Clinical trial NCT03597347
Conditions: Mycobacterium Infections, Nontuberculous Cystic Fibrosis (CF)
Keywords: Nontuberculosis mycobacterial infection Cystic fibrosis M. avium complex M. abscessus complex Mycobacterium Infections, Nontuberculous
Sponsor: Savara Inc.
Start date: 2019-06-20; Completion date: 2020-10-02
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the efficacy of inhaled molgramostim administered open-label to adult cystic fibrosis (CF) subjects with chronic pulmonary nontuberculous mycobacterial (NTM) infection, with or without ongoing antimycobacterial guideline based combination therapy.

Detailed description:
A Screening period will begin up to 10 weeks prior to the Baseline visit for collection of the sputum sample, but the remainder of the assessments including Safety labs will be completed within 6 weeks of Baseline, to determine eligibility. Adult participants with a history of CF and chronic pulmonary NTM infection will be considered for enrollment. Chronic pulmonary NTM infection will be defined by at least 3 positive NTM cultures (sputum or broncho-alveolar lavage (BAL)) for the same species/subspecies of mycobacterium avium (MAC) or mycobacterium abscessus complex (MABSC) within the 2 years prior to screening, with at least one positive within the past 6 months prior to screening and a minimum of 50% of NTM cultures positive over the past 2 years. Participants must additionally provide a positive sputum culture with the same species/subspecies obtained from the central laboratory during the Screening period to be eligible.

Three groups of participants will be recruited:

* Group 1: Participants with chronic pulmonary MAC or MABSC infection who have not consistently achieved negative NTM sputum cultures while currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 9 months prior to the Baseline visit.
* Group 2: Participants with chronic pulmonary MAC or MABSC infection 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.
* Group 3: Participants with chronic pulmonary MAC or MABSC infection not meeting recommendations for treatment with a multidrug NTM guideline-based antimycobacterial regimen based on failure to meet American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria for NTM pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond what is expected from underlying CF).

All participants will have Screening, Baseline, Week 1, 2 and followed by monthly Treatment visits from week 4 during the Treatment period. The Treatment period will be 48 weeks. Following the End of Treatment (Week 48), subjects will have a Follow-up visit at 4 and 12 weeks, and the End of Study visit 24 weeks after the End of Treatment. At the Baseline visit, eligible participants will start treatment with inhaled molgramostim.

At each visit any changes in concomitant medication will be recorded. Participants will be encouraged to contact the clinic between visits if they experience adverse events (AE), worsening of their condition or have any other concerns. If needed, unscheduled visits will be conducted at the Investigator's discretion. All participants will be maintained on their standard CF treatment and medications independent of NTM treatment status.

Treatment with inhaled molgramostim will be given at a dosage of 300 μg once daily for 48 weeks. Dosing will be done in the morning, after completion of the subject's normal airway clearance routine, where medications should be taken in the following order: bronchodilator, dornase alfa (Pulmozyme), inhaled antibiotics (e.g. TOBI) and lastly inhaled molgramostim.

Participants on a cyclical on-off anti-Pseudomonal regimen will have their trial visits (Baseline and subsequent visits in the Treatment Period) scheduled during a week after at least three weeks off treatment or after at least one week on-treatment of the antibiotic. Participants on a continuous inhaled regimen, including continuous alternating therapy (CAT), should have been on a stable regimen for at least 28 days prior to Baseline.

A data review will be conducted after the first 6 participants have completed 12 weeks of treatment. If safety concerns or poor tolerability are identified in this review, the review committee may decide on less frequent dosing for subsequent participants in the study. Additional safety reviews will be conducted at regular intervals thereafter. During the study, participants in Group 1 will continue use of antimycobacterial treatment, whereas participants in Groups 2 and 3 will receive inhaled molgramostim as monotherapy for their NTM infection. For participants in Group 1, the antimycobacterial therapy should preferably not change during the treatment period except in case of drug toxicity or adverse reactions. Antibiotics discontinued due to toxicity may be replaced, with drug selection and dose modification at the discretion of the treating physician. All changes in antimycobacterial treatment will be recorded, including reasons for each change. In the event the Investigator has evidence of infection while on treatment which requires more intensive therapy (i.e. additional antibiotics in Group 1 or addition of antibiotics to Group 2 or 3) the participant may be allowed to continue after discussion with the Sponsor medical monitor.

No formal sample size calculation was done as this is an initial pilot study. To be able to assess response in each of the three groups, a minimum of 8 participants with MAC or MABSC will be enrolled into each of the 3 groups, and a minimum of 30 participants will be enrolled across all 3 groups. The maximum number of participants enrolled into each group will be 12, and the maximum number of participants enrolled into the study will be 34.

Arms: arm 1: Participants with chronic pulmonary MAC or MABSC infection who have not consistently achieved negative NTM sputum cultures while currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 9 months prior to the Baseline visit. arm 2: Participants with chronic pulmonary MAC or MABSC infection 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. arm 3: Participants with chronic pulmonary MAC or MABSC infection not meeting recommendations for treatment with a multidrug NTM guideline-based antimycobacterial regimen based on failure to meet American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria for NTM pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond what is expected from underlying CF).
Interventions: intervention 1: Molgramostim nebulizer solution intervention 2: PARI eFlow nebulizer system
Intervention descriptions: intervention 1: 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation intervention 2: PARI eFlow nebulizer system

Protocol documents:
Prot_000.pdf: 
 
 
 
MOLGRAMOSTIM NEBULIZER SOLUTION 
 
CLINICAL TRIAL PROTOCOL 
 
SAV008-02 
 
An OpEn-label, Non-controlled, MultiCenter, PilOt Trial, using Inhaled 
Molgramostim in Cystic FibRosis Subjects with Nontuberculous Mycobacterial 
(NTM) InfEction 
(ENCORE) 
 
 
Product Name: 
Molgramostim Nebulizer Solution 
(Molgradex®) 300 µg 
Indication: 
Pulmonary NTM infection  
Phase: 
IIA 
EudraCT No. 
IND Number: 
N/A 
139376 
Sponsor: 
Savara Inc 
6836 Bee Cave Road, Building 3, Suite 200 
Austin, TX, 78746 
United States  
Date of Protocol: 
12-DEC-2019 
 
Version: 
3.0 
 
 
 


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Protocol Signature Page 
This Clinical Trial Protocol is approved by: 
 
BIOSTATISTICIAN 
 
 
 
 
Date: 
Lars Korsholm, PhD 
Director, Biostatistics 
Savara Aps. 
 
 
 
SPONSOR TRIAL MANAGER 
 
 
 
 
Date: 
Amy Beasley, MPH 
Manager, Clinical Operations 
Savara Inc.  
 
 
 
SPONSOR MEDICAL EXPERT 
 
 
 
 
Date: 
Maj Dinesen, MD 
Director, Clinical Development, Savara ApS 
Slotsmarken 17, 2th,  
2970 Hørsholm, Denmark 
+45 7930 1414  
 
 
 
 
 


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PROTOCOL AGREEMENT 
 
 
Protocol Title: 
An Open-label, Non-controlled, Multicenter, Pilot Trial, using Inhaled 
Molgramostim in Cystic Fibrosis Subjects with Nontuberculous Mycobacterial 
(NTM) Infection 
 
Trial Code: 
SAV008-02 
Protocol Version: 
3.0 
Protocol Date: 
12DEC2019 
 
I confirm that I have received the abovementioned protocol.   
By signing below, and in accordance with ICH GCP, I confirm that I: 
• 
Will personally conduct or supervise the trial 
• 
Will ensure that the trial is conducted in compliance with ICH GCP 
• 
Assume responsibility for the proper conduct of the trial in accordance with the approved 
protocol 
• 
Will ensure that site staff assisting with the trial are adequately informed about this protocol  
• 
Will maintain adequate and accurate source documents and trial records, and will make those 
records available for inspection and audit 
 
 
 
Investigator Signature  
 
 
 
Date of Signature  
Investigator Printed Name 
 
Site Number 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Savara Inc. 
Name of Investigational Product: 
Molgramostim nebulizer solution (Molgradex®) 
Name of Active Ingredient: 
Molgramostim (recombinant human Granulocyte Macrophage Colony Stimulating Factor 
[rhGM-CSF]) 
Title of Study: An Open-label, Non-controlled, Multicenter, Pilot Trial, using Inhaled Molgramostim 
in Cystic Fibrosis Subjects with Nontuberculous Mycobacterial (NTM) Infection 
Study center(s): A sufficient number of centers located in, but not necessarily limited to, the United 
States of America (USA). 
US Lead Investigator:  Jerry A. Nick, MD, National Jewish Health, Denver, CO. 
Study period:  
Trial duration for each subject is 72 weeks (48 weeks 
Treatment period and 24 weeks Follow-up period) 
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 pulmonary function. 
• 
To investigate efficacy of inhaled molgramostim on patient reported outcomes. 
• 
To investigate efficacy of inhaled molgramostim on body mass index (BMI). 
• 
To investigate safety of inhaled molgramostim in subjects with NTM infection 
Exploratory: 
• 
To investigate efficacy in subjects infected with M. abscessus complex (MABSC) and M. 
avium complex (MAC), respectively. 
• 
To investigate efficacy in subjects on concurrent anti-mycobacterial treatment and subjects 
not on anti-mycobacterial treatment, respectively. 
• 
To investigate rates of recurrence and reinfection after End of Treatment. 
• 
To investigate efficacy of inhaled molgramostim on bacterial co-infections. 


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• 
To investigate efficacy of inhaled molgramostim on frequency of pulmonary exacerbations. 
• 
To investigate efficacy of inhaled molgramostim on morphologic findings on computed 
tomography (CT) scans of the lung. 
Methodology:  
The Screening period will begin up to 10 weeks prior to the Baseline visit for collection of the sputum 
sample, but the remainder of the assessments including safety labs will be completed within 6 weeks 
of Baseline, to determine eligibility. Adult subjects with a history of cystic fibrosis (CF) and chronic 
pulmonary NTM infection will be considered for enrollment. Chronic pulmonary NTM infection will 
be defined by at least three positive NTM cultures (sputum or broncho-alveolar lavage (BAL)) for the 
same species/subspecies of MAC or MABSC within the 2 years prior to screening, with at least one 
positive within the past 6 months prior to screening and a minimum of 50% of NTM cultures positive  
over the past 2 years. Subjects must additionally provide a positive sputum culture with the same 
species/subspecies obtained from the central laboratory during the Screening period to be eligible 
Three groups of subjects will be recruited: 
• 
Group 1: Subjects with chronic pulmonary MAC or MABSC infection who have not 
consistently achieved negative NTM sputum cultures while currently on a multidrug 
NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 
9 months prior to the Baseline visit. 
• 
Group 2: Subjects with chronic pulmonary MAC or MABSC infection  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. 
• 
Group 3: Subjects with chronic pulmonary MAC or MABSC - infection not meeting 
recommendations for treatment with a multidrug NTM guideline-based antimycobacterial 
regimen based on failure to meet American Thoracic Society/Infectious Diseases Society 
of America (ATS/IDSA) criteria for NTM pulmonary disease (i.e. absence of radiologic 
findings and clinical symptoms beyond what is expected from underlying CF).  
All subjects will have Screening, Baseline, Week 1, 2 and followed by monthly Treatment visits from 
week 4 during the Treatment period. The Treatment period will be 48 weeks. Following the End of 
Treatment (Week 48), subjects will have a Follow-up visit at 4 and 12 weeks, and the End of Study 
visit 24 weeks after the End of Treatment. At the Baseline visit, eligible subjects will start treatment 
with inhaled molgramostim.   A detailed Schedule of Assessments is outlined in Table 1. At each visit 
any changes in concomitant medication 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. If needed, unscheduled visits will be conducted at the Investigator’s 
discretion. All subjects will be maintained on their standard CF treatment and medications 
independent of NTM treatment status.    
Treatment with inhaled molgramostim will be given at a dosage of 300 µg once daily for 48 weeks. 
Dosing will be done in the morning, after completion of the subject’s normal airway clearance 
routine, where medications should be taken in the following order: bronchodilator, dornase alfa 
(Pulmozyme), inhaled antibiotics (e.g. TOBI) and lastly inhaled molgramostim.  


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Subjects on a cyclical on-off anti-Pseudomonal regimen will have their trial visits (Baseline and 
subsequent visits in the Treatment Period) scheduled during a week after at least three weeks off-
treatment or after at least one week on-treatment of the antibiotic. Subjects on a continuous inhaled 
regimen, including continuous alternating therapy (CAT), should have been on a stable regimen for at 
least 28 days prior to Baseline. 
A data review will be conducted after the first 6 subjects have completed 12 weeks of treatment. If 
safety concerns or poor tolerability are identified in this review, the review committee may decide on 
less frequent dosing for subsequent subjects in the study. Additional safety reviews will be conducted 
at regular intervals thereafter. During the study, subjects in Group 1 will continue use of 
antimycobacterial treatment, whereas subjects in Groups 2 and 3 will receive inhaled molgramostim 
as monotherapy for their NTM infection. For subjects in Group 1, the antimycobacterial therapy 
should preferably not change during the treatment period except in case of drug toxicity or adverse 
reactions. Antibiotics discontinued due to toxicity may be replaced, with drug selection and dose 
modification at the discretion of the treating physician. All changes in antimycobacterial treatment 
will be recorded, including reasons for each change. In the event the Investigator has evidence of 
infection while on treatment which requires more intensive therapy (i.e. additional antibiotics in 
Group 1 or addition of antibiotics to Group 2 or 3) the subject may be allowed to continue after 
discussion with the Sponsor medical monitor. 
Number of subjects (planned):  
No formal sample size calculation was done as this is an initial pilot study. To be able to assess 
response in each of the three groups, a minimum of 8 subjects with MAC or MABSC will be enrolled 
into each of the 3 groups, and a minimum of 30 subjects will be enrolled across all 3 groups.  The 
maximum number of subjects enrolled into each group will be 12, and the maximum number of 
subjects enrolled into the study will be 34.  


