciled against the CRF data.  
 
The final data transfer will be incorporated into the End of Study analysis once the final 
transfer has been received, reconciled and any issues are considered resolved. 
 Microbiology Analysis (UK) 
Microbiology analysis of samples from UK sites will be analysed and reported by Royal 
Brompton Hospital (RBH) as specified in the RBH Data Transfer Specification. Data transfers 
are being processed on a monthly basis throughout the study, with each transfer being 
reconciled against the CRF data.  
 
The final data transfer will be incorporated into the End of Study analysis once the final 
transfer has been received, reconciled and any issues are considered resolved. 
 
 


Protocol Number: SAV008-01 
 
 19 February 2020 
Document status: SAP Version 1.0 (FINAL) 
 
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Page 10 of 33
 
3.3 Statistical Programming 
 CDISC 
 SDTM 
All study datasets will be structured according to Clinical Data Interchange Standards 
Consortium (CDISC) Study Data Tabulation Model (SDTM) conventions as detailed in Table 
1. 
 
Table 1: SDTM Specifications and Deliverables 
Deliverable 
Specification 
SDTM convention 
SDTM Model v1.4, SDTMIG v3.2 
CDISC Validator 
Pinnacle21 v2.2.0 or later 
SAS Version 
V 9.4, vlatin1 
SDTM Export Datasets 
*.xpt 
SDTM Annotated CRF 
Required, aCRF.pdf in searchable pdf with required 
colour annotation 
Define.XML 
Required, v2.0.0 
Study Data Reviewer’s Guide 
Required, sdrg.pdf 
 ADaM 
Analysis datasets will be structured according CDISC Analysis Data Model (ADaM) 
conventions as detailed in Table 2. 
 
Table 2: ADaM Specifications and Deliverables 
Deliverable 
Specification 
ADaM convention 
ADaMIG v1.1 
CDISC Validator 
Pinnacle21 v2.2.0 or later 
SAS Version 
V 9.4, vlatin1 
ADaM Export Datasets 
*.xpt 
Define.XML 
Required, v2.0.0 
Analysis Data Reviewer’s Guide 
Required, adrg.pdf (paper size - Letter) 
 
 
 


Protocol Number: SAV008-01 
 
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Document status: SAP Version 1.0 (FINAL) 
 
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Page 11 of 33
 
 Study Terminology 
 
Study-specific standard terms are detailed in Table 3. 
 
Table 3: Study CDISC Terminology 
Subject Elements 
Screen (SCRN) 
Molgramostim (MOLG) 
Follow-Up (FU) 
Epochs 
SCREENING 
OPEN LABEL TREATMENT 
FOLLOW-UP 
Treatment Arms 
GROUP 1 
GROUP 2 
Visit Numbers / Visits 
SCREENING EPOCH 
1.0  
Screening 
 
TREATMENT EPOCH 
2.0 
Baseline Visit* 
3.0 
Week 4 
4.0 
Week 8 
5.0 
Week 12 
6.0 
Week 16 
7.0 
Week 20 
8.0 
Week 24 
9.0 
Week 28 
10.0 
Week 32 
11.0 
Week 36 
12.0 
Week 40 
13.0 
Week 44 
14.0 
Week 48 
888 
Early Discontinuation 
999 
End of Study 
 
FOLLOW-UP EPOCH 
15.0 
Follow Up Visit 
 
Unscheduled visits: x.n where x is the visit number of the 
closest previous scheduled visit and n is the sequence number 
of the unscheduled visit, restarting at 1 after each scheduled 
visit. EPOCH will be assigned according to the epoch of the 
closest previous visit. 
 
* “Baseline Visit” will be used when referring to Visit 2.  The 
term “Baseline” will also be used as detailed in 3.3.3. 
 
 
 
 


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 Baseline 
For sputum data, baseline will be derived from the combined pre-treatment visits (i.e. 
Screening and Baseline), where at least one positive sample will be assigned as positive as 
baseline.  For gradings, the most severe/highest grade will be used. 
 
For all other parameters, baseline will be defined as the last available assessment prior to 
first study drug administration. 
 Change from Baseline 
Absolute change from Baseline will be calculated as: 
 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏= (𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣) −𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 
 Listings, Tables and Figures 
Listings, tables and figures will be delivered as individual .rtf files in accordance with the mock 
listings, tables and figures. 
 
Data listings will present all data, with subjects grouped by Group. 
 
Tabulations will summarise data by Group and Total. 
4. ANALYSIS SETS 
One (1) analysis dataset will be used for study all analyses: Full Analysis Set (FAS). 
   
Additional analysis sets or subgroups of interest may be required as part of post-hoc 
analyses. These will be detailed in the CSR.  
The number and percentage of subjects in each analysis set will be summarised. 
4.1 Analysis Set Descriptions 
 Full Analysis Set (FAS) 
The FAS will comprise all subjects enrolled into the study.  
5. PROTOCOL DEVIATIONS 
Analysis Set: Full Analysis Set (FAS) 
 
All deviations recorded during the trial will be categorised as Minor and Major.  The major 
deviations will be further assessed in order to identify critical deviations. A critical protocol 
deviation will be defined as a deviation that contributes to the following:  
 
• 
Treatment compliance below 80 % during the treatment period. 
• 
No sputum samples at 2 visits.  
 