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Diagnosis and main criteria for inclusion: 
Inclusion Criteria:  
1. Written informed consent obtained from participant. 
2. Confirmed diagnosis of CF according to the Cystic Fibrosis Foundation (CFF) 2017 
Consensus Guidelines.  
3. History of chronic pulmonary infection with M. avium complex (MAC) or M. abscessus 
complex (MABSC) (defined as at least three positive NTM cultures (sputum or BAL for the 
same species (MAC) or subspecies (MABSC) within the 2 years prior to the screening visit, 
with at least one positive within the past 6 months and a minimum of 50% of NTM cultures 
positive over the past 2 years) that does not demonstrate response to current treatment course 
based on decreasing NTM burden or frequency of positive cultures, and in the opinion of the 
Investigator is unlikely to resolve with current treatment course. 
4. Subject fulfills criteria for inclusion in one of the following groups: 
• 
Group 1:  Subject with chronic pulmonary MAC or MABSC infection currently on a 
multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing for 
at least 9 months prior to the Baseline visit. 
• 
Group 2:  Subject with chronic pulmonary MAC or MABSC infection who has 
stopped a multidrug NTM guideline-based antimycobacterial regimen at least 28 days 
prior to Screening due to lack of response or intolerance. 
• 
Group 3:  Subjects with chronic pulmonary MAC or MABSC - infection not meeting 
recommendations for treatment with a multidrug NTM guideline-based antimycobacterial 
regimen based on failure to meet ATS/IDSA criteria for NTM pulmonary disease (i.e. 
absence of radiologic findings and clinical symptoms beyond what is expected from 
underlying CF).  
5. Ability to produce sputum or be willing to undergo an induction protocol that produces 
sputum for clinical evaluation. 
6. An additional sputum culture performed by the central laboratory, which is positive for the 
same species (MAC) or subspecies (MABSC) of NTM as before the trial within 10 weeks of 
Baseline.  
7. CF which in the Investigator’s opinion is clinically stable and not expected to require lung 
transplantation within the next year.  
8. FEV1 ≥ 30% of predicted at screening that is normalized for age, gender, race, and height, 
using the Global Lung Function Initiative (GLI) equation. 
9. Subjects who are co-infected with a respiratory pathogen, e.g.  P. aeruginosa or S. aureus, 
must either be stable on a regular suppression antibiotic regimen or must be, in the opinion of 
the Investigator, stable despite the lack of such treatment. 
10. Female or male ≥18 years of age. 
11. If female, subjects 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) during and until 30 days after last 


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dose of trial treatment, having 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.  
For purposes of this study, the Sponsor defines “acceptable methods of contraception” as: 
• 
Oral birth control pills administered for at least 1 monthly cycle prior to administration of 
the study drug. 
• 
A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior to 
the study drug administration but not beyond the 4th successive year following insertion. 
• 
Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 monthly cycle 
prior to study drug administration. 
• 
Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 
1 monthly cycle prior to administration of the study drug and continuing through 1 month 
following study completion. 
• 
Hysterectomy or surgical sterilization. 
• 
Vasectomized partner 
• 
Abstinence. 
Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive foam) 
is not considered an acceptable form of contraception.  
 
NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal 
contraceptive exposure, reducing the effectiveness and increasing the incidence of 
menstruation-associated adverse reactions. Hormonal contraceptives, including oral, 
injectable, transdermal, and implantable, should not be relied upon as an effective method of 
contraception when co-administered with Orkambi. 
 
12. If male, subjects who, if sexually active of reproductive potential and non-sterile (i.e., male 
who has not been sterilized by vasectomy for at least 6 months and not diagnosed with 
infertility through demonstration of azoospermia in a semen sample and/or absence of vas 
deferens through ultrasound) are willing to use a barrier method of contraception, or their 
female partner must use an acceptable method of contraception, during the study and until 
30 days after last dose of medication. 
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
trial procedures specified in the protocol as judged by the Investigator. 
Exclusion criteria: 
1. Use of non-maintenance antibiotic for a concurrent pulmonary or extrapulmonary infection 
within 28 days prior to the Baseline visit. 
2. Use of a maintenance antibiotic regimen containing azithromycin for a concurrent non-NTM 
pulmonary infection within 28 days prior to the Baseline visit. For subjects in Group 1, 
azithromycin is allowed if part of ongoing multidrug NTM guideline-based antimycobacterial 
regimen. 


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3. Prior therapy with inhaled or systemic granulocyte macrophage colony stimulating factor 
(GM-CSF). 
4. Subjects with hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to Screening. 
5. Life expectancy of less than 6 months according to Investigator’s judgement. 
6. History of, or present, myeloproliferative disease, leukemia or other hematological 
malignancy. 
7. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring 
chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during the 
study period. 
8. Active autoimmune disorder or other condition requiring therapy associated with significant 
immunosuppression, e.g such as systemic corticosteroids at a dose equivalent of 10 mg/day or 
more of prednisolone or other significant immunosuppressant medications, within 3 months 
prior to Screening or anticipated during the study period.  Inhaled or topical corticosteroids, 
or brief courses (< 14 days) of systemic corticosteroids for pulmonary exacerbations or other 
self-limited conditions are permitted. 
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications, or 
changes in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, 
within 28 days prior to the Baseline visit. 
10. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening. 
11. History of human immunodeficiency virus (HIV) infection or other disease associated with 
significant immunodeficiency. 
12. History of lung or other solid organ transplantation or currently on the list to receive lung or 
other solid organ transplantation. 
13. History of congestive heart failure (CHF) New York Heart Association (NYHA) Class III or 
greater in severity. 
14. History of cardiovascular ischemic event within 6 months of Baseline. 
15. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to 
Screening. 
16. Treatment with any investigational medicinal product within 28 days of Screening. 
17. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product. 
18. Any other condition that, in the opinion of the Investigator, would preclude informed consent 
or assent, make study participation unsafe, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives. 
Investigational product, dosage and mode of administration:  
Investigational Medicinal Product (IMP): Molgramostim nebulizer solution 
Active Substance: Molgramostim (rhGM-CSF) 


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Pharmaceutical form: Nebulizer solution  
Dosage: 300 µg once daily 
Route of administration: Inhalation 
Inhalation device: Investigational eFlow Nebulizer System (PARI Pharma GmbH) 
Duration of treatment:  
Treatment will be given for 48 weeks. 
Reference therapy, dosage and mode of administration:  
Not applicable 
 
 
Efficacy: 
Primary Endpoint: 
• 
NTM sputum culture conversion to negative (defined as at least three consecutive 
negative mycobacterial cultures collected at least 4 weeks apart during the Treatment 
period). 
Secondary Endpoints: 
• 
NTM sputum culture microbiological cure (defined as multiple consecutive negative but 
no positive cultures with the causative species after last culture conversion and until the 
End of Treatment (Week 48). 
• 
Time to first NTM sputum culture conversion during the Treatment period. 
• 
Sputum smear conversion to negative (defined as at least three consecutive negative acid-
fast bacilli (AFB) stained sputum smears on microscopy, collected at least 4 weeks apart 
in subjects who were smear positive at Baseline) during the Treatment period. 
• 
Consistent sputum smear conversion to negative (defined as multiple consecutive 
negative but no positive smears after last smear conversion and until the End of 
Treatment (Week 48) in subjects who were smear positive at Baseline). 
• 
Time to first NTM sputum smear conversion during the Treatment period. 
• 
Durable NTM sputum microbiological cure for the NTM isolate(s) treated without 
recurrence at Week 12 after End of Treatment. 
• 
Durable NTM sputum smear conversion to negative without subsequent positive smears 
at Week 12 after End of Treatment. 
• 
Change in semi-quantitative grade of number of NTM on microscopy of AFB stained 
sputum smears from Baseline to End of Treatment and Week 12 after End of Treatment. 
• 
Absolute change in FEV1 (percent predicted) from Baseline to End of Treatment and 
Week 12 after End of Treatment. 


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• 
Change in respiratory domain score assessed by Cystic Fibrosis Questionnaire-Revised 
(CFQ-R) from Baseline to End of Treatment and Week 12 after End of Treatment. 
• 
Change in BMI from Baseline to End of Treatment and Week 12 after End of Treatment. 
Exploratory Endpoints: 
• 
Change from Baseline in time to positivity on NTM liquid culture media at Treatment 
visits and Follow-up.  
• 
Change in semi-quantitative grade of sputum cultures from Baseline to Treatment visits 
and Follow-up. 
• 
Number of subjects with recurrence (re-emergence of the treated NTM species after End 
of Treatment), or reinfection (emergence of a different NTM species, after End of 
Treatment). 
• 
Eradication and/or reduction in bacterial load of co-infections in sputum. 
• 
Frequency of pulmonary exacerbations compared to the previous year. 
• 
Change in CFQ-R domains scores for physical functioning, vitality, health perceptions, 
treatment burden, role functioning, emotional functioning, and social functioning. 
• 
Change in CT scans of the lung from Baseline to End of Treatment (Week 48). 
Safety: 
• 
Number of AEs, serious adverse events (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 
Treatment visits. 
• 
A clinically significant decrease in FEV1 (% predicted) from Baseline to Treatment visits 
that does not respond to typical CF treatment (including treatment of pulmonary 
exacerbation if suspected) and in the judgement of the Investigator is not due to typical 
complication of CF (i.e. acute pulmonary exacerbation).  
• 
GM-CSF levels during Treatment period. 
• 
Development of anti-drug antibodies during Treatment period and Follow-up period. 
Methods of Assessment 
Microbiological characterization and quantification – Microbiological assessments will be conducted 
at a specialized central laboratory. Sputum culture will be done on liquid and solid media to confirm 
growth or absence of growth of NTM. The time to positivity on liquid media and semi-quantitative 
assessment of bacterial load will be explored.  
Samples will additionally be stored for potential quantitative polymerase chain reaction (PCR) 
analysis. These data may be reported separately, outside of the clinical trial report. 
Identification to NTM species level (MAC) or subspecies (MABSC) will be conducted on positive 
samples using established methods. Isolates from selected samples may further be subject to 
molecular identification to the subspecies level, and whole genome sequencing to track potential 


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polyclonal infections and/or new acquisition of NTM infection during the follow-up period as part of 
a separate research protocol. These data may be reported separately, outside of the clinical trial report. 
Using AFB staining (Fluorescence and/or Ziehl–Neelsen [ZN] stain), NTM in sputum will be 
identified and a semi-quantitative assessment of bacterial load (graded as 0, scant, 1+, 2+, 3+) will be 
conducted.  
Routine CF bacteriology and fungal culture will be done locally on one sputum sample per visit. 
Subject Reported Outcomes – clinical symptoms will be assessed using the CFQ-R questionnaire. 
Radiology CT scans of the lung will be conducted per institutional standard of care technique, and 
images - will be uploaded into the eCRF. A scoring system for central reading of the scans will be 
defined at a later timepoint. If a chest X-ray 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. 
PK and Anti-drug antibodies – A specialized central laboratory will be used for analysis of GM-CSF 
levels and anti-drug antibodies.  
Pulmonary function testing (PFT) –Spirometry will be performed and in accordance with the current 
ATS recommendations for the performance and interpretation of tests.  
Participants who routinely use bronchodilators should use them consistently throughout the study. 
Standard guidelines are noted below as a reference:  
• 
Participants who routinely use short acting inhaled bronchodilators should use them 
15 minutes to 2 hours prior to PFTs. 
• 
Participants who routinely use long acting bronchodilator agents should use them 
15 minutes to 6 hours prior to PFTs. 
Electrocardiogram (ECG) – ECG will be done using local equipment. No central overreading will be 
done. 
Statistical methods: 
Each group (Group 1, Group 2 and Group 3) will be analyzed separately. Data will be presented 
descriptively and using 95% confidence intervals (CIs). Statistical summaries comparing post-
treatment values with Baseline will be conducted for selected endpoints. For the time until sputum 
culture and smear conversion, Kaplan-Meier survival curves will be prepared. 
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.  


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2. 
TRIAL FLOW CHART 
Table 1: 
Study Schedule of Assessments 
 
 
Screening 
Baseline 
Treatment Period 
End of 
Treatment 
(EOT) 
Follow-up (FU) 
End of 
Study 
Unsche
duled 
Visit number 
1  
2 
3 
4 
5  
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
UV  
Study Week 
-10 to -1 d 
0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
FU4 
FU12 
FU24  
a 
Day 
-70 to -7 
1 
7 
14 
28  
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
 
 
 
Window (days) 
 
 
±3 
±3 
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
 
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 
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 
X 
X 
X 
X 
Pregnancy test 
and 
contraceptive 
check 
X 
Xm 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
(X) 
Physical 
exam/Brief 
Exam 
X 
 
Xl 
Xl 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
(X) 


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Screening 
Baseline 
Treatment Period 
End of 
Treatment 
(EOT) 
Follow-up (FU) 
End of 
Study 
Unsche
duled 
Visit number 
1  
2 
3 
4 
5  
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
UV  
Study Week 
-10 to -1 d 
0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
FU4 
FU12 
FU24  
a 
Day 
-70 to -7 
1 
7 
14 
28  
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
 
 
 
Window (days) 
 
 
±3 
±3 
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
 
Vital signs 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
X 
X 
Xj 
X 
X 
Xj 
X 
X 
Xj 
X 
X 
X 
(X) 
ECG 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
(X) 
PFTs b 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collection of 
sputum sample 
for 
microbiology 
Xc,d 
Xc 
 
 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
(X) 
Laboratory 
safety sampling 
X 
Xi 
Xk 
Xk 
Xi 
X 
Xi 
X 
X 
Xi 
X 
X 
Xi 
X 
X 
Xi 
X 
X 
X 
(X) 
Samples for 
GM-CSF and 
anti-GM-CSF 
antibodies 
 
Xe 
 
Xe 
 
 
Xe  
 
 
Xe  
 
 
Xe  
 
 
X e 
 
X 
X 
(X) 
CTf 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
(X) 
Questionnaire 
CFQ-R 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Subject Diary 
Dispensed 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Trial drug 
administration 
trainingg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
Trial drug 
dosing at site 
 
 Xh 
Xh 
Xh 
Xh 
Xh 
Xh  
Xh 
Xh 
Xh  
Xh 
Xh 
Xh  
Xh 
Xh 
Xh 
 
 
 
(X) 
Dispense trial 
drug 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 


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Screening 
Baseline 
Treatment Period 
End of 
Treatment 
(EOT) 
Follow-up (FU) 
End of 
Study 
Unsche
duled 
Visit number 
1  
2 
3 
4 
5  
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
UV  
Study Week 
-10 to -1 d 
0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
FU4 
FU12 
FU24  
a 
Day 
-70 to -7 
1 
7 
14 
28  
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
 
 
 
Window (days) 
 
 
±3 
±3 
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
 
Return of used 
trial drug 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
(X) 
Compliance 
 
 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
 
Abbreviations: PFT=pulmonary function test; AE=adverse event; CFQ-R= Cystic Fibrosis Questionnaire-Revised; CT= Computed tomography; ECG= electrocardiogram; 
GM-CSF=granulocyte macrophage colony stimulating factor;  
a Procedures marked with brackets should be performed as necessary. 
b Pulmonary function tests (FEV1, FVC and FEV1/FVC).  At Baseline, PFTs will be performed pre-dose and post dose according to section 11.12.1. 
c Two additional sputum samples collected for NTM culture will be collected at home preferably on consecutive days and within 5 days of the site visit. 
d The screening NTM sample may be collected up to 10 weeks prior to baseline, after collection of informed consent. The remainder of screening visit should occur within 6 
weeks of the Baseline visit.   
e Samples for GM-CSF and anti-GM-CSF antibodies to be taken before dosing at the site. An additional sample for GM-CSF to be taken approximately 2 hours post dose for 
subjects that remain on IMP. 
f A CT scan of the lung performed up to 6 months prior to the Baseline visit is acceptable.   If Early End of Treatment Visit occurs prior to or at Week 12, then a CT scan is 
not required at End of Treatment.  In case of a clinically significant drop in FEV1 not responding to standard CF care, the CT scan may be repeated. If a chest radiograph is 
done information on the results will be collected. 
g Re-training can take place at all visits in the treatment period 
h Trial drug dosing should be performed after blood sampling.   
i Safety laboratory samples to be taken before dosing at the site. White blood cell count (WBC) and differentials to be repeated approximately 2 hours post dose for subjects 
that remain on IMP. 
j Repeat vital signs approximately 2 hours post dosing for subjects that remain on IMP.  
k CBC with differential will be collected pre-dose and approximately 2 hours post dose at visits 3 and 4.  No additional safety laboratory assessments will be collected at this 
visit.   
l For Week 1 and 2, Brief exam of lungs and symptom oriented physical exam should be performed. 
m A urine pregnancy test will be performed for females in addition to the serum pregnancy test at the baseline visit.


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TRIAL FLOW CHART ..............................................................................................13 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Background .................................................................................................................24 
5.2. 
Trial Rationale ............................................................................................................30 
5.3. 
Potential Risks and Benefits .......................................................................................33 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................35 
6.1. 
Primary Objective .......................................................................................................35 
6.2. 
Secondary Objectives .................................................................................................35 
6.3. 
Exploratory Objectives ...............................................................................................35 
6.4. 
Endpoints ....................................................................................................................36 
6.4.1. 
Efficacy Endpoints ......................................................................................................36 
6.4.1.1. 
Primary Efficacy Endpoint: ........................................................................................36 
6.4.1.2. 
Secondary Efficacy Endpoints: ...................................................................................36 
6.4.1.3. 
Exploratory Endpoints: ...............................................................................................36 
6.4.2. 
Safety Endpoints .........................................................................................................37 
7. 
INVESTIGATIONAL PLAN .....................................................................................38 
7.1. 
Overall Trial Design ...................................................................................................38 
7.1.1. 
Trial Period .................................................................................................................40 
7.1.2. 
End of Trial .................................................................................................................40 
7.1.3. 
Trial Completion .........................................................................................................40 
7.2. 
Number of Subjects ....................................................................................................40 
7.3. 
Treatment Assignment ................................................................................................40 
7.4. 
Screen Failures ............................................................................................................41 
7.5. 
Dose Adjustment Criteria ...........................................................................................41 
7.5.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................41 


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7.5.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................41 
7.6. 
Criteria for Study Termination ...................................................................................41 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................43 
 
. ...................................................................................................................................43 
8.1. 
Subject Inclusion Criteria ...........................................................................................43 
8.2. 
Subject Exclusion Criteria ..........................................................................................45 
8.3. 
Subject Withdrawal Criteria .......................................................................................46 
8.3.1. 
Discontinuation from Trial Treatment ........................................................................46 
8.3.2. 
Withdrawal from the Trial ..........................................................................................46 
9. 
TREATMENT OF SUBJECTS ..................................................................................47 
9.1. 
Description of Study Drug ..........................................................................................47 
9.2. 
Prohibited Medications ...............................................................................................47 
9.3. 
Treatment Compliance ................................................................................................48 
9.4. 
Randomization and Blinding ......................................................................................48 
9.5. 
Subject Identification List ...........................................................................................48 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................49 
10.1. 
Study Drug ..................................................................................................................49 
10.2. 
Study Drug Packaging and Labeling ..........................................................................49 
10.3. 
Study Drug Storage .....................................................................................................49 
10.4. 
Study Drug Preparation ..............................................................................................49 
10.5. 
Administration ............................................................................................................49 
10.6. 
Study Drug Accountability .........................................................................................50 
10.7. 
Study Drug Handling and Disposal ............................................................................50 
11. 
ASSESSMENTS.........................................................................................................51 
11.1. 
Informed Consent .......................................................................................................51 
11.2. 
Collection of Sputum Samples for Microbiological Characterization and 
Quantification .............................................................................................................51 
11.3. 
Prior and Concomitant Medication .............................................................................52 
11.4. 
Patient Reported Outcomes ........................................................................................53 
11.5. 
Subject Diary ..............................................................................................................53 
11.6. 
Adverse Events ...........................................................................................................53 
11.7. 
Demographics/Medical History/Body Measurements ................................................53 
11.8. 
Physical Examination .................................................................................................54 


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11.9. 
Vital Signs ..................................................................................................................54 
11.10. 
Electrocardiogram (ECG) ...........................................................................................54 
11.11. 
Radiology ....................................................................................................................55 
11.11.1. 
CT Scan ......................................................................................................................55 
11.12. 
Pulmonary Function Tests ..........................................................................................55 
11.12.1. 
Spirometry ..................................................................................................................55 
11.13. 
Laboratory Assessments .............................................................................................55 
11.13.1. 
Levels of GM-CSF and Anti-GM-CSF Antibodies ....................................................56 
11.13.2. 
Laboratory Safety Assessments ..................................................................................56 
11.13.2.1. Blood Hematology ......................................................................................................56 
11.13.2.2. Blood Chemistry .........................................................................................................56 
11.13.2.3. Urinalysis ....................................................................................................................56 
11.13.2.4. Pregnancy Screen ........................................................................................................57 
11.14. 
Adverse and Serious Adverse Events .........................................................................57 
11.14.1. 
Definition of Adverse Events .....................................................................................57 
11.14.1.1. Adverse Event (AE) ....................................................................................................57 
11.14.1.2. Serious Adverse Event (SAE) ....................................................................................57 
11.14.1.3. Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................58 
11.15. 
Recording Adverse Events .........................................................................................58 
11.16. 
Reporting Adverse Events ..........................................................................................60 
11.16.1. 
Reporting of Serious Adverse Events .........................................................................60 
11.16.2. 
SUSAR Reporting Procedure .....................................................................................61 
11.16.3. 
Adverse Events of Special Interest .............................................................................61 
11.16.4. 
Precautions/Overdose .................................................................................................62 
11.16.5. 
Pregnancy ...................................................................................................................62 
11.16.6. 
Safety Management Plan ............................................................................................62 
12. 
STATISTICS ..............................................................................................................63 
12.1. 
Efficacy Endpoints ......................................................................................................63 
12.2. 
Safety Endpoints .........................................................................................................64 
12.3. 
General ........................................................................................................................64 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................65 
13.1. 
Access to Source Data and Documentation ................................................................65 
13.2. 
Subject Records and Source Data ...............................................................................65 


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13.3. 
Study Monitoring ........................................................................................................65 
13.4. 
Audits and Inspections ................................................................................................65 
13.5. 
Institutional Review Board (IRB) ...............................................................................66 
14. 
ETHICS ......................................................................................................................67 
14.1. 
Ethics Review .............................................................................................................67 
14.2. 
Ethical Conduct of the Study ......................................................................................67 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
15.1. 
Data Management .......................................................................................................68 
15.2. 
Protocol Deviations ....................................................................................................68 
15.3. 
Inspection of Records .................................................................................................68 
15.4. 
Retention of Records ..................................................................................................68 
16. 
FINANCE AND INSURANCE .................................................................................69 
17. 
TRIAL ORGANIZATION .........................................................................................70 
18. 
PUBLICATION POLICY ..........................................................................................71 
19. 
LIST OF REFERENCES ............................................................................................72 
20. 
APPENDICES ............................................................................................................77 
APPENDIX 1. RATIONALE FOR AMENDMENTS AND LIST OF REVISIONS ................78 
APPENDIX 2. QUESTIONNAIRES ..........................................................................................79 
2.1 CYSTIC FIBROSIS QUESTIONNAIRE -REVISED ............................................................80 
 


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LIST OF TABLES 
Table 1: 
Study Schedule of Assessments..................................................................................13 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................21 
Table 3.      Number of Subjects ....................................................................................................40 
Table 4: 
Investigational Product ...............................................................................................47 
Table 5: 
Table of Revisions ......................................................................................................78 
  
  


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4. 
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 
AFB 
Acid Fast Bacilli 
aPAP 
Autoimmune Pulmonary Alveolar Proteinosis 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
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 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CAT 
Continuous Alternating Therapy 
CF 
Cystic Fibrosis 
CFF 
Cystic Fibrosis Foundation 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
Cystic Fibrosis Transmembrane Conductance Regulator 
CI 
Confidence Interval 
CHF 
Congestive Heart Failure 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
CPK 
Creatine Phosphokinase 
CRP 
C-Reactive Protein 
CT 
Computer Tomography 
CTR 
Clinical Trial Report 


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Abbreviation or Specialist Term 
Explanation 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EFD 
Embryo Fetal Development 
eGFR 
Estimated Glomerular Filtration Rate 
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 
GLI 
Global Lung Function Initiative 
GMP 
Good Manufacturing Practice 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonization 
ICMJE 
International Committee of Medical Journal Editors  
IDSA 
Infectious Diseases Society of America 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LSLV 
Last Subject Last Visit 
MABSC 
M. abscessus Complex 
MAC 
M. avium Complex 
MAD 
Multiple Ascending Dose 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
M-CSF 
Macrophage Colony Stimulating Factor 
MCV 
Mean Cell Volume 


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Abbreviation or Specialist Term 
Explanation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NK 
Natural Killer Cells 
NOAEL 
No Observed Adverse Effect Level 
NTM 
Nontuberculous Mycobacteria 
NTM-PD 
Nontuberculous Mycobacterial Pulmonary Disease 
NYHA 
New York Heart Association 
PCR 
Polymerase Chain Reaction 
PCV/EVF 
Packed Cell Volume (PCV) Or Erythrocyte Volume 
Fraction (EVF) Also known as Hematocrit 
PFT 
Pulmonary Function Test 
PT 
Preferred Term 
PT-INR 
Prothrombin Time International Normalized Ratio 
PVDS 
Pharmacovigilance and Device Safety 
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 
ss 
Subspecies 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
tmax 
Time of Maximum Plasma Concentration 
UK 
United Kingdom 
USA 
United States of America 
WBC 
White Blood Cells 
WGS 
Whole Genome Sequencing 
ZN 
Ziehl–Neelsen stain 
 
 


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5. 
INTRODUCTION 
5.1. 
Background  
Nontuberculous mycobacterial (NTM) infection  
Pulmonary disease due to NTM is an increasing problem in the United States of America (USA) 
and most western countries. Over the last three decades an increasing incidence of pulmonary 
NTM isolation has been observed [Stout 2016, Wassilew 2016] and NTM are now recognized to 
be a major cause of chronic lung disease. Nontuberculous 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 prevalence ranging from 
0.2 to 2.9 per 100,000 have been reported [Wassilew 2016] and across the USA prevalence 
ranges from 1 to 9 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 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 [Stout 
2016,Wassilew 2016].  
The cystic fibrosis (CF) population has an especially high risk for NTM infection and poses 
unique challenges with regards to diagnosis, treatment, and prevention [Floto 2016]. The 
reported prevalence of positive NTM cultures and/or NTM disease within various CF patient 
cohorts or at single centers varies dramatically but in the largest studies the overall prevalence is 
6-13% [Adjemian 2014, Aitken 1993, Olivier 2003, Qvist 2014, Roux 2009, Sermet-Gaudelus 
2003, Valenza 2008]. In a recent review of data from the CF Foundation Patient Registry, the 
median state prevalence of NTM in CF patients was 12% although this ranged from 0 to 28% 
[Adjemian 2014]. 
The overwhelming majority of NTM species recovered in CF samples in the USA are from 
either the M. avium complex (MAC) or the M. abscessus complex (MABSC) [Adjemian 2014]. 
Historically, MAC has been the most common NTM isolated, and in the largest USA survey it 
was present in up to 72% of patients with NTM-positive sputum cultures [Olivier 2003]. The 
percentage of MABSC reported in CF patients with NTM-positive sputum cultures has ranged 
from 18 to 64% [Olivier 2003, Pierre-Audigier 2005, Qvist 2014, Roux 2009, Seddon 2013  
Sermet-Gaudelus 2003, Valenza 2008] and it does appear that the proportion of MABSC is 


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increasing with some centers reporting a greater frequency than MAC. In part, this effect may be 
due to geographic factors, as MABSC appears especially prevalent in Europe [Qvist 2014, Roux 
2009, Sermet-Gaudelus 2003,Valenza 2008]. Differences in relative prevalence of MAC and 
MABSC may also relate to the age of the cohorts studied, as MAC is more often associated with 
older CF patients, often diagnosed in adulthood, while MABSC is frequently seen in younger 
patients and those with more severe lung disease [Catherinot 2013, Qvist 2014].  
While MABSC is generally considered to be more virulent than MAC, in the setting of CF lung 
disease there are many examples where both of these microbes have been associated with 
fulminate disease. In the past several years, important distinctions between species within the 
MABSC have been defined. Clarithromycin exposure of M. abscessus subspecies (ss) abscessus 
strains typically induces resistance by day 7. In contrast, M. abscessus ss massiliense isolates 
nearly always remain susceptible to clarithromycin, as a result of a non-functioning erm(41) gene 
[Nash 2009]. This distinction appears to have considerable clinical significance, as in a recent 
study eradication was achieved in response to treatment in 88% of patients who grew M. 
abscessus ss massiliense, compared with only 25% (p <0.001) in those with M. abscessus ss 
abscessus [Koh 2011]. It is possible that similar differences in virulence and treatment response 
exist between species and subspecies within MAC.  
Historically, NTM infections have been attributed to environmental exposure [Bange 2001, 
Jonsson 2007, Sermet-Gaudelus 2003].  
Recently, there have been reports of local outbreaks of M. abscessus ss massiliense within CF 
centers [Aitken 2012, Tettelin 2014] which suggests the potential for patient-to-patient 
transmission. In the Papworth CF Center, in the United Kingdom (UK), whole genome 
sequencing (WGS) as well as analysis of antibiotic resistance patterns identified two clustered 
outbreaks of M. abscessus ss massiliense [Bryant 2013]. Five patients who had overlapping 
clinical encounters at the University of Washington CF Center were found to have identical 
isolates of M. abscessus ss massiliense from the same genetic clade as the Papworth outbreak. 
Through WGS of the CF strains from the Seattle and Papworth outbreaks, as well as an outbreak 
of soft tissue infections in Brazil, research groups worldwide have found a very high-level of 
relatedness among these “transmissible strains”, when compared to a collection of worldwide 
strains [Tettelin 2014]. In CF patients, these transmissible strains appear especially virulent, with 
high mortality and treatment failure [Aitken 2012, Bryant 2013]. 
Successfully treating NTM disease is a major problem for clinicians and patients. Antibiotic 
options for NTM are poor [Griffith 2007, Griffith 2016]. The standard regimen for NTM (M. 
avium, M. intracellulare and M. kansasii) is a 3-drug regimen of a macrolide (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 [Aksamit 2017, Griffith 2007, Rawson 2016]. For this reason, the intention to treat cure 
rates in clinical trials are usually only 40-60% [Field 2004, Stout 2016, Xu 2014]. Clinical 
experience is that ‘normal’ practice outside of clinical trials is much worse than this [Rawson 
2016]. Typical side effects are severe 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]. 