 
 
 
 
 


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6. SUBJECT DISPOSITION 
Analysis Set: Full Analysis Set (FAS) 
 
A listing of subject disposition will present: 
• 
Date of informed consent 
• 
Date of treatment commencement 
• 
Date of treatment discontinuation 
• 
Study day of treatment discontinuation (Days after first dose) 
• 
Last visit before treatment discontinuation 
• 
Primary reason for discontinuation of treatment 
• 
Date of study completion/End of participation 
• 
Study day of study completion/End of participation (Days after first dose) 
• 
Last visit before study completion/End of participation 
• 
Primary reason for ending study participation 
 
Subject withdrawal information, including date and reason for treatment termination, will also 
be listed in a separate listing. 
 
The number and percentage of subjects entering and discontinuing the study will be 
summarised along with the reason for discontinuation.  The subject disposition summary 
table will include: 
• 
Number of subjects enrolled 
• 
Number of subjects who received at least one dose of study medication 
• 
Number of subjects who completed 24 weeks treatment 
• 
Number of subjects who completed 48 weeks treatment 
• 
Number of subjects who completed the full study 
• 
Number of subjects withdrawn early 
• 
Reason for early withdrawal 
 
7. DEMOGRAPHIC AND BASELINE INFORMATION 
Analysis Set: Full Analysis Set (FAS) 
7.1 Demographics 
 Definition of variables 
• 
Age (years) 
• 
Sex 
• 
Race (White/Asian/Black/American Indian or Alaska Native/Native Hawaiian or Other 
Pacific Islander) 
• 
Female reproductive status 
• 
Male reproductive status 
• 
Smoking status (Previous/Current/Never) 
 Biostatistical methods 
Demographic data will be listed and summarised. 
 
 


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7.2 Baseline Characteristics 
Select baseline characteristics will be presented in a summary table, including: 
• 
Height 
• 
Weight 
• 
BMI 
• 
FVC 
• 
FEV1 
7.3 Medical history 
All medical history data will be listed. Medical history (other than disease under study) will be 
coded using the Medical Dictionary for Regulatory Activities, MedDRA® and summarised by 
system organ class (SOC) and preferred term (PT).  
7.4 Pregnancy Test 
Pregnancy test data will be listed for all women of childbearing potential.    
7.5 Eligibility 
All eligibility data will be listed. 
7.6 Disease specific Medical History 
 Definition of variables 
From the CRFs: 
• 
Date of microbiological diagnosis of current pulmonary infection  
• 
Type of NTM (Mycobacterium avium complex (MAC) | Mycobacterium abscessus) 
• 
Body weight at time of initial diagnosis 
• 
Age at time of initial diagnosis 
• 
Forced Vital Capacity (FVC) at time of initial diagnosis 
• 
Forced Expiratory Volume in 1 second (FEV1) at time of initial diagnosis 
• 
ATS/IDSA 2017 criteria fulfilled 
 
Derived: 
• 
Duration of infection: defined as the number of days from the date of initial diagnosis 
to the date of informed consent. 
 Biostatistical methods 
NTM history data will be listed for all subjects.  
 
An NTM History summary table will present: 
• 
Duration of infection 
• 
Frequency of NTM type 
• 
Forced Vital Capacity (FVC) at time of initial diagnosis 
o FVC (L) 
o Relative FVC (%) 
• 
Forced Expiratory Volume in 1 Second (FEV1) at time of initial diagnosis: 
o FEV1 (L) 
o Relative FEV1 (%) 
• 
Number of subjects with each ATS/IDSA2017 criterion 
7.7 NTM Sampling 
All NTM sampling history will be listed. 
 


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8. TREATMENT EXPOSURE 
Analysis Set: Full Analysis Set (FAS) 
 Definition of variables 
 
From the CRFs: 
• 
Confirmation of subject training 
• 
Date/time of clinic study drug administration 
• 
Dispense data 
o Number of kits dispensed by visit 
• 
Compliance data 
o Number of used vials 
o Number of unused vials 
o Number of used lost vials 
o Number of unused lost vials 
o Compliance (visit level) 
• 
Dose change details 
o Start date of changed dose regimen 
o Number of doses 
o Frequency of dose 
o Reason for changed dose 
 
Derived: 
• 
Number of subjects who had a break in treatment after completing Week 24 and 
commencing the remaining treatment period to Week 48 
 
• 
Duration of exposure: 
 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 − 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 +  1 
• 
Overall compliance (%) 
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑∗
𝑥𝑥100 
 
* 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 = (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒𝑒𝑒 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 –  𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 2) + 1 
 Biostatistical methods 
 
All treatment exposure data, including kit dispense, compliance, study drug administration 
and dose change details, will be listed. 
 
Duration of exposure and compliance (by visit and overall) will be summarised. 
 
 


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9. EFFICACY 
Analysis Set: Full Analysis Set (FAS) 
9.1 Endpoints 
 Primary Efficacy Endpoint: 
• 
Sputum culture conversion defined as at least three consecutive negative sputum 
samples during the treatment period. 
 Secondary Efficacy Endpoints: 
• 
Sputum smear conversion defined as at least three consecutive negative AFB stained 
sputum smears on microscopy during the treatment period in subjects who were 
smear positive at Baseline. 
• 
Durability of sputum culture conversion (defined as conversion at or before Week 48 
and culture still negative at 12-weeks follow-up). 
• 
Durability of sputum smear conversion (defined as conversion at or before Week 48 
and smear still negative at 12-weeks follow-up). 
• 
Change in semi-quantitative grade of number of NTM on microscopy of AFB stained 
sputum smears from Baseline to Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 
and 12-week follow-up. 
• 
Change in semi-quantitative grade of sputum cultures from Baseline to Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 12-week follow-up.  
• 
Change in symptom scores (assessed using Lower Respiratory Tract Infections – 
Visual Analogue Scale (LRTI-VAS) and Quality of Life Questionnaire– Bronchiectasis 
(QOLB) from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 12-week follow-
up. 
• 
Change in Global Rating of Health (GRH) from Baseline to Weeks 4, 8, 12, 16, 20, 24, 
32, 40, 48 and 12-week follow-up. 
• 
Change in body weight from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and 
12-week follow-up. 
• 
Change in 6MWD, oxygen desaturation and Borg CR10 scores during a 6MWT from 
Baseline to Week 12, 24, 48 and 12-week follow-up. 
9.2 Variables 
 Primary Endpoint Variables 
• 
Sputum culture conversion during the treatment period defined as all available 
samples from three consecutive visits to be negative 
• 
The time of culture conversion: Defined as the time the first of three consecutive visits 
with 100% negative samples was obtained. Subjects with no conversion will be 
censored at the date of their last visit. 
 


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 Secondary Endpoint Variables 
• 
Sputum smear conversion: Defined as at least three consecutive visits with 100% 
negative AFB stained sputum smears on microscopy during the treatment period in 
subjects that were smear positive at Baseline. 
• 
Durability of sputum culture conversion: Defined as conversion at or before Week 48 
and culture still negative at 12-weeks follow-up (with no positives in between). 
• 
Durability of sputum smear conversion: Defined as conversion at or before Week 48 
and smear still negative at 12-weeks follow-up (with no positives in between). 
• 
Change from baseline in semi-quantitative grade of number of NTM on microscopy of 
AFB stained sputum smears 
• 
Change from baseline in semi-quantitative grade of sputum cultures (measured by 
time to positivity and exploratory quantitation of cultures) 
• 
Change from baseline in symptom scores 
o Lower Respiratory Tract Infections – Visual Analogue Score (LRTI-VAS) 
o Quality of Life Questionnaire – Bronchiectasis (QOL-B) 
• 
Change from baseline in Global Rating of Health (GRH) 
• 
Change from baseline in body weight 
• 
Change from baseline in 6MWD, oxygen desaturation and Borg CR10 scores 
9.3 Biostatistical methods 
 Primary Endpoint 
 Sputum Culture Conversion 
Sputum culture conversion data will be listed, including time of culture conversion. 
 
Sputum culture conversion rates (number of subjects who convert to negative out of the 
number per group) will be presented with 95% exact binomial confidence intervals. 
 
On the basis of the poor historical success rates of current standard therapy, a 30% response 
rate for the primary endpoint will be considered clinically relevant. 
 
Time to culture conversion will be evaluated using Kaplan Meier estimates, with 95% 
confidence intervals. 
 
 Sensitivity Analyses 
In a sensitivity analysis, culture conversion will be re-defined as requiring at least 2 samples 
are available from each of the three consecutive visits.   Sputum culture conversion rates and 
time to culture conversion will be analysed as part of this sensitivity analysis. 
 
 


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 Secondary Endpoints 
 Sputum Smear Conversion (Primary) 
Sputum smear conversion will be evaluated and presented in the same way as the primary 
endpoint for culture conversion.  
 
 Sputum Smear Conversion (Sensitivity) 
In a sensitivity analysis, smear conversion will be re-defined as requiring at least 2 samples 
are available from each of the three consecutive visits.   Sputum smear conversion rates and 
time to smear conversion will be analysed as part of this sensitivity analysis. 
 
 Mycobacterial Microscopy Grading  
Mycobacterial microscopy data will be listed for each sample, including AFB positivity and 
AFB semi-quantitative grading.  The listing will also include the overall visit AFB positivity and 
grading statuses.  Laboratory grading terminology will be re-named as detailed in Table 4.  
 