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Clinical trials in NTM show microbiologic disease recurrence both during and following 
treatment. One study found that during therapy microbiologic disease occurred in 14% of 
patients (73% with reinfection MAC isolates, 27% with true relapse isolates: p = 0.03) and 
microbiologic recurrence occurred in 74 of 155 patients (48%) after completion of therapy (75% 
reinfection isolates, 25% true relapse isolates) [ Wallace 2014]. 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]. Nontuberculous mycobacteria do progressively acquire drug-resistance, including to 
rifampicin, amikacin, macrolides and quinolones [Cowman 2016, Heidarieh 2016,  Zhao 2014]. 
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 Escherichia 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 Saccharomyces 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 characterized by accumulation of inflammatory cells, mostly macrophages, accompanied by 
an increased cellularity in the lymphoid tissue that is associated with the respiratory tract and 
minimal to mild exudation of red blood cells (RBC) into the alveoli. The infiltration of 
inflammatory cells was not associated with any signs of inflammation or impaired lung function, 
and it is interpreted as an exaggerated pharmacological effect of molgramostim. Its severity was 
graded slight at the 10 μg/kg/day dose level and moderate above this level. Duration of treatment 
did not affect the severity of this finding. Reduced severity of the lung and tracheobronchial 


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changes following 4 weeks off dose in recovery animals suggests partial resolution of the 
changes. 
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 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. The NOAELs from other toxicity studies than the 26-week study were 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 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 4 subjects in each of 
the three SAD dose levels (150 µg, 300 µg and 600 µg) and 6 subjects receiving placebo. In the 
MAD part, 24 subjects were included with 9 subjects in each of the two MAD dose levels (300 
µg or 600 µg) and 6 subjects receiving placebo once daily for 6 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 


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GM-CSF levels returned to levels below quantification limits after each dose, there was evidence 
of some accumulation after multiple dosing. Cmax increased from 32 pg/mL on Day 1 to 90 
pg/mL on Day 6 for the 300 μg dose level and from 96 pg/mL to 251 pg/mL from Days 1 to 6 for 
the 600 μg dose level. Likewise, AUClast increased from 97 to 248 pg•h/mL from Days 1 to 6 for 
the 300 μg dose level and from 350 to 802 pg•h/mL for the 600 μg dose level. Minimum 
measurable plasma concentrations (Cmin) on Day 6 were 3.6 and 5.1 pg/mL measured at 8 and 12 
hours, respectively for the 300 and 600 μg dose levels.  
Changes in 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 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. A dose-dependent slight increase in heart rate was 
observed after dosing. There were no SAEs, severe AEs, dose-limiting toxicity, or other 
remarkable findings of clinical concern from review of clinical safety data.  
The following clinical studies of inhaled molgramostim are ongoing: 
• Study MOL-PAP-002 in subjects with autoimmune pulmonary alveolar proteinosis 
(aPAP) 
This pivotal clinical trial is ongoing in Australia, Europe, Israel, Japan, Russia, South 
Korea, Turkey, and the US. It is a randomized, double-blind, placebo-controlled trial, in 
which has enrolled 139 subjects 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 
placebo daily. 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. Five 
reviews of unblinded safety data by an independent data safety monitoring board 
(DSMB) have been conducted, including 10, 38, 59, 96, and 134 randomized subjects, 
respectively. Data reviewed comprised AEs, safety laboratory data, vital signs and 
pulmonary function tests from up to 72 weeks of treatment. At all reviews the DSMB 
recommended that the trial could continue as planned.  
• Study SAV006-03 in subjects with aPAP 
This is an open label, noncontrolled extension to MOL-PAP-002 to investigate safety of 
long term use of inhaled molgramostim (300 µg) administered intermittently in cycles of 
7 days molgramostim, administered once daily, and 7 days off treatment for up to 3 years. 


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• Study SAV008-01 in non-CF subjects with NTM 
This pilot clinical trial is ongoing in Australia and the UK. It is an open-label, non-
controlled, multicenter pilot trial, in which has enrolled 32 non-CF subjects with NTM 
infections. Treatment is given for 48 weeks and consists of daily administration of 
molgramostim nebulizer solution 300 µg. A safety data review was conducted after the 
first 6 subjects had completed 12 weeks of treatment. At this review the safety committee 
endorsed continuation of the trial and extension of the treatment duration from 24 to 48 
weeks to increase the ability to observe a more robust anti-infective effect. 
An interim analysis was conducted after 14 subjects had completed 24 weeks of 
treatment. The interim analysis focused on safety and tolerability, assessed for all 32 
subjects enrolled in the trial, and efficacy as assessed by microbiological results, in 14 
subjects who completed the 24-week treatment period and had culture results available up 
to at least the 16-week timepoint. Ten of the evaluable subjects had MAC infection and 
four had MABSC infection. Of the subjects with MAC infection, eight were in treatment 
Group 1 (on anti-mycobacterial treatment) and two were in treatment Group 2 (not on 
anti-mycobacterial treatment). The four evaluable MABSC subjects were evenly split 
between both treatment groups.  
Summary of Microbiological Data 
The data showed that among the 10 subjects with MAC infection, four experienced a 
consistent sputum smear conversion to negative by week 24, and three experienced a 
negative sputum culture at weeks 16 and 20, with culture results pending for the week 24 
timepoint. Sputum smear or sputum culture conversions were not observed in the four 
subjects with MABSC infection.  
Summary of Safety Information 
Among the 32 enrolled subjects, six (19%) experienced serious adverse events (SAEs), 
including one subject who died by suicide. The death was considered unrelated to 
treatment. One SAE was subsequently downgraded to a non-serious AE. The majority of 
SAEs consisted of hospitalizations due to pulmonary exacerbations or worsening of NTM 
infection, of which one was considered possibly treatment-related, i.e. one case of 
pulmonary exacerbation starting approximately 2.5 months after trial start. 
Molgramostim nebulizer solution was generally well tolerated, with nine subjects (28%) 
reporting mostly mild, potentially treatment-related respiratory adverse events (shortness 
of breath, chest tightness or wheeze) shortly after initiation of dosing. Respiratory 
adverse events were defined as shortness of breath, chest tightness or wheeze. A total of 
three subjects (9%) discontinued treatment due to adverse events, which were nausea and 
stomach pain, or shortness of breath. Two of these subjects subsequently restarted study 
drug on reduced dosage which was well tolerated. 
In line with its pharmacological effect as a stimulator of blood cells, molgramostim 
induced increased levels of eosinophils in blood in 17 subjects. The Investigators 
reported this as an asymptomatic finding, and a review of data did not identify a trend of 
decreased pulmonary function tests or respiratory adverse events associated with the 


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eosinophilia. The increase peaked at 4 weeks after start of treatment and levels decreased 
or plateaued at subsequent visits on continued treatment. 
Subjects with CF were excluded from this study as, unlike the non-CF setting of NTM 
infection, these subjects typically have multiple pathogens identified at the time of NTM 
isolation. 
5.2. 
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% [Field 2004, 
Stout 2016, Xu 2014]. 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 (30–48%), especially in patients with 
nodular bronchiectatic lung disease [Lee 2015, Wallace 2014]. There is limited data on treatment 
outcomes in patients with CF and NTM infection. However, 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 or 
inability to tolerate the drug regimen. Response to further conventional NTM treatments in this 
group would be not expected. In addition, the potential of inhaled molgramostim to eradicate 
NTM infection in subjects who are not eligible for guideline-based antimycobacterial treatment 
due to lack of accelerated decline in pulmonary function or worsening of clinical symptoms 
beyond what is expected in CF will be explored. An increased risk of death has been shown with 
both NTM-PD (hazard ratio 1.63) and NTM isolation without pulmonary disease (hazard ratio 
1.33) compared to matched controls [Marras 2013]. Thus, there is a rationale for treatment also 
of this group of patients. 
Due to their thick cell wall and resistance to normal extracellular defense mechanisms, 
successful killing of mycobacteria requires phagocytosis by macrophages. 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 subjects 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 subjects 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. 


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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 granulocytes, 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 
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 [Bermudez 1994, Newman 1997, Onyeji 1995,  Suzuki 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 including patients with CF 
with rhGM-CSF are also available. During the Acquired Immunodeficiency Syndrome (AIDS) 
epidemic, the administration of parenteral rhGM-CSF was reported to control systemic NTM 
infection resistant to antibiotic therapy and increase anti-mycobacterial activity [de Silva 2007, 
Hariadi 2017, Kemper 1998, Kedzierska 2000]. In addition a case of disseminated cutaneous 
MAC lesions refractory to conventional antimycobacterial therapy in a patient with chronic 
lymphocytic leukemia responded to the addition of subcutaneous GM-CSF and compounds that 
had recently been discovered to have anti-MAC activity (linezolid, mefloquine, moxifloxacin) 
[Nannini 2001]  
 
There are also three case reports of patients with pulmonary diseases who have been successfully 
treated with GM-CSF. A 44 year old male with PAP and a partial response to repeated whole 
lung lavage was successfully treated with subcutaneous GM-CSF following discovery of M. 
Kansasii in the BAL fluid. Several cavitating lesions were apparent on his chest radiographs and 
CT scan. He was initially treated with isoniazid, rifampicin and ethambutanol for 12-18 months 
which was subsequently switched to rifabutin, clarithrimycin and ethambutol until he underwent 
another set of BAL to relieve his breathlessness. Two months later a chest radiograph showed a 
recurrence of the pulmonary infiltrates so after a fourth set of BAL he commenced GM-CSF for 
3 months to prevent recurrence. The patient was reported as remaing well for more than 6 
months since GM-CSF treatment stopped [AbdulRahman 2004]. 
 
Two cases of adult patients with CF 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]. A recent publication also details the successful treatment of two CF patients with 


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evidence of M. abscessus colonization who were experiencing a decline in pulmonary function 
and clinical stability with inhaled GM-CSF [Scott 2018]. The first patient (a 10-year-old delta 
F508 homozygous female) had a 3.5-year history of persistent M. abscessus colonization. The 
patient had lack of response to aminoglycosides and/or linezolid. Aerosolized rhGM-CSF was 
added and administered on alternate weeks. Clinical improvement and stability were noted 
without toxicity. GM-CSF was continued, and antibiotics were discontinued after 3 months. 
After remaining off antibiotics for 3 months a decision was made to recombine aerosolized GM-
CSF with linezolid (IV) and amikacin (inhaled). After 4 months of combined therapy both acid-
fast bacilli smear and cultures became negative. The patient remains on inhaled GM-CSF alone. 
Over 90 weeks, her FEV1 increased from 64.7 to 78.0 percent predicted. The second patient (a 
25-year-old delta F508 homozygous male) had a 13-year history of persistent M. abscessus 
colonization, which was not treated with antibiotics. When the clinical status worsened (weight 
loss, decreased pulmonary function tests, and new radiological infiltrates), aerosolized GM-CSF 
treatment was administered on alternate weeks without antibiotic therapy. Clinical improvement 
was noted without toxicity. After 6 months of GM-CSF sputum smears became negative and 
culture burden decreased to 1 colony per plate. His FEV1 increased from 55.2 to 63.9 percent 
predicted. 
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 it is well tolerated. In animal studies as well as in the human Phase I study there was no 
increase in airways reactivity and in the Phase I study there was no anti-drug antibody 
development. The interim data from trial SAV008-01 indicate that some subjects may experience 
respiratory adverse events such as shortness of breath, chest tightness and wheeze, mainly mild 
and reversible, after initiation of dosing. In case of symptoms of bronchoconstriction or drop in 
FEV1 by 15 % or more, a short-acting bronchodilator should be administered 10-45 minutes 
prior to each subsequent dosing in the trial. 
Furthermore, in accordance with the pharmacological effect of molgramostim, increased levels 
of eosinophils in blood was observed in 17 subjects in trial SAV008-01. A review of data did not 
identify a trend of decreased pulmonary function tests or respiratory adverse events associated 
with the eosinophilia. In the current trial, white blood cells and differentials will be monitored 
before and 2 hours after dosing at selected visits to further characterize this effect. 
In the phase I trial in healthy volunteers a dose-dependent slight increase in heart rate was 
observed after dosing. Subjects with CHF NYHA Class III or IV and those with a recent 
ischemic heart event will therefore be excluded. Vital signs will be repeated 2 hours after dosing 
at selected visits. 
Clinical experience in using inhaled molgramostim in the setting of alveolar proteinosis has so 
far shown the drug to be well tolerated with few adverse drug reactions reported in the more than 
100 subjects 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 subjects in the setting of alveolar proteinosis. 
In the current study, the subject population is adult CF subjects with persistent pulmonary NTM 
infection as evidenced by at least three positive sputum cultures in the prior 2 years, one of 


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which has to be within 6 months prior to Screening, and a positive culture within 10 weeks prior 
to Baseline. Within the CF population, subjects with NTM disease can have sporadic negative 
cultures, and thus subjects will be allowed to rescreen if known to have NTM disease but were 
found to have a negative culture at the time of Screening. A population of treatment-resistant or 
treatment-intolerant subjects was selected as these are the subjects 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 they have given up on treatment or 
could not tolerate treatment) subjects will be stratified into Group 1 and Group 2 as follows. In 
addition, subjects without signs of NTM-PD but who still might benefit from a potential 
eradication of NTM infection will be recruited into a third group. 
• Group 1: Subjects with chronic pulmonary MAC or MABSC infection who have not 
consistently achieved negative NTM sputum cultures while currently on a multidrug 
NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 
9 months prior to the Baseline visit. 
• Group 2: Subjects with chronic pulmonary MAC or MABSC infection 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. 
• Group 3: Subjects with chronic -pulmonary MAC or MABSC infection not meeting 
recommendations for treatment with a multidrug NTM guideline-based 
antimycobacterial regimen based on failure to meet ATS/IDSA criteria for NTM 
pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond 
what is expected from underlying CF).   
In this trial, molgramostim 300 µg once daily will be administered for 48 weeks via inhalation 
using the Investigational eFlow Nebulizer System (PARI Pharma GmbH, Germany). The same 
dose and regimen are being investigated over a 48-week treatment period in the pilot clinical trial 
of inhaled molgramostim in non-CF subjects with persistent pulmonary NTM infection (Study 
SAV008-01) and for 24 weeks in the pivotal clinical trial in aPAP (MOL-PAP-002). In the 
current trial the treatment duration was set to 48 weeks as prolonged treatment is generally 
required when treating NTM in CF subjects with antimycobacterials, and the published case 
report of inhaled GM-CSF indicate that treatment beyond 6 months may be beneficial [Scott 
2018].  
A data review will be conducted after the first 6 subjects have completed 12 weeks of treatment. 
If safety concerns or poor tolerability are identified in this review, the review committee may 
decide on less frequent dosing for subsequent subjects in the study. Additional safety reviews 
will be conducted at regular intervals thereafter.  
5.3. 
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 


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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, NTM-PD 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. 
As the majority of inhalational use of rhGM-CSF has been in the context of aPAP, where 
subjects 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. 
Based on previous trials, these effects may include respiratory adverse events, eosinophilia and a 
slight increase in heart rate. 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 will be conducted by a review 
committee (the lead Investigators and sponsor representatives) after the first 6 subjects have 
completed 12 weeks treatment as outlined above. This may result in reduced dosing frequency if 
there are safety concerns or poor tolerability. Recruitment beyond the 6 first subjects will not be 
stopped during the review period. Additional safety reviews will be conducted at regular 
intervals thereafter. If needed, unscheduled visits will be conducted at Investigator’s discretion.  
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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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective is: 
• To investigate efficacy of inhaled molgramostim on NTM sputum culture conversion to 
negative. 
6.2. 
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 pulmonary function. 
• To investigate efficacy of inhaled molgramostim on patient reported outcomes.  
• To investigate efficacy of inhaled molgramostim on BMI. 
• To investigate safety of inhaled molgramostim in subjects with NTM infection. 
6.3. 
Exploratory Objectives 
The exploratory objectives are: 
• 
To investigate efficacy in subjects infected with MABSC and MAC, respectively. 
• 
To investigate efficacy in subjects on concurrent anti-mycobacterial treatment and 
subjects not on anti-mycobacterial treatment, respectively. 
• 
To investigate rates of recurrence and reinfection after End of treatment. 
• 
To investigate efficacy of inhaled molgramostim on bacterial co-infections. 
• 
To investigate efficacy of inhaled molgramostim on frequency of pulmonary 
exacerbations 
• 
To investigate efficacy of inhaled molgramostim on morphologic findings on CT scans 
of the lung. 
 