Table 4: Mycobacterial Microscopy Grading 
SNP 
RBH 
Cross-Tabulation 
No acid fast bacilli seen 
No AFB Seen 
Negative 
Acid fast bacilli – occasional 
Scanty AFB Seen +/- 
Scant 
Acid fast bacilli + 
Moderate AFB Seen 1+ 
1+ 
Acid fast bacilli ++ 
Moderate AFB Seen 2+ 
2+ 
Acid fast bacilli +++ 
 AFB Seen 3+ 
3+ 
Acid fast bacilli ++++ 
 
4+ 
 
The number of subjects who decrease over the scale (and proportion out of the number per 
group) will be presented with 95% exact binomial confidence intervals. 
 
A summary table will present continuous descriptive statistics of grade for each scheduled 
visit. 
 
 Mycobacterial Culture Grading  
Mycobacterial culture data will be listed for each sample, including culture positivity, culture 
semi-quantitative grading, time to detection in liquid media (MGIT) and organisms isolated.  
The listing will also include the overall visit AFB positivity and grading statuses. 
 
The following is noted: 
• 
MGIT and semi-quantitative grading will need to be extracted from the Comment 
column in the SNP data transfer.  
• 
Semi-quantitative grading is not available for mycobacterial culture data from RBH. 
 
For each scheduled visit, the number of subjects (and proportion out of the number per 
group) who report a decreased culture grade compared to Baseline will be presented with 
95% exact binomial confidence intervals. Where multiple samples were taken at a visit, the 
worst grade will be used for comparison to Baseline. 
 
A figure will present the mean change from baseline of semi-quantitative sputum culture 
grades, with error bars representing the standard deviation. 
 
 
 


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 Symptom Scores 
Symptoms scores (assessed using LRTI-VAS and QOL-B) will be listed for all subjects. 
 
Scoring of LRTI-VAS 
Separate scores will be calculated for each symptom and a total score will be calculated, 
consisting of all symptom scores added up, where the same weight is assigned to all 
symptom domains.  
 
Symptom and total scores will not be calculated for LRTI-VAS records with missing data. 
 
A summary table will present a summary of total scores, including actual values and change 
from Baseline, by group and overall, for all scheduled visits. 
 
Scoring QOL-B 
QOL-B data will be scored according to the Manual Scoring Instructions for QOL-B 
Version 3.1 and domain scores will be presented in a separate listing. 
 
A summary table will present a summary of domain scores, including actual values and 
change from Baseline, by group and overall, for all scheduled visits. 
 Global Rating of Health (GRH) 
Global Rating of Health (GRH) data will be listed for all subjects. 
 
A summary table will present a summary of actual values and change from Baseline, by 
group and overall, for all scheduled visits. 
 
 Body Weight 
Body weight will be listed for all subjects. 
 
A summary table will present a summary of actual values and change from Baseline, by 
group and overall, for all scheduled visits. 
 
 6 Minute Walk Test 
6 Minute Walk Test data, including distance walked (6MWD), oxygen saturation (SpO2) 
before and during the test as well as oxygen desaturation (delta SpO2) and Borg (CR-10) 
Dyspnoea scores before and after the test, will be listed for all subjects. 
 
A summary table will present a summary of actual values and change from Baseline, by 
group and overall, for all scheduled visits, for the following variables: 
• 
Dyspnoea Score (Borg CR-10) (pre and post walk) 
• 
Blood oxygen saturation (SpO2) pre walk 
• 
Worst SpO2 during the walk 
• 
Distance walked 
 
The proportion of subjects that complete all 6 minutes walking during the test will be 
summarised for all scheduled visits. 
 
Where the two scheduled 6MWT tests were performed at a given scheduled timepoint, the 
summary table will use the data from the assessment where the subject walked the longest 
distance. 
 
 


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10. SAFETY  
Analysis Set: Full Analysis Set (FAS) 
10.1 Safety Endpoints 
• 
Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment 
discontinuation during the trial period. 
• 
Change in WBC and differentials in blood from Baseline to Weeks 4, 12 24, 32, 40, 48 
and 12-week follow-up. 
• 
Change in DLCO from Baseline to Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48 and at 12-
week follow-up. 
• 
Change in forced expiratory volume in 1 second (FEV1) (% predicted) and forced vital 
capacity (FVC) (% predicted) from Baseline to Weeks 12, 24, 32, 40 and 48. 
• 
Development of anti GM-CSF antibodies at Week 4, 12, 24, 32, 48 and at 12-week 
follow-up. 
10.2 Adverse Events 
 Definition of variables 
• 
AE, any untoward medical occurrence in a subject or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with 
this treatment. 
• 
Treatment Emergent Adverse Event (TEAE), defined as an AE that commences on, or 
after, the date of the first administration of study drug until and including the day of the 
12-week Follow-up visit. 
• 
Serious Adverse Event (SAE), as defined in the protocol section 12.16: 
o Results in death 
o Is life-threatening 
o Requires hospitalization or prolongation of existing hospitalization 
o Results in persistent or significant disability or incapacity 
o Is a congenital anomaly or birth defect 
o May jeopardize the subject or may require intervention to prevent one or more 
of the other outcomes listed above (Important Medical Events) 
• 
Severity 
o Mild 
o Moderate 
o Severe 
• 
Outcome 
o Not Recovered 
o Recovered 
o Recovered with Sequelae 
o Fatal 
o Unknown 
• 
Causality, categorised as described in the protocol section 12.16: 
o Not applicable 
o Unlikely 
o Possible 
o Probable 
• 
Causality (Binary categorisation), where: 
o Not related = Not Related or Unlikely 
o Related = Possible or  Probable 
 
 


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• 
Actions taken with study drug 
o Dose delayed 
o Dose stopped 
o Treatment withdrawn 
• 
Other actions taken 
o Medical procedure 
o Medication administered 
o Other 
 Biostatistical methods 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  
 
All adverse events recorded during the study will be listed. All serious AE and AEs leading to 
treatment discontinuation and study withdrawal will be listed. 
 
Summary tables will be produced for treatment emergent adverse events (TEAEs). The 
number and percentage of subjects with adverse events by system organ class (SOC) and 
preferred term (PT) will be tabulated. Similar summaries will be produced by severity and 
relatedness.  
10.3 Deaths 
All details relating to subject deaths will be presented in a Death listing. 
10.4 Prior and Concomitant Medication 
Concomitant therapies will be coded using the World Health Organization-Drug Reference 
List (WHODRL).  
 
Prior and concomitant medications will be presented in separate listings.  Medications 
stopped on the same day as first study drug administration will be considered as prior 
medication only. Both prior and concomitant listings will flag antimycobacterial treatments and 
include data related to changes of the patient’s NTM treatment regimen and the reason for a 
change to patient’s NTM treatment regimen. 
 
Prior and concomitant medication summaries will be presented in separate tabulations, with 
data summarised by Anatomical Therapeutic Chemical (ATC) (Level 2) and Preferred Name 
(PN) using frequency counts and percentages. For the summaries of prior and concomitant 
medications, subjects who take the same medication (in terms of the PN) more than once will 
be counted only once for that medication. An additional concomitant medication table will be 
prepared to present antimycobacterial treatments. 
 
 


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10.5 Laboratory 
 Definition of variables 
 Hematology 
• 
Basophils (absolute and %) 
• 
MCV 
• 
Eosinophils (absolute and %) 
• 
Monocytes (absolute and %) 
• 
Hematocrit 
• 
Neutrophils (absolute and %) 
• 
Hemoglobin 
• 
Platelet count 
• 
Lymphocytes (absolute and %) 
• 
Red blood cell count (RBC) 
• 
MCH 
• 
Red Cell Distribution Width (RDW) 
• 
MCHC 
• 
White blood cell count (WBC) 
 
 Chemistry 
• 
Alanine Aminotransferase (ALT) 
• 
Glucose 
• 
Albumin 
• 
Lactate dehydrogenase (LDH) 
• 
Alkaline phosphatase 
• 
Phosphate 
• 
Aspartate Aminotransferase (AST) 
• 
Potassium 
• 
Calcium 
• 
S-Creatinine 
• 
Chloride 
• 
Sodium 
• 
C-Reactive Protein (CRP) 
• 
Total bilirubin 
• 
Estimated glomerular filtration rate 
(eGFR) 
• 
Total protein 
• 
Gamma Glutamyl Transpeptidase (GGT) • 
Urea 
 
 Urinalysis with Microscopy 
• 
Glucose 
• 
Protein 
• 
Microalbuminuria 
• 
Red Blood Cells (RBC) 
• 
pH 
• 
White Blood Cells (WBC) 
 
 Coagulation 
• 
PT-INR 
 
 Biostatistical methods 
All laboratory parameters will be listed with flags for values outside the reference ranges and 
values considered to be clinically significant. 
 
Each parameter will be summarised descriptively (including actual values and changes from 
baseline) for each scheduled visit. Shift tables will also be presented for hematology and 
chemistry variables. 
 
 


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10.6 Vital Signs 
 Definition of variables 
• 
Systolic Blood Pressure (SBP) (mmHg) 
• 
Diastolic Blood Pressure (DBP) (mmHg) 
• 
Heart rate (beats per minute) 
• 
Respiratory Rate (breaths per minute) 
• 
Body temperature (°C) 
 Biostatistical methods 
Vital sign parameters will be listed for all subjects and time points, including assessment 
(normal, abnormal) and clinical significance (clinically significant, not clinically significant). 
 
Observed values, as well as changes from baseline, will be summarised descriptively for all 
vital sign parameters for each planned assessment.   
10.7 Body Measurements 
 Definition of variables 
• 
Weight (kg)  
• 
Height (cm) (Baseline only) 
 Biostatistical methods 
Height and weight will be listed for all subjects and time points.   
 