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6.4. 
Endpoints 
6.4.1. 
Efficacy Endpoints 
6.4.1.1. 
Primary Efficacy Endpoint: 
• Number of subjects with NTM sputum culture conversion to negative (defined as at least 
three consecutive negative mycobacterial cultures collected at least 4 weeks apart during 
the Treatment period). 
6.4.1.2. 
Secondary Efficacy Endpoints: 
• NTM sputum culture microbiological cure (defined as multiple consecutive negative but 
no positive cultures with the causative species after last culture conversion and until the 
End of Treatment (Week 48)). 
• Time to first NTM sputum culture conversion during the Treatment period. 
• Sputum smear conversion to negative (defined as at least three consecutive negative AFB 
stained sputum smears on microscopy, collected at least 4 weeks apart in subjects who 
were smear positive at Baseline) during the Treatment period. 
• Consistent sputum smear conversion to negative (defined as multiple consecutive 
negative but no positive smears after last smear conversion and until the End of 
Treatment (Week 48) in subjects who were smear positive at Baseline). 
• Time to first NTM sputum smear conversion during the Treatment period. 
• Durable NTM sputum microbiological cure for the NTM isolate(s) treated without 
recurrence at Week 12 after End of Treatment. 
• Durable NTM sputum smear conversion to negative without subsequent positive smears 
at Week 12 after End of Treatment. 
• Change in semi-quantitative grade of number of NTM on microscopy of AFB stained 
sputum smears from Baseline to End of Treatment and Week 12 after End of Treatment. 
• Absolute change in FEV1 (percent predicted) from Baseline to End of Treatment and 
Week 12 after End of Treatment. 
• Change in respiratory domain score assessed by CFQ-R from Baseline to End of 
Treatment and Week 12 after End of Treatment. 
• Change in BMI from Baseline to End of Treatment and Week 12 after End of Treatment. 
6.4.1.3. 
Exploratory Endpoints: 
• Change from Baseline in time to positivity on NTM liquid culture media at Treatment 
visits and Follow-up.  
• Change in semi-quantitative grade of sputum cultures from Baseline to Treatment visits 
and Follow-up. 


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• Number of subjects with recurrence (re-emergence of the treated NTM species after End 
of Treatment), or reinfection (emergence of a different NTM species, after End of 
Treatment). 
• Eradication and/or reduction in bacterial load of co-infections in sputum. 
• Frequency of pulmonary exacerbations compared to the previous year. 
• Change in CFQ-R domains scores for physical functioning, vitality, health perceptions, 
treatment burden, role functioning, emotional functioning, and social functioning. 
• Change in CT scans from Baseline to End of Treatment (Week 48). 
6.4.2. 
Safety Endpoints 
• Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment discontinuation 
during the trial period. 
• Change in WBC counts and differentials in blood from Baseline to Treatment visits. 
• A clinically significant decrease in FEV1 (% predicted) from Baseline to Treatment visits 
that does not respond to typical CF treatment (including treatment of pulmonary 
exacerbation if suspected) and in the judgement of the Investigator is not due to typical 
complication of CF (i.e. acute pulmonary exacerbation).  
• GM-CSF levels during Treatment period. 
• Development of anti-drug antibodies during Treatment period and Follow-up period. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Trial Design 
This is an open-label, non-controlled, multicenter, pilot clinical trial of inhaled molgramostim in 
CF subjects with NTM infections. The study will include up to 34 subjects. 
The primary objective is to investigate efficacy of inhaled molgramostim on NTM sputum 
culture conversion to negative. The primary endpoint is NTM sputum culture conversion to 
negative (defined as at least three consecutive negative mycobacterial cultures collected at least 4 
weeks apart during the Treatment period). 
Secondary objectives include investigation of the efficacy of inhaled molgramostim on NTM 
sputum smear conversion to negative, reduction of NTM bacterial load in sputum, pulmonary 
function, Patient Reported Outcomes, and BMI as well as evaluation of the safety of inhaled 
molgramostim in these subjects. Secondary efficacy endpoints and the safety endpoints are 
detailed in Section 6.4. 
The Screening period will begin up to 10 weeks prior to the Baseline visit for collection of the 
sputum sample, but the remainder of the assessments including Safety labs will be completed 
within 6 weeks of Baseline, to determine eligibility. Adult subjects with a history of CF and 
chronic pulmonary NTM infection will be considered for enrollment. Chronic pulmonary NTM 
infection will be defined by at least three positive NTM cultures (sputum or BAL) for the same 
species/subspecies of MAC or MABSC within the 2 years prior to screening, with at least one 
positive within the past 6 months prior to screening and a minimum of 50% of NTM cultures 
positive over the past 2 years. Subjects must additionally provide - a positive sputum culture with 
the same species/subspecies from the central laboratory at Screening to be eligible. The 
Screening sample may be collected up to 10 weeks prior to Baseline, provided informed consent 
is signed. Subjects who have a negative sputum culture at the time of Screening will be allowed 
to rescreen. 
Three groups of subjects will be recruited: 
• Group 1: Subjects with chronic pulmonary MAC or MABSC infection who have not 
consistently achieved negative NTM sputum cultures while currently on a multidrug 
NTM guideline-based antimycobacterial regimen, which has been ongoing for at least 
9 months prior to the Baseline visit. 
• Group 2: Subjects with chronic pulmonary MAC or MABSC infection 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. 
• Group 3: Subjects with chronic pulmonary MAC or MABSC infection not meeting 
recommendations for treatment with a multidrug NTM guideline-based 
antimycobacterial regimen based on failure to meet ATS/IDSA criteria for NTM 
pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond 
what is expected from underlying CF). 
 


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All subjects will have a Screening, Baseline, Week 1 and 2, followed by monthly visits from 
week 4 during the Treatment period. The Treatment period will be 48 weeks. Following the End 
of Treatment, subjects will have a Follow-up visit at 4 and 12 weeks, and the End of Study visit 
24 weeks after the End of Treatment.  
Subjects on a cyclical on-off anti-Pseudomonal regimen will have their trial visits (Baseline and 
subsequent visits in the Treatment Period) scheduled during a week after at least three weeks off-
treatment or after at least one week on-treatment of the antibiotic. Subjects on a continuous 
inhaled regimen, including CAT, should have been on a stable regimen for at least 28 days prior 
to Baseline. 
At the Baseline visit, eligible subjects will start treatment with inhaled molgramostim. 
At Screening, Baseline, each monthly visit during the Treatment Period, and all Follow-up visits, 
sputum samples for staining and microscopy, and microbiological culture will be collected. If 
required, induced sputum may be obtained according to local practice. At Screening, Baseline, 
and all monthly visits during the treatment period and all follow up visits, subjects will be asked 
to collect two samples at home, preferably on the consecutive days after the site visit but within 5 
days of the visit.  
At Baseline, and subsequent visits, clinical assessments including body weight, vital signs, 
patient reported outcomes (CFQ-R), and PFTs to include FEV1, FVC and FEV1/FVC will be 
conducted (according to Table 1). A low-dose CT scan  or CT Scan performed to institutional 
standard of care will be conducted at Baseline and at End of Treatment. In case of a clinically 
significant drop in FEV1 not responding to standard CF care the CT scan may be repeated. Safety 
assessments will include FEV1, ECG, safety laboratory assessments, serum anti-drug antibodies 
and GM-CSF levels. At Screening, Baseline, and monthly visits in the Treatment Period and at 
the 4-week Follow-up visit a pregnancy test/contraceptive check will be conducted. At each visit 
any changes in concomitant medication will be recorded. Participating subjects will be 
encouraged to contact the clinic between visits if they experience AEs, worsening of their 
condition or have any other concerns. If needed, unscheduled visits will be conducted at 
Investigator’s discretion. 
All subjects will be maintained on their standard CF treatment and medications independent of 
NTM treatment status. 
During the study, subjects in Group 1 will continue use of antimycobacterial treatment whereas 
Groups 2 and 3 will receive inhaled molgramostim as monotherapy for their NTM infection. For 
subjects in Group 1, the antimycobacterial therapy should preferably not change during the 
treatment period except in case of drug toxicity or adverse reactions. Antibiotics discontinued 
due to toxicity may be replaced, with drug selection and dose modification at the discretion of 
the treating physician. All changes in antimycobacterial treatment will be recorded, including 
reasons for each change. In the event the Investigator has evidence of infection while on 
treatment which requires more intensive therapy (i.e. additional antibiotics in Group 1 or 
addition of antibiotics to Group 2 or 3) the subject may be allowed to continue after discussion 
with the Sponsor medical monitor. 
A schedule of study assessments is available in Table 1. 


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Treatment with inhaled molgramostim will be given at a dosage of 300 µg once daily for 
48 weeks administered via the Investigational eFlow Nebulizer System. Dosing will be done in 
the morning, after completion of the subject’s normal airway clearance routine, and inhaled 
antibiotics. A data review will be conducted after the first 6 subjects have completed 12 weeks of 
treatment. If safety concerns or poor tolerability are identified in this review, the review 
committee may decide on less frequent dosing for subsequent subjects in the study. Any changes 
to the conduct of the study such as change of dose, dose regimen or duration will be documented 
in a protocol amendment. Additional safety reviews will be conducted at regular intervals 
thereafter. 
7.1.1. 
Trial Period 
The duration of trial participation for each subject is approximately 73 to 82 weeks: 
• Screening period for the subjects is 1 to 10 weeks  
• Treatment period is 48 weeks (+/- 7 days) 
• Follow-up for 24 weeks (+/- 7 days) 
7.1.2. 
End of Trial 
The end of the trial is defined as the last subject’s last visit (LSLV). 
7.1.3. 
Trial Completion  
Trial completion is defined as the date of the Clinical Trial Report (CTR). 
7.2. 
Number of Subjects 
A minimum of 30 subjects will be enrolled. No formal sample size calculation was done as this 
is an initial pilot study. To be able to assess response in each of the three groups, a minimum of 8 
subjects with MAC or MABSC will be enrolled in each group, and a minimum of 30 
subjects will be enrolled across all 3 groups.  The maximum number of subjects enrolled into 
each group will be 12, and the maximum number of subjects enrolled into the study will be 34.  
 
Table 3. Number of Subjects 
Organism 
Group 1 
Group 2 
Group 3 
Total 
MAC/MABSC 
8-12 
8-12 
8-12 
30-34 
 
7.3. 
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.   
At the Baseline visit, all subjects found to be eligible according to the inclusion/exclusion criteria 
will be classified into one of the three treatment groups by a central electronic data capture 


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system. Subjects successfully assigned to one of the treatment groups will then start treatment 
with open-label molgramostim nebulizer solution.   
7.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently enrolled in the study. A minimal set of screen failure information is required to be 
captured in the eCRF. Minimal information includes informed consent and demography, 
eligibility criteria, screen failure details, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened upon approval from Sponsor. Rescreened subjects will be assigned a new site-specific 
subject number. 
7.5. 
Dose Adjustment Criteria 
7.5.1. 
Safety Criteria for Adjustment or Stopping Doses 
There are no prespecified dose adjustment criteria.  
A data review will be conducted by a safety review committee comprised of the lead 
Investigators and sponsor representatives after the first 6 subjects have completed 12 weeks of 
treatment. If safety concerns or poor tolerability are identified in this review, the review 
committee may decide on less frequent dosing for subsequent subjects in the study. Additional 
safety reviews will be conducted at regular intervals thereafter.  
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. The Sponsor medical monitor should be consulted prior to dose reduction. 
7.5.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
Not applicable. 
7.6. 
Criteria for Study Termination 
The Investigator or the sponsor may terminate this trial prematurely for any reasonable cause. 
The 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, 


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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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8. 
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. 
8.1. 
Subject Inclusion Criteria 
1. Written informed consent obtained from participant. 
2. Confirmed diagnosis of CF according to the CFF 2017 Consensus Guidelines. 
3. History of chronic pulmonary infection with MAC or MABSC (defined as at least three 
positive NTM cultures (sputum or BAL) for the same species (MAC) or subspecies 
(MABSC) within the 2 years prior to screening, with at least one positive within the 6 
months prior to screening, and a minimum of 50% of NTM cultures positive over the past 
2 years) that does not demonstrate response to current treatment course based on 
decreasing NTM burden or frequency of positive cultures, and in the opinion of the 
Investigator is unlikely to resolve with current treatment course. 
4. Subject fulfills criteria for inclusion in one of the following groups: 
o Group 1:  Subject with chronic pulmonary MAC or MABSC infection currently 
on a multidrug NTM guideline-based antimycobacterial regimen, which has been 
ongoing for at least 9 months prior to the Baseline visit. 
o Group 2:  Subject with chronic pulmonary MAC or MABSC infection who has 
stopped a multidrug NTM guideline-based antimycobacterial regimen at least 28 
days prior to Screening due to lack of response or intolerance. 
o Group 3:  Subject with chronic pulmonary MAC or MABSC infection not 
meeting recommendations for treatment with a multidrug NTM guideline-based 
antimycobacterial regimen based on failure to meet ATS/IDSA criteria for NTM 
pulmonary disease (i.e. absence of radiologic findings and clinical symptoms 
beyond what is expected from underlying CF). 
5. Ability to produce sputum or be willing to undergo an induction that produces sputum for 
clinical evaluation. 
6. An additional sputum culture performed by central laboratory, which is positive for the 
same species (MAC) or subspecies (MABSC) of NTM as before the trial within 10 weeks 
of Baseline.  
7. CF which in the Investigator’s opinion is clinically stable and is not expected to require 
lung transplantation within the next year.  
8. FEV1 ≥ 30% of predicted at screening that is normalized for age, gender, race, and height, using 
the Global Lung Function Initiative (GLI) equation. 
 
9. Subjects who are co-infected with a respiratory pathogen, e.g. P. aeruginosa or S. aureus, 
must either be stable on a regular suppression antibiotic regimen or must be, in the opinion 
of the Investigator, stable despite the lack of such treatment. 


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10. Female or male ≥18 years of age. 
11. If female, subjects 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) during and until 30 days 
after last dose of trial treatment, having 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.  
 
For purposes of this study, the Sponsor defines “acceptable methods of contraception” as: 
o Oral birth control pills administered for at least 1 monthly cycle prior to 
administration of the study drug. 
o A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle 
prior to the study drug administration but not beyond the 4th successive year 
following insertion. 
o Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 monthly 
cycle prior to study drug administration. 
o Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum 
of 1 monthly cycle prior to administration of the study drug and continuing 
through 1 month following study completion. 
o Hysterectomy or surgical sterilization. 
o Vasectomized partner 
o Abstinence. 
 
Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive 
foam) is not considered an acceptable from of contraception.  
 
NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal 
contraceptive exposure, reducing the effectiveness and increasing the incidence of 
menstruation-associated adverse reactions. Hormonal contraceptives, including oral, 
injectable, transdermal, and implantable, should not be relied upon as an effective method 
of contraception when co-administered with Orkambi. 
12. If male, subjects who, if sexually active of reproductive potential and non-sterile (i.e., 
male who has not been sterilized by vasectomy for at least 6 months, and not diagnosed 
with infertility through demonstration of azoospermia in a semen sample and/or absence 
of vas deferens through ultrasound) are willing to use a barrier method of contraception, or 
their female partner must use an acceptable method of contraception, during the study and 
until 30 days after last dose of medication. 
13. 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. 


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8.2. 
Subject Exclusion Criteria 
1. Use of non-maintenance antibiotic for a pulmonary or extrapulmonary concurrent 
infection within 28 days prior to the Baseline visit. 
2. Use of a maintenance antibiotic regimen containing azithromycin for a concurrent non-
NTM pulmonary infection within 28 days prior to the Baseline visit. For subjects in 
Group 1, azithromycin is allowed if part of an ongoing multidrug NTM guideline-based 
antimycobacterial regimen. 
3. Prior therapy with inhaled or systemic GM-CSF. 
4. Subjects with hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to 
Screening. 
5. Life expectancy of less than 6 months according to Investigator’s judgement. 
6. History of, or present, myeloproliferative disease, leukemia or other hematological 
malignancy. 
7. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring 
chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during 
the study period. 
8. Active autoimmune disorder or other condition requiring therapy with significant 
immunosuppression, e.g. such as corticosteroids at a dose equivalent of 10 mg/day or 
more of prednisolone, or other immunosuppressant medications, within 3 months prior to 
Screening or anticipated during the study period.  Inhaled or topical corticosteroids, or 
brief courses (< 14 days) of systemic corticosteroids for pulmonary exacerbations or 
other self-limited conditions are permitted. 
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid 
medications, or changes in CFTR modulators, within 28 days prior to the Baseline visit. 
10. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening. 
11. History of human immunodeficiency virus (HIV) infection or other disease associated 
with significant immunodeficiency. 
12. History of lung or other solid organ transplantation or currently on the list to receive lung 
or other solid organ transplantation. 
13. History of congestive heart failure (CHF) New York Heart Association (NYHA) Class III or 
greater in severity. 
14. History of cardiovascular ischemic event within 6 months of Baseline. 
15. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior 
to Screening. 
16. Treatment with any investigational medicinal product within 28 days of Screening. 
17. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product. 


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18. Any other condition that, in the opinion of the Investigator, would preclude informed 
consent or assent, make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
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 and attend the remaining visits.   
The reason and date the subject is discontinued from treatment will be documented in the 
electronic case report form (eCRF).  
8.3.2. 
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 AE 
• 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 11.14.  
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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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name: 
Molgramostim nebulizer solution 
Dosage Form: 
Nebulizer solution 
Unit Dose 
300 µg 
Route of Administration 
Inhalation using the Investigational eFlow Nebulizer System 
(PARI Pharma GmbH) 
Physical Description 
Clear, colorless solution containing molgramostim, a 
recombinant human Granulocyte Macrophage Colony 
Stimulating Factor (rhGM-CSF).  
Excipients are mannitol, polyethylene glycol 4000, 
recombinant human albumin, disodium phosphate 
(anhydrous), citric acid (monohydrate), and water for 
injection 
9.2. 
Prohibited Medications 
The following concomitant medications are not allowed during the trial (See exclusion 
criteria Section 8.2): 
• Treatment with azithromycin for a concurrent pulmonary infection. Note: For subjects in 
Group 1, azithromycin is allowed as part of an ongoing multidrug NTM guideline-based 
antimycobacterial regimen. 
• Treatment with other inhaled or systemic GM-CSF. 
• Therapy associated with significant immunosuppression such as e.g. systemic 
prednisolone at a dose equivalent of 10 mg/day or more.   
 
Inhaled or topical corticosteroids, or brief courses (< 14 days) of systemic corticosteroids for 
pulmonary exacerbations or other self-limited conditions are permitted.  The Medical 
Monitor should be consulted if systemic corticosteroids at a dose equivalent of 10mg/day or 
more are expected to last more than 14 days for a pulmonary exacerbation or self-limited 
condition.   
 


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9.3. 
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.  
9.4. 
Randomization and Blinding 
Not applicable. 
9.5. 
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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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Each vial of molgramostim nebulizer solution contains 300 µg molgramostim in 1.2 mL solution 
(250 µg/mL). 
10.2. 
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 4 weeks will be supplied in adequate 
amounts at the dispensing visits.   
Labels will comply with local regulations and will be printed in local language. 
10.3. 
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, 28, 32, 36, 40, and 44 (Visits 5-15) during the Treatment period.  
Subjects will be instructed to store the kit at 2-8°C in a safe and secure place away from sunlight 
and out of the reach of children. The IMP must not be frozen or shaken and not be used beyond 
the expiration date on the vial.   The IMP should be removed from refrigeration 10 minutes prior 
inhalation.  
Subjects will be asked to return used and unused medication at the next clinic visit to check 
compliance.  At Weeks 1 and 2 (Visits 3 and 4) subjects will be asked to bring their used IMP 
and one unused IMP dose with them to the clinic.     
10.4. 
Study Drug Preparation 
Not applicable. 
10.5. 
Administration 
The Investigational eFlow Nebulizer System (PARI Pharma GmbH, Germany) will be used to 
administer the IMP. The eFlow Nebulizer 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 (maximum fill 4 mL) that can produce aerosols with high density 
of active drug, precisely defined droplet size (mass median diameter 2.9-3.9 µm) and a high 
proportion of respirable droplets. 


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All subjects, Investigators and trial nurses will be trained in IMP administration and medical 
device maintenance procedure. The training of the subjects will take place at the Baseline visit 
and will be checked at subsequent clinic visits. The subjects will also receive written 
instructions.  
The subjects will administer the first dose of IMP at the Baseline visit (Visit 2) and subsequent 
visits in the Treatment period under the supervision of trial personnel.  
When administering as part of the morning routine at home, the following order should be 
applied: bronchodilator, dornase alfa (Pulmozyme), inhaled antibiotics such as TOBI, and lastly 
IMP. 
10.6. 
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.  
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. 
10.7. 
Study Drug Handling and Disposal 
Used and Unused IMP must be returned to supply vendor after agreement with the Sponsor, but 
only after drug accountability has been completed by the CRA. 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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11. 
ASSESSMENTS  
The timing of all trial assessments is shown in the Schedule of Procedures in Table 1. 
11.1. 
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, including 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 consent form. Information provided to a subject can be 
delegated to a qualified member of the research team, but the Investigator must be available for 
questions and this should be documented in source documents.. 
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 informed consent form will be updated by Savara and approved by 
an IRB. The subject must be informed in a timely manner about the updated information and 
written informed consent must be obtained. 
11.2. 
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 Table 1 . 
The analysis of the samples for NTM will be performed at a central specialized mycobacterial 
laboratory.  
If required, induced sputum may be obtained using local standards.  
At all visits other than Visit 3 and 4 subjects will be asked to collect two additional morning 
sputum samples at home on different days preferably on consecutive days after the site visit but 
within 5 days of the site visit. On dosing days, the samples should be collected prior to the 
dosing of trial drug. 
Additional samples for NTM testing may be collected between visits according to Investigator’s 
discretion and will then be recorded as an unscheduled visit. 


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The sputum samples must be refrigerated immediately after sampling unless being shipped to the 
central laboratory on the same date. Details regarding the collection and handling of sputum 
samples will be provided in a separate document. 
Using AFB staining (fluorescence and /or ZN stain) NTM in sputum will be identified and a 
semi-quantitative assessment of bacterial load (graded as 0, scant, 1+, 2+, 3+) will be conducted.  
Microbiological culture to identify growth of NTM will be conducted using established 
standards. A semi-quantitative assessment of sputum cultures will be reported.  Identification to 
NTM species level (MAC) or subspecies level (MABSC) will be conducted on positive samples 
(one per visit) using established methods. Isolates from selected samples may also be subject to 
molecular identification to the subspecies level, and whole genome sequencing to track potential 
polyclonal infections and/or new acquisition of NTM infection during the follow-up period at the 
central laboratory, according to a separate research protocol. These data may be reported outside 
the CTR.   
If sufficient sputum volume is obtained, an additional aliquot may be frozen and stored for 
potential post-hoc analysis by quantitative polymerase chain reaction (PCR). Such PCR analysis 
will be performed no later than 2 years after trial completion. The PCR data will not be included 
in the CTR but reported separately. 
Routine CF bacteriology and fungal cultures will be performed locally on the sputum sample 
collected at the site. Semiquantitative assessment of bacterial load will be done for pathogens 
according to clinical standard. 
11.3. 
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 all antimycobacterials taken 
for the current NTM infection within 2 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.  
Treatments for cystic fibrosis, including inhaled antibiotics and CFTR modulators, should have 
been used in a stable regimen for at least 28 days prior to Baseline.  
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.  
If new antibiotics are prescribed for a concurrent infection, it will be assessed to determine 
whether the reason for the antibiotic therapy is a pulmonary exacerbation. All exacerbations must 
be reported as AEs. 
Antimycobacterial therapy should preferably not change during the treatment period except in 
case of toxicity or adverse reactions. For subjects in Group 1, the antimycobacterial therapy 
should preferably not change during the treatment period except in case of drug toxicity or 
adverse reactions. Antibiotics discontinued due to toxicity may be replaced, with drug selection 


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and dose modification at the discretion of the treating physician. In the event the Investigator has 
evidence of infection while on treatment which requires more intensive therapy (i.e. additional 
antibiotics in Group 1 or addition of antibiotics to Group 2 or 3) the subject may be allowed to 
continue after discussion with the Sponsor medical monitor. 
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.  
11.4. 
Patient Reported Outcomes 
The patient reported outcome (CFQ-R) will be assessed at the timepoints shown in Table 1. 
The CFQ-R is a disease-specific health-related quality of life measure for patients with CF with a 
two-week recall period. The CFQ-R measures functioning in a variety of domains, including 
Physical Functioning, Vitality, Health Perceptions, Respiratory Symptoms, Treatment Burden, 
Role Functioning, Emotional Functioning, and Social Functioning. The CFQ-R should be 
conducted prior to any other study visit procedure. A sample of the questionnaire is presented in 
Appendix 2. 
11.5. 
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. For the week 1 (Visit 3) and Week 2 (Visit 4) the subject will be asked to bring the diary 
back to the site for review by the study staff.  At all other visits during the treatment period the 
subject will return their diary to the study staff.    
11.6. 
Adverse Events 
Any AEs will be reported at every visit from Baseline (Visit 2) to the completion of the 24-week 
follow-up (Visit 19). Subjects will be encouraged to contact the clinic in between visits if they 
experience AEs or have any concerns. SAEs will be captured from the time the informed consent 
has been signed, up the last visit.  For further information of definitions and reporting of AEs and 
SAEs, see Section 11.14. 
11.7. 
Demographics/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 


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• Race (White/Asian/Black/American Indian/Alaska Native/Native Hawaiian/Other Pacific 
Islander)  
• Smoking (Previous/Current/Never) 
• Relevant prior and concurrent disorders, including other pertinent respiratory history such 
as number of pulmonary exacerbations within the last year and dates, all concurrent and 
relevant prior respiratory infections, and other CF related co-morbidities. 
• Details of NTM history, such as results from all NTM cultures obtained during the last 2 
years, will be recorded. If the participant has ever been treated for NTM previously, the 
species treated, and year treatment ended will be recorded. 
11.8. 
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 focusing on lungs may be performed as 
clinically indicated. New abnormal clinically significant physical examination findings not 
present during the Baseline visit should be recorded as AEs and followed during subsequent 
visits.  
11.9. 
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  
• Body temperature (°C) 
At selected visits as shown in Table 1, vital signs will be repeated approximately 2hours after 
dosing. 
The observed values will be recorded and assessed as ‘normal’ or ‘abnormal’. Abnormal findings 
will be assessed as ‘clinically significant’ or ‘not clinically significant’. 
11.10. 
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, QT and QTc 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 


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classified as normal, having a non-clinically significant abnormality, or having a clinically 
significant abnormality. All clinically significant abnormalities will be recorded as AEs. 
11.11. 
Radiology 
11.11.1. 
CT Scan 
A low dose CT scan or CT scan using institutional standard of care of the lung will be performed 
at Baseline and the End of Treatment visit (Table 1).  In case of a clinically significant drop in 
FEV1 not responding to standard CF care, the CT scan of the lung may be repeated. The same 
type of CT scan (i.e. either low- or high- dose CT scan) should preferably be used at the Baseline 
and the End of Treatment visits to the extent feasible according to local institutional standard of 
care. Images will be uploaded into the eCRF and a standardized system for central scoring will 
be implemented at a later timepoint. If a chest radiograph is done information on the results will 
be collected in the eCRF. 
11.12. 
Pulmonary Function Tests 
11.12.1. 
Spirometry 
All subjects will undergo standardized pulmonary function testing as shown in Table 1 by site 
staff with documented training in PFTs. Assessments will include FEV1, FVC and FEV1/FVC 
and be done in accordance with American Thoracic Society (ATS) guidelines (2005). Subjects 
will be tested using the same spirometry equipment provided by the Sponsor. Up to 8 efforts 
should be performed to obtain 3 acceptable and reproducible test results. The results will be 
uploaded and read centrally.  
At Baseline (Visit 2) PFTs will be conducted before and 1.5 hours (+/- 30 minutes) after dosing 
of IMP. At all other dosing visits PFTs should be done 1.5 hours (+/- 30 minutes) after dosing. If 
there are symptoms of bronchoconstriction after inhalation of study drug at any time during the 
study, or if FEV1 drops by 15% or more after dosing, a short-acting bronchodilator (e.g. 2 puffs 
of albuterol) may be prescribed at the investigators discretion for use 10-45 minutes prior to 
inhalation of study drug for the remainder of the treatment period.     
Participants who routinely use bronchodilators should use them consistently throughout the 
study. Standard guidelines are noted below as a reference:  
• Participants who routinely use short acting inhaled bronchodilators should use them 
15 minutes to 2 hours prior to PFTs. 
• Participants who routinely use long acting bronchodilator agents should use them 
15 minutes to 6 hours prior to PFTs. 
11.13. 
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 325 mL with a maximum of 
30 mL for one visit.  