Refer to Section 9.3.2.6 regarding presentation of post-Baseline weight data. 
10.8 Physical Examination 
 Definition of variables 
• 
General appearance 
• 
Abdomen 
• 
HEENT (Head, Eyes, Ears, Nose, 
Throat) 
• 
Extremities 
• 
Neck 
• 
Dermatological 
• 
Cardiovascular 
• 
Neurological 
• 
Respiratory 
• 
Other 
 Biostatistical methods 
Physical examination data will be listed for all subjects and time points. 
 
 


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10.9 12-lead ECG 
 Definition of variables 
• 
Heart rate (beats/minute) 
• 
QRS interval (msec) 
• 
PR interval (msec) 
• 
QT interval (msec) 
• 
ECG status (Normal/Abnormal) (Clinical significance will be flagged where abnormal) 
 Biostatistical methods 
ECG parameters will be listed for all subjects and time points. 
 
Observed values  and change from baseline will be summarised descriptively for all ECG 
parameters for all planned assessments.   
10.10 Pulmonary Function Tests 
 DLCO 
DLCO data, including predicted DLCO and absolute DLCO will be listed. Predicted DLCO 
and average absolute DLCO measurement will be descriptively summarised by visit, 
including change from baseline. Percent predicted DLCO will be calculated as: 
 
% 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 = 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑥𝑥 100 
 Spirometry 
Spirometry data, including Absolute Forced Expiratory Volume in 1 second (FEV1) and 
Absolute Forced Vital Capacity (FVC), will be listed. FEV1 and FVC will be descriptively 
summarised by visit, including change from baseline. 
 
Percent predicted FVC and FEV1 will be calculated using the GLI-2012 SAS Macro.   
Baseline height will be used for all derivations. 
10.11 Radiology 
 CT Scan 
CT scan data will be listed. 
 Chest X-Ray 
Chest x-ray data will be listed. 
10.12 Pregnancy Test 
Pregnancy test data will be listed. 
 
 


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11. IMMUNOGENICITY 
Analysis Set: Full Analysis Set (FAS) 
11.1 Definition of variables 
• 
Anti-GM-CSF antibodies 
• 
Neutralising antibodies 
11.2 Biostatistical methods 
All immunogenicity data will be listed. 
 
The incidence of anti-GM-CSF antibodies and neutralising antibodies in each treatment group 
by visit will be summarised by frequency counts and percentages (in a cumulative manner). 
Individual titre profiles will also be plotted by group. 
12. HANDLING OF MISSING DATA 
Only recorded data will be analysed/presented and any subjects who have missing data will 
only have observed data reported, with no imputation for missing data. 
13. CHANGES TO THE PLANNED ANALYSIS 
The following changes to the biostatistical methods planned in the protocol are defined below: 
 
• 
The 5x5 cross-tabulation summaries of the semi-quantitative grading described in 
Section 13.2 of the protocol (Secondary Endpoints) has been replaced with 
alternative summary tabulations, in order to present the data in a clearer and 
useful way. 
13.1 Interim Analysis 
An interim analysis was not initially planned, nor incorporated into the protocol. A planned 
interim analysis was subsequently added. 
14. INTERIM AND FINAL ANALYSIS 
An interim analysis is planned for this study, focusing primarily on the microbiology data up to 
Week 16.  
 
The following endpoints will be assessed: 
• 
Sputum culture negative samples during the treatment period up to week 16, 
• 
Sputum smear conversion, defined as at least three consecutive negative AFB stained 
sputum smears on microscopy during the treatment period (up to Week 16) in subjects who 
were smear positive at Baseline, 
• 
Change in semi-quantitative grade of number of NTM on microscopy of AFB stained sputum 
smears from Baseline to Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 12-week 
follow-up.   
• 
Change in semi-quantitative grade of sputum cultures from Baseline to Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48 and 12-week follow-up. 
  
Safety data (Adverse Events and laboratory data) will also be reviewed. 
15. SOFTWARE 
The following software will be used to perform the statistical analyses: SAS® Version 9.4 or 
higher (SAS Institute, Cary, North Carolina, USA). 


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16. REFERENCES 
1) 
Clinical Trial Protocol SAV008-01, Version 4.0, 4th Oct 2018 
2) 
GLI-2012 - SAS Macro; Quanjer et al., GLI Spiro Eur Respir J. 2012 Dec 40(6):1324-43; 
Macro Version 2 - April 7, 2013 (https://www.ers-education.org/guidelines/global-lung-
function-initiative/spirometry-tools/sas-macro.aspx) 
3) 
Manual Scoring Instructions for QOL-B Version 3.1 
 
 


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17. APPENDIX 1: QOL-B SCORING MANUAL 
 
 
Manual Scoring Instructions for QOL-B Version 3.1 
 
 
Step 1: Item-by-item responses 
 
The values assigned to participants’ responses for each question are listed below.  
Enter them on the Item-by-Item Worksheet. 
 
 For questions 1 – 4: A lot of difficulty = 1, Moderate difficulty = 2, A little 
difficulty = 3,  No difficulty = 4 
 For questions 5 – 11: Always = 1, Often = 2, Sometimes = 3, Never = 4 
 For questions 12 – 15: Use the assigned number designated for each specific 
response 
 For questions 16 – 26: Completely true = 1, Mostly true = 2, A little true = 3, 
Not at all true = 4 
 For question 27: Use the assigned number designated for each specific 
response 
 For question 28: Always = 1, Often = 2, Sometimes = 3, Never = 4 
 For questions 29 – 31: A lot = 1, A moderate amount = 2, A little = 3, 
Not at all = 4 
 For question 32: Clear = 1, Clear to yellow = 2, Yellowish-green = 3, 
Brownish-dark = 4, Green with traces of blood = 4, Don’t know = 6 
 For questions 33 – 37: Always = 1, Often = 2, Sometimes = 3, Never = 4 
 
Step 2: Scoring multiple responses or skipped questions 
 
If two responses are marked and there is no opportunity to ask the respondent which 
one is correct, the worst response should be selected for data entry and scoring.  
This provides a conservative estimate of their response to this item.  For example, 
item #29 asks: “Have you felt congestion in your chest?”  The response choices 
range from “A lot” to “Not at all.”  If the respondent marks “a lot” and “a moderate 
amount” you should enter “a lot” for this question. 
 
Please note that some items are reverse-keyed and therefore, the worst response is 
not necessarily the lower number. 
 
If participants skip a question, do not assign a response value (i.e. leave it blank). 
 
 
 
 
 
 


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Step 3: Scaling item 32 and reverse coding 
 
Item 32 (resp32) has 5 possible answers that are scored and all other items on the 
QOL-B questionnaire have only 4 possible answers.  Possible scores for resp32 are 
1, 2, 3, 4, 5 (scored as 4) and 6 (not scored), whereas for other questions the 
possible scores are 1, 2, 3, and 4.  Resp32 and eight other items are also reverse 
coded; because of the wording for these particular items, reverse coding is necessary 
to make higher scores correspond to better health outcomes.  Reverse coding is 
conducted for resp32, and for health5, vital8, treat12, treat14, health15, role20, 
health24, and role27.  These items are marked with an asterisk on the Item-by-Item 
Worksheet and the reverse-coded values are shown in the box on the worksheet. 
 
For item 32:  
 
Original value = Reverse-coded value 
 
1 = 4 
2 = 3 
3 = 2 
4 = 1 
6 = Not scored 
 
For item 19: 
 
“doesn’t apply” = Not scored 
 
For items 5, 8, 12, 14, 15, 20, 24, 27:  
Original value = Reverse-coded value 
1 = 4 
2 = 3 
3 = 2 
4 = 1 
 
Step 4: Preparing to calculate scaled scores and missing values 
 
Transfer the values from the Item-by-Item Worksheet to the Scaled Score Worksheet.  
For reverse-coded items, use the reverse-coded values.  Do not enter any values for 
missing responses; leave the line blank.  If the responses are missing for more than 
half the items in a scale, the score for that scale should not be calculated.  Missing 
values are not imputed.  Note that missing responses within a scale will change the 
number of points corresponding to a change of one answer category for one item for 
that respondent. 
 
Step 5: Calculate the scaled scores 
 
Calculate scores for the eight QOL-B domains using the formulas on the Scaled 
Score Worksheet.  Note that a total QOL-B score is not calculated. 


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Item-by-Item Worksheet 
Numbers correspond to items on the QOL-B Version 3.1 questionnaire.  Fill in the 
values using the scoring rules described in steps 1 – 3. 
 
 
 
1.   _____ 
 
 
 
 
 
 
 
34. _____ 
2.   _____ 
 
 
 
 
 
 
 
35. _____ 
3.   _____ 
 
 
 
 
 
 
 
36. _____ 
4.   _____ 
 
 
 
 
 
 
 
37. _____ 
5.*  _____=_____ 
 
 
 
 
 
 
 
6.   _____ 
 
 
 
 
 
 
 
 
7.   _____ 
 
 
 
 
 
 
 
 
8.*  _____=_____ 
 
 
 
 
 
 
 
9. _____ 
 
 
 
 
 
 
 
 
10. _____ 
 
 
 
 
 
 
 
 
11. _____ 
 
 
 
 
 
 
 
 
12.*_____=_____  
 
 
 
 
 
 
13. _____ 
 
 
 
 
 
 
 
 
14.*_____=_____  
 
 
 
 
 
 
15.*_____=_____  
 
 
 
 
 
 
16. _____ 
 
 
 
 
 
 
 
17. _____ 
18. _____ 
19. _____ 
20.*_____=_____ 
21. _____ 
22. _____ 
23. _____ 
24.*_____=_____ 
25. _____ 
26. _____ 
27.*_____=_____ 
28. _____ 
29. _____ 
30. _____ 
31. _____ 
32.*_____=_____ 
33. _____ 
 
 
 
 
*Reverse-Coded Values 
For items 5, 8, 12, 14, 15, 20, 24, 27: 
Original Value = Reverse-Coded Value 
1 = 4 
2 = 3 
3 = 2 
4 = 1 
For item 32:  
 
Original Value = Reverse-Coded Value 
1 = 4 
2 = 3 
3 = 2 
4 = 1 
6 = Not scored 
 


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Scaled Scores Worksheet – Page 1 of 3 
 
Enter the values from the Item-by-Item Worksheet.  Use the reverse-coded values, if 
applicable.  Do not enter any values for missing responses; leave the line blank.  
Assess the number of missing values and calculate scores as described in Steps 4 
and 5 (see page 2). 
 