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11.13.1. 
Levels of GM-CSF and Anti-GM-CSF Antibodies 
Blood samples for assessment of GM-CSF and anti-GM-CSF antibodies will be taken prior to 
dosing at the clinic visit at the timepoints shown in Table 1. An additional blood sample for 
assessment of GM-CSF will be taken approximately 2 hours post dose.  
Analyses will be performed at a central laboratory. If neutralizing antibodies to GM-CSF are 
identified, additional analyses exploring GM-CSF signaling may be done on a stored sample at a 
specialized laboratory. 
11.13.2. 
Laboratory Safety Assessments 
Blood samples for laboratory safety assessment should be taken prior to dosing at the clinic visit. 
At selected visits as shown in Table 1, sampling for analysis of WBC count and differentials will 
be repeated approximately 2 hours after dosing.  
The laboratory safety analyses (hematology, clinical chemistry and urinalysis) will be performed 
by a central laboratory. 
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’.  
11.13.2.1. Blood Hematology 
The following parameters will be analyzed: 
Hemoglobin, RBC count, red blood cell distribution width (RDW), hematocrit (PCV/EVF), 
mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration 
(MCHC), platelet count, WBC count, and white cell differential absolute count: neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, and prothrombin time international normalized 
ratio (PT-INR). 
11.13.2.2. Blood Chemistry 
The following parameters will be analyzed: 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl 
transpeptidase (GGT), alkaline phosphatase, amylase, bilirubin, blood urea nitrogen (BUN), 
creatinine, estimated glomerular filtration rate (eGFR), creatine phosphokinase (CPK), 
potassium, sodium, calcium, chloride, bicarbonate, phosphate, magnesium, total protein, 
albumin, lactate dehydrogenase (LDH), C-reactive protein (CRP), and glucose (non-fasting). 
11.13.2.3. Urinalysis 
The following parameters will be analyzed: 
pH, specific gravity, bilirubin, glucose, ketones, RBCs, WBCs, protein, microalbuminuria, and 
microscopic elements. 


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11.13.2.4. Pregnancy Screen 
A serum pregnancy test and contraceptive check will be performed for female subjects at the 
timepoints 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. 
11.14. 
Adverse and Serious Adverse Events 
11.14.1. 
Definition of Adverse Events 
11.14.1.1. 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. 
11.14.1.2. Serious Adverse Event (SAE) 
Any untoward medical 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 subject 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). 


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11.14.1.3. Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is an AE which 
• has a reasonable possibility of causal relationship to an IMP 
• is serious; and 
• is unexpected. 
Therefore, due to the nature and/or severity of the adverse reaction, a SUSAR is not consistent 
with the applicable product information (i.e. the reference safety information in the IB) for the 
IMP used in this study. 
11.15. 
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 24-week follow-up visit (Visit 19). 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 


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The AE interferes with daily activity, but the subject is still able to function. Medical 
intervention may be considered. 
Severe 
The AE is incapacitating and requires medical intervention. 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description. 
Causality 
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 


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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.  
Abnormal Laboratory Values/Vital Signs 
An asymptomatic abnormal laboratory/vital sign finding should only be reported as an AE if it is 
clinically significant according to the Investigator’s assessment, if it fulfils the criteria for an 
SAE or if it causes the subject to discontinue the trial. 
If an abnormal laboratory/vital sign value is associated with clinical signs and symptoms, the 
sign/symptom should be reported as an AE and the associated laboratory/vital sign result should 
be considered additional information. 
11.16. 
Reporting Adverse Events 
11.16.1. 
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. Any SAEs occurring to a subject after the subject 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 IRB (if applicable) with 
any additional requested information (e.g. autopsy reports and terminal medical reports). 
The Investigator must contact Premier Research by email or fax directly to Premier Research 
Pharmacovigilance and Device Safety in case of all SAEs within 24 hours after awareness of 
the event. 


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SAE REPORTING CONTACT DETAILS 
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 IRB, the 
Investigator should also comply with this legislation. If any such reporting is planned, this must 
be stated in the SAE report, and once the reporting has been performed, a copy of the reporting 
documentation must be enclosed with the 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 
Pharmacovigilance as soon as possible. All 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 subject, the Investigator has to provide any additional information 
necessary as requested by the sponsor, the competent authorities concerned and ethics 
committees concerned. 
11.16.2. 
SUSAR Reporting Procedure 
The FDA and/or other applicable Regulatory Authorities and all participating Investigators will 
be notified by a written Investigational New Drug Application (IND) safety report and/or other 
applicable regulatory report (eg, expedited case report) of any suspected adverse reaction that is 
both serious and unexpected (i.e. a SUSAR), no later than 15 calendar days from the “date 
learned” of the event. In addition, all applicable regulatory bodies will be notified within 7 
calendar days of any unexpected fatal or life-threatening suspected adverse reaction. 
An untoward and unintended response to a non-study drug is, by definition, not a SUSAR. 
11.16.3. 
Adverse Events of Special Interest 
There are currently no AEs of special interest identified due to limited previous experience of 
Savara’s molgramostim. 


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11.16.4. 
Precautions/Overdose 
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/or neutrophilia may occur in case of 
systemic exposure. With high doses of similar products administered systemically, 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. 
11.16.5. 
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 
11.16.1. 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. 
11.16.6. 
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 subjects 
from immediate risks. 


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12. 
STATISTICS 
A minimum of 30 subjects will be enrolled.  No formal sample size calculation was done as this 
is an initial pilot study.   To be able to assess response in each of the three groups, a minimum of 
8 subjects with MAC or MABSC will be enrolled in each group, and a minimum of 30 
subjects will be enrolled across all 3 groups.  The maximum number of subjects enrolled into 
each group will be 12, and the maximum number of subjects enrolled into the study will be 34  
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 (SAP).  
12.1. 
Efficacy Endpoints 
Each group (Group 1, Group 2 and Group 3) will be analyzed separately. Data will be presented 
descriptively and using 95% CIs. Statistical summaries comparing post-treatment values with 
Baseline will be conducted for selected endpoints. For the time until sputum culture and smear 
conversion, Kaplan-Meier survival curves will be prepared. 
Frequency of pulmonary exacerbations will be compared with frequency in the year prior to the 
trial.  
Primary Endpoint: 
• NTM sputum culture conversion to negative (defined as at least three consecutive 
negative mycobacterial cultures collected at least 4 weeks apart during the Treatment 
period). 
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.  
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 to negative (defined as at least three consecutive negative 
AFB stained sputum smears on microscopy, collected at least 4 weeks apart in 
subjects who were smear positive at Baseline) during the Treatment period. 
• Consistent sputum smear conversion to negative (defined as multiple consecutive 
negative but no positive smears after smear conversion and until the End of 
Treatment (Week 48) in subjects who were smear positive at Baseline). 
• Durable NTM sputum smear conversion to negative without subsequent positive 
smears at Week 12 after End of Treatment. 
Endpoints that are of the form “cure” (and similar) will be presented in the same way as the 
primary endpoint. This includes:  
• NTM sputum culture microbiological cure (defined as multiple consecutive negative 
but no positive cultures with the causative species after culture conversion and until 
the End of Treatment (Week 48)). 


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• Durable NTM sputum microbiological cure for the NTM isolate(s) treated without 
recurrence at Week 12 after End of Treatment. 
Semi-quantitative grading: 
• The change in semi-quantitative grade of number of NTM on microscopy of AFB 
stained sputum smears from Baseline to End of Treatment and Week 12 after End of 
Treatment will be cross-tabulated in 5-by-5 tables of negative, scant, 1+, 2+, or 3+ 
comparing Baseline to each visit and to the follow-up visit. 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. 
The “time to event” endpoints will be summarized by Kaplan-Meier survival plots. The event 
will be regarded as having occurred at the time of the first consecutive negative culture: 
• Time to first NTM sputum culture conversion during the Treatment period. 
• Time to first NTM sputum smear conversion during the Treatment period. 
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:  
• Absolute change in FEV1 (percent predicted) from Baseline to End of Treatment and 
Week 12 after End of Treatment. 
• Change in respiratory domain score assessed by CFQ-R from Baseline to End of 
Treatment and Week 12 after End of Treatment. 
• Change in BMI from Baseline to End of Treatment and Week 12 after End of 
Treatment. 
12.2. 
Safety Endpoints 
All AEs will be summarized in total and for Groups 1, 2 and 3 separately. 
All AE will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized by System Organ Class (SOC) and Preferred Term (PT). 
All SAE and AEs leading to study withdrawal will be listed and individual-subject narratives 
written for all SAEs. 
12.3. 
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, sorted by Group and subject and visit (when relevant). 
 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
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 IRB, if required. 
13.2. 
Subject Records and Source Data 
The origin of source data in the trial will be specified for each trial site in a separate document.  
It is the responsibility of the Investigator to record essential information in the medical records in 
accordance with national regulations and requirements. The following information should be 
included as a minimum: 
• A statement that the subject is in a clinical trial 
• The identity of the trial e.g. Trial code 
• Subject number 
• That informed consent was obtained and the date 
• Diagnosis 
• Dates of all visits 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. 
13.3. 
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. 
13.4. 
Audits and Inspections 
Authorized representatives of Savara, a regulatory authority or an IRB may visit the site to 
perform audits or inspections, including source data verification. The purpose of a Savara audit 


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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, ICH GCP, and any applicable 
regulatory requirements. The Investigator should contact Savara immediately if contacted by a 
regulatory agency about an inspection. 
13.5. 
Institutional Review Board (IRB) 
The Investigator must obtain IRB approval for the investigation. Initial IRB approval, and all 
materials approved by the IRB for this study including the subject 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 IRB. 


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14. 
ETHICS 
14.1. 
Ethics Review 
This protocol and any amendments will be submitted to a properly constituted IRB, in 
accordance with the ICH guidelines, and applicable national regulations, for approval/favorable 
opinion. An approval/favorable opinion must be obtained in writing before the first subject can 
be recruited. 
14.2. 
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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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Data Management  
Data management and handling of data will be conducted according to the trial specific Data 
Management Plan with ICH guidelines and SOPs. 
An eCRF system will be used to capture data from the trial. Data entry will be performed by the 
trial site personnel. Validation and data queries will be handled by qualified 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. 
15.2. 
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 with the relevant dates (start and stop) and the action taken. 
Deviation reports will be kept in the Investigator’s file and in the trial master file. 
15.3. 
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. 
15.4. 
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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16. 
FINANCE AND INSURANCE 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.   This insurance policy is in accordance with local laws and 
requirements.  The insurance of the Sponsor does not relieve the Investigator and the 
collaborators from any obligation to maintain their own liability insurance policy.    An insurance 
certificate will be provided to the IEC/IRBs or regulatory authorities in countries requiring this 
document. 


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17. 
TRIAL ORGANIZATION 
The telephone numbers and fax numbers of relevant Sponsor staff, laboratories and other 
vendors are listed in the Investigator site file. 
 


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18. 
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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19. 
LIST OF REFERENCES 
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Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous 
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Adjemian J, Olivier KN, Prevots DR. Nontuberculous mycobacteria among cystic fibrosis 
patients in the united states: Screening practices and environmental risk. Am J Respir Crit Care 
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mycobacterial disease in adult cystic fibrosis patients. Chest 1993;103:1096-1099. 
Aitken ML, Limaye A, Pottinger P, Whimbey E, Goss CH, Tonelli MR et al. Respiratory 
outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic 
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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 
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Awuh JA, Flo TH. Molecular basis of mycobacterial survival in macrophages. Cellular and 
molecular life sciences : CMLS. 2017. 
Bange FC, Brown BA, Smaczny C, Wallace Jr RJ, Bottger EC. Lack of transmission of 
mycobacterium abscessus among patients with cystic fibrosis attending a single clinic. Clin 
Infect Dis 2001;32:1648-1650 
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-
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Bryant JM, Grogono DM, Greaves D, Foweraker J, Roddick I, Inns T, et al. Whole-genome 
sequencing to identify transmission of mycobacterium abscessus between patients with cystic 
fibrosis: A retrospective cohort study. Lancet 2013;381:1551-1560. 
Catherinot E, Roux AL, Vibet MA, Bellis G, Ravilly S, Lemonnier L, et al. Mycobacterium 
avium and mycobacterium abscessus complex target distinct cystic fibrosis patient 
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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. 
Field SK, Fisher D and Cowie RL. Mycobacterium avium complex pulmonary disease in 
patients without HIV infection. Chest 2004; 126(2): 566-81. 
Fleetwood AJ, Cook AD, Hamilton JA. Functions of granulocyte-macrophage colony-
stimulating factor. Crit Rev Immunol 2005;25(5):405-428. 
Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis 
Foundation and European Cystic Fibrosis Society consensus recommendations for the 
management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax 
2016;71 Suppl 1:i1-22.  
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. 
Hariadi NI, Blackwood RA. Disseminated Mycobacterium avium complex in an adolescent with 
perinatally-acquired HIV infection. Inf Dis Reports 2017; 9:6884 
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 
Jonsson BE, Gilljam M, Lindblad A, Ridell M, Wold AE, Welinder-Olsson C. Molecular 
epidemiology of mycobacterium abscessus, with focus on cystic fibrosis. J Clin Microbiol 
2007;45:1497-1504. 
Kedzierska K, Mak J, Mijch A, et al. Granulocyte-macrophage colony-stimulating factor 
augments phagocytosis of Mycobacterium avium complex by human immunodeficiency virus 
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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. 
Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, et al. Clinical significance of 
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of Mycobacterium avium Complex Lung Disease. Am J Respir Crit Care Med. 2006. 
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Chemother 2015; 59(6): 2972-7. 
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20. 
APPENDICES 


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APPENDIX 1. RATIONALE FOR AMENDMENTS AND LIST OF 
REVISIONS  
The protocol has undergone two amendments. 
Table 5: 
Table of Revisions 
Date 
Version 
Description of Document 
23AUG2018 
1.0 
Final Protocol 
01FEB2019 
2.0 
Updates based on Safety review of SAV008-01 and MOL-001 
studies.   
A number of clarifications and administrative changes were also 
implemented. 
12DEC2019 
3.0 
Removed the requirement for balanced enrollment in the 
MAC and MABSC subgroups 1, 2, and 3 
Updated Sample Size 
 A number of clarifications and administrative changes were also 
implemented. 
  


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APPENDIX 2. QUESTIONNAIRES 


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2.1 CYSTIC FIBROSIS QUESTIONNAIRE -REVISED 
 
 


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SAP_001.pdf: 
 
 
 
 
 
 
 
MOLGRAMOSTIM NEBULIZER SOLUTION 
STATISTICAL ANALYSIS PLAN 
SAV008-02 
 
An OpEn-label, Non-controlled, MultiCenter, PilOt Trial, using Inhaled Molgramostim in 
Cystic FibRosis Subjects with Nontuberculous Mycobacterial (NTM) InfEction 
(ENCORE) 
 
 
 
Product Name: 
Molgramostim Nebulizer Solution (Molgradex®) 300 µg 
Indication: 
Pulmonary NTM infection 
Phase: 
IIA 
IND Number: 
139376 
Sponsor: 
Savara Inc 
6836 Bee Cave Road, Building 3, Suite 200 
Austin, TX, 78746 
United States 
 
Date of Protocol: 
12-DEC-2019 
Protocol Version: 
3.0 
 
Date of SAP: 
09-DEC-2020 
SAP Version: 
1.0 


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ENCORE SAV008-002 SAP V1.0 
09DEC2020 
Page 2 of 53 
 
 
 
1 
SIGNATURE PAGE 
The signatures below indicate that these individuals have reviewed this project specific 
Statistical Analysis Plan and consent to this document as governing the tasks outlined 
within. The signatures below also indicate that the processes and quality standards set forth 
by this Statistical Analysis Plan are approved for use in this study. 
 