 
Physical Functioning Domain (5 items) 
  1.  _____ 
  2.  _____ 
  3.  _____ 
  4.  _____ 
16.  _____ 
 
If 3 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
Role Functioning Domain (5 items) 
17.  _____ 
20.  _____ 
25.  _____ 
27.  _____ 
28.  _____ 
 
If 3 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
Vitality Domain (3 items) 
6.  _____ 
8.  _____ 
9.  _____ 
 
If 2 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
 
 
 
 


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Scaled Scores Worksheet – Page 2 of 3 
 
Emotional Functioning Domain (4 items) 
  7.  _____ 
10.  _____ 
11.  _____ 
23.  _____ 
 
If 3 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
Social Functioning Domain (4 items) 
18.  _____ 
19.  _____ (* “doesn’t apply” = Not scored) 
22.  _____ 
26.  _____ 
 
If 3 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
Treatment Burden Domain (3 items) 
12.  _____ 
13.  _____ 
14.  _____ 
 
If 2 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
Health Perceptions Domain (4 items) 
  5.  _____ 
15.  _____ 
21.  _____ 
24.  _____ 
 
If 3 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 


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Scaled Score Worksheet – Page 3 of 3 
 
Respiratory Symptoms Domain (9 items) 
29.  _____ 
30.  _____ 
31.  _____ 
32.  _____ 
33.  _____ 
34.  _____ 
35.  _____ 
36.  _____ 
37.  _____ 
 
If 5 or more responses are missing, do not score this domain. 
Scaled score = [(( 
 
 
     )-1)/3] x 100 =  
 
 
      mean of responses 
 
Note: No total score is calculated. 
 
 


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SAS Programming Code for Scoring QOL-B V3.1 
 
Note: To enter data, refer to Step 1: Item-by-item responses, and for decision rules 
regarding multiple responses or skipped questions, refer to Step 2: Scoring multiple 
responses or skipped questions (see page 1). 
 
/*This scoring program requires that the data be imported into a SAS table titled 
"QOLB" and that the variable names in the table match those listed below.*/ 
 
Data QOLB; set QOLB; 
 
/* Rescaling Respiratory 32 */ 
if resp32=6 then resp32=.; 
else if resp32=1 then resp32= 4; 
else if resp32=2 then resp32= 3; 
else if resp32=3 then resp32= 2; 
else if resp32=4 then resp32= 1; 
else if resp32=5 then resp32= 1; 
 
/* Rescaling “doesn’t apply” Social 19 */ 
if social19=5 then social19=.; 
 
/* Recoding Some Variables */ 
health5=5-health5; 
vital8=5-vital8; 
treat12=5-treat12; 
treat14=5-treat14;  
health15=5-health15; 
role20=5-role20;  
health24=5-health24; 
role27=5-role27; 
run;       
 
/* Calculating Scores */ 
 
Data QOLB; set QOLB;  
if nmiss (phys1, phys2, phys3, phys4, phys16) <= 2 then 
physical = (mean (phys1, phys2, phys3, phys4, phys16)-1)/3*100; 
 
if nmiss (role17, role20, role25, role27, role28) <= 2 then 
role = (mean (role17, role20, role25, role27, role28)-1)/3*100; 
 
if nmiss (vital6, vital8, vital9) <= 1 then 
vitality = (mean (vital6, vital8, vital9)-1)/3*100; 
 
if nmiss (emot7, emot10, emot11, emot23) <= 2 then 
emotion = (mean (emot7, emot10, emot11, emot23)-1)/3*100; 
 
if nmiss (social18, social19, social22, social26) <= 2 then 
social = (mean (social18, social19, social22, social26)-1)/3*100; 
 
if nmiss (treat12, treat13, treat14) <= 1 then 
treat = (mean (treat12, treat13, treat14)-1)/3*100; 
 
if nmiss (health5, health15, health21, health24) <= 2 then 
health = (mean (health5, health15, health21, health24)-1)/3*100; 
 
if nmiss (resp29, resp30, resp31, resp32, resp33, resp34, resp35, resp36, resp37) 
<= 4 then respirat = (mean (resp29, resp30, resp31, resp32, resp33, resp34, 
resp35, resp36, resp37)-1)/3*100; 
run;