 
Name 
Title, 
Organization 
Signature 
Date 
Victoria 
Swaidan 
Lead, Statistical Programmer 
Biostatistician 
Biorasi, LLC 
09 December 2020 
Maj Dinesen, 
MD 
Clinical and Medical Lead, 
Savara 
09 December 2020 


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2 
DOCUMENT REVISION HISTORY 
 
 
 
Version # 
Issue Date 
Author 
Revisions 
0.1 
14-Jan-2020 
Jose Nabut 
Original document 
0.2 
25-Jun-2020 
Tri Tat 
SAP revised all in sections 
0.3 
31-Jul-2020 
Victoria 
Swaidan 
Generated mock TLF shells and finalized 
for submission of 1st draft. Revised 
sections 6.3.12, 6.3.18, 10.5. 
1.0 
07-Dec-2020 
Victoria 
Swaidan 
Finalization of SAP and mock TLF shells 
to be routed for signatures. 


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3 
TABLE OF CONTENTS 
1 
SIGNATURE PAGE .................................................................................................................. 2 
2 
DOCUMENT REVISION HISTORY ............................................................................................. 3 
3 
TABLE OF CONTENTS ............................................................................................................. 5 
4 
ABBREVIATIONS AND DEFINITIONS ....................................................................................... 9 
5 
INTRODUCTION .................................................................................................................. 11 
PREFACE ......................................................................................................................................................................................... 11 
PURPOSE OF THE ANALYSES ........................................................................................................................................................... 12 
6 
SUMMARY OF CHANGES TO THE PLANNED ANALYSES .......................................................... 12 
7 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................... 13 
STUDY OBJECTIVES ......................................................................................................................................................................... 13 
7.1.1 
Primary objectives .......................................................................................................................... 13 
7.1.2 
Secondary objectives ...................................................................................................................... 13 
7.1.3 
Exploratory objectives .................................................................................................................... 14 
ENDPOINTS..................................................................................................................................................................................... 14 
7.2.1 
Efficacy endpoints .......................................................................................................................... 14 
7.2.2 
Safety endpoints ............................................................................................................................. 16 
DERIVED VARIABLES ....................................................................................................................................................................... 16 
7.3.1 
NTM sputum culture conversion to negative ................................................................................. 16 
7.3.2 
NTM sputum smear conversion to negative ................................................................................... 16 
7.3.3 
Time to conversion ......................................................................................................................... 17 
7.3.4 
NTM sputum culture microbiological cure and Consistent NTM sputum smear conversion to 
negative (on-treatment) .................................................................................................................................... 17 
7.3.5 
Durable NTM sputum microbiological cure for NTM isolates & Durable NTM sputum smear 
conversion to negative (off-treatment) ............................................................................................................. 18 
7.3.6 
Change in semi-quantitative grade ................................................................................................ 18 
7.3.7 
Time to positivity ............................................................................................................................ 19 
7.3.8 
FEV1% predicted ............................................................................................................................. 19 
7.3.9 
Cystic Fibrosis Questionnaire-Revised (CFQ-R) ............................................................................... 19 
7.3.10 
Body mass index ............................................................................................................................. 20 
7.3.11 
Recurrence or reinfection after EOT ............................................................................................... 20 
7.3.12 
Eradication and/or reduction in bacterial load of co-infections ..................................................... 20 


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7.3.13 
Annual rate of pulmonary exacerbation ......................................................................................... 20 
7.3.14 
Change in CT scan interpretation .................................................................................................... 21 
7.3.15 
Change in WBC and differentials..................................................................................................... 21 
7.3.16 
GM-CSF concentration .................................................................................................................... 21 
8 
STUDY METHODS ................................................................................................................. 22 
GENERAL STUDY DESIGN AND PLAN .............................................................................................................................................. 22 
INCLUSION-EXCLUSION CRITERIA AND GENERAL STUDY POPULATION .......................................................................................... 28 
8.2.1 
Subject inclusion criteria ................................................................................................................. 28 
8.2.2 
Subject exclusion criteria ................................................................................................................. 30 
STUDY VARIABLES .......................................................................................................................................................................... 32 
8.3.1 
Study day ......................................................................................................................................... 32 
8.3.2 
End of treatment (EOT) visit ............................................................................................................ 32 
8.3.3 
Treatment period and Follow-up period ......................................................................................... 32 
8.3.4 
Visit windows .................................................................................................................................. 32 
8.3.5 
Baseline value ................................................................................................................................. 32 
9 
SAMPLE SIZE ........................................................................................................................ 33 
10 
GENERAL CONSIDERATIONS ................................................................................................. 33 
ANALYSIS POPULATIONS ................................................................................................................................................................ 33 
COVARIATES AND SUBGROUPS ...................................................................................................................................................... 33 
MISSING DATA ............................................................................................................................................................................... 33 
10.3.1 
Imputation of Adverse Start Event Dates ........................................................................................ 34 
10.3.2 
Imputation of Adverse Event Stop Dates ......................................................................................... 35 
10.3.3 
Imputation of Start and End Dates for Prior/Concomitant Medication and Surgical Procedures 35 
INTERIM ANALYSES AND DATA MONITORING .............................................................................................................................. 36 
MULTIPLE TESTING ........................................................................................................................................................................ 36 
11 
SUMMARY OF STUDY DATA ................................................................................................. 36 
SUBJECT DISPOSITION ................................................................................................................................................................... 36 
PROTOCOL DEVIATIONS ................................................................................................................................................................ 37 
DEMOGRAPHIC AND BASELINE VARIABLES ................................................................................................................................... 37 
CONCURRENT ILLNESSES AND MEDICAL CONDITIONS ................................................................................................................. 37 
PRIOR AND CONCURRENT MEDICATIONS ..................................................................................................................................... 37 
TREATMENT COMPLIANCE............................................................................................................................................................. 38 
12 
EFFICACY ANALYSES ............................................................................................................. 38 
PRIMARY EFFICACY ANALYSIS........................................................................................................................................................ 39 


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SECONDARY EFFICACY ANALYSES .................................................................................................................................................. 39 
12.2.1 
Overall Response Variables ............................................................................................................. 39 
12.2.2 
By-Visit Response Variables ............................................................................................................ 39 
12.2.3 
Time to Event Variables................................................................................................................... 39 
12.2.4 
Continuous Variables ...................................................................................................................... 40 
EXPLORATORY EFFICACY ANALYSES .............................................................................................................................................. 40 
12.3.1 
Overall Response ............................................................................................................................. 40 
12.3.2 
By-Visit Response ............................................................................................................................ 40 
12.3.3 
Continuous Variables ...................................................................................................................... 40 
13 
SAFETY ANALYSES ................................................................................................................ 41 
EXTENT OF EXPOSURE.................................................................................................................................................................... 41 
13.1.1 
Inhaled molgramostim .................................................................................................................... 41 
13.1.2 
Antimycobacterial therapy .............................................................................................................. 41 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, DEATHS, AND OTHER SIGNIFICANT ADVERSE EVENTS ..................................... 41 
13.2.1 
Overview of TEAEs ........................................................................................................................... 42 
13.2.2 
TEAEs by SOC and PT ....................................................................................................................... 43 
PREGNANCIES................................................................................................................................................................................. 43 
CLINICAL LABORATORY EVALUATIONS .......................................................................................................................................... 43 
13.4.1 
Change from same visit baseline..................................................................................................... 45 
OTHER SAFETY MEASURES ............................................................................................................................................................ 45 
13.5.1 
Pulmonary Function Test (PFT) ........................................................................................................ 45 
13.5.2 
Vital signs ........................................................................................................................................ 45 
13.5.3 
Electrocardiogram (ECG) ................................................................................................................. 45 
13.5.4 
Computed Tomography (CT) ........................................................................................................... 46 
13.5.5 
Physical examination (PE) ............................................................................................................... 46 
14 
PHARMACOKINETICS ........................................................................................................... 46 
GM-CSF CONCENTRATION .......................................................................................................................................................... 46 
15 
FIGURES ............................................................................................................................... 47 
EFFICACY ........................................................................................................................................................................................ 47 
SAFETY ............................................................................................................................................................................................ 47 
16 
REPORTING CONVENTIONS .................................................................................................. 47 
17 
REFERENCES ........................................................................................................................ 47 
18 
LISTING OF TABLES, LISTINGS AND FIGURES .......................................................................... 49 
19 
APPENDICES ........................................................................................................................ 50 


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CFQ-R TEEN/ADULT VERSION SCORING INSTRUCTIONS ............................................................................................................ 50 
19.1.1 
General Scoring Instructions ........................................................................................................... 50 
19.1.2 
SAS Program Codes for Scoring the CFQ-R Teen/Adult Version ...................................................... 51 
PULMONARY EXACERBATION MEDDRA SEARCH LIST................................................................................................................. 53 
ANTI-MYCOBACTERIAL MEDICATION WHO DRUG DICTIONARY SEARCH LIST ......................................................................... 54 


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4 
ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation or Specialist Term 
Explanation 
AFB 
Acid Fast Bacilli 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ATS 
American Thoracic Society 
BMI 
Body Mass Index 
CF 
Cystic Fibrosis 
CFF 
Cystic Fibrosis Foundation 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFTR 
Cystic Fibrosis Transmembrane Conductance Regulator 
CI 
Confidence Interval 
CHF 
Congestive Heart Failure 
CT 
Computed Tomography 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
FEV1 
Forced Expiratory Volume in One Second 
FVC 
Forced Vital Capacity 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
GLI 
Global Lung Function Initiative 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IDSA 
Infectious Diseases Society of America 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower Limit of Quantification 
MABSC 
M. abscessus Complex 
MAC 
M. avium Complex 


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MedDRA 
Medical Dictionary for Regulatory Activities 
NTM 
Nontuberculous Mycobacteria 
NTM-PD 
Nontuberculous Mycobacterial Pulmonary Disease 
NYHA 
New York Heart Association 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetics 
PT 
Preferred Term 
Q1 
1st Quartile (25th Percentile) 
Q3 
3rd Quartile (75th Percentile) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
WBC 
White Blood Cells 


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5 
INTRODUCTION 
 
Preface 
 
Clinical trials in NTM show microbiologic disease recurrence both during and following 
treatment. One study found that during therapy microbiologic disease occurred in 14% of 
patients (73% with reinfection MAC isolates, 27% with true relapse isolates: p = 0.03) and 
microbiologic disease recurred in 74 of 155 patients (48%) after completion of therapy (75% 
reinfection isolates, 25% true relapse isolates) [ Wallace 2014]. 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]. Nontuberculous mycobacteria do progressively acquire drug-resistance, including to 
rifampicin, amikacin, macrolides and quinolones [Cowman 2016, Heidarieh 2016, Zhao 2014]. 
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 recurrence after apparent cure is 
desperately required [Griffith 2016]. 
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% [Field 
2004, Stout 2016, Xu 2014]. 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 (30–48%), especially in patients with 
nodular bronchiectatic lung disease [Lee 2015, Wallace 2014]. There is limited data on 
treatment outcomes in patients with CF and NTM infection. However, new treatments are 
urgently required. The current study is a pilot study in three groups of subjects, all with a 
confirmed CF diagnosis and chronic pulmonary NTM infection: 1. subjects who are on NTM 
antimycobacterial therapy who have not consistently achieved negative NTM sputum cultures; 
2. subjects who are not on NTM antimycobacterial therapy as they have not responded to 
multidrug NTM guideline-based antimycobacterial regimens in the past for reasons of lack of 
efficacy or inability to tolerate the drug regimen; and 3. subjects who are not on NTM 
antimycobacterial therapy as they do not meet established guidelines for treatment despite 
persistent sputum culture positivity (ref: ATS position statement, CF guidelines). An increased 
risk of death has been shown with both NTM-pulmonary disease (hazard ratio 1.63) and NTM 
isolation without pulmonary disease (hazard ration 1.33) compared to matched controls 


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[Marras 2013]. Thus, there is a rationale for treatment also of the previously untreated group of 
patients. 
 
Purpose of the analyses 
 
As described in the protocol the analyses will assess the efficacy and safety of inhaled 
molgramostim in the three groups of subjects. Results will be included in the clinical study 
report. 
 
6 
SUMMARY OF CHANGES TO THE PLANNED ANALYSES 
The protocol states that the statistical analyses will be conducted on the three groups of 
subjects separately. In addition, (not described in the protocol) the analyses will also assess the 
efficacy and safety of inhaled molgramostim in the overall group of subjects combining the 
three described groups. 
According to the protocol, secondary efficacy analyses in the form of “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 at each assessment visit. The SAP expands 
these analyses by also including statistics for the mean, standard deviation (SD), 25th percentile 
(Q1), and 75th percentile (Q3). 
Additional analyses not covered in the protocol are included in the SAP for elucidation of all 
safety data collected. These analyses include Summary of and Change from Baseline in FVC, 
FEV1/FVC, Vital Sign parameters, and ECG parameters. 
Although the protocol states that a minimum of 30 subjects are to be enrolled, the study 
terminated early (with 14 subjects) due to COVID-19, with concerns related to challenges in 
recruitment, continued participation, and site operations. Due to this early termination, not all 
patients have completed the planned 48-week treatment period and some specified analyses 
may have insufficient data (e.g., CT scans, anti-drug antibodies, clinically significant decrease in 
FEV1 % predicted). 
The protocol states that “A scoring system for central reading of the scans will be 
defined at a later timepoint.” In view of the early termination of the trial, the low 
number of enrolled subjects, and CT being an exploratory endpoint only, a scoring 
system for central reading will not be defined after all. Instead, CT scans will be 
evaluated by whether they are reported as Normal, Abnormal but Not Clinically 
Significant, or Abnormal and Clinically Significant. 


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“Development of anti-drug antibodies during Treatment period and Follow-up period” is 
included as safety endpoint 7.5 in the protocol. However, as a validated assay is not available 
currently (nor in the foreseeable future) this endpoint will not be included after all. 
The safety endpoint 7.3 “A clinically significant decrease in FEV1 (% predicted) from Baseline to 
Treatment visits that does not respond to typical CF treatment (including treatment of 
pulmonary exacerbation if suspected) and in the judgement of the Investigator is not due to 
typical complication of CF (i.e. acute pulmonary exacerbation).” is included in the protocol, but 
has been removed from the planned analyses due to lack of process for obtaining this 
information as well as low sample-size and premature trial termination. 
 
7 
STUDY OBJECTIVES AND ENDPOINTS 
 
Study objectives 
 
There are 13 objectives in the study, numbered [1] to [13]. Endpoints addressing these 
objectives are listed in section 7.2. Objectives [8] and [9] are subgroup analyses using subgroup 
variables in section 10.2 and relevant endpoints from section 7.2. 
 
7.1.1 
Primary objectives 
 
To investigate efficacy of inhaled molgramostim on NTM sputum culture conversion to 
negative. [objective 1] 
 
7.1.2 
Secondary objectives 
 
• 
To investigate efficacy of inhaled molgramostim on NTM sputum smear conversion to 
negative. [objective 2] 
• 
To investigate efficacy of inhaled molgramostim on reduction of NTM bacterial load in 
sputum. [objective 3] 
• 
To investigate efficacy of inhaled molgramostim on pulmonary function. [objective 4] 
• 
To investigate efficacy of inhaled molgramostim on patient reported outcomes. [objective 
5] 
• 
To investigate efficacy of inhaled molgramostim on body mass index (BMI). [objective 6] 
• 
To investigate safety of inhaled molgramostim in subjects with NTM infection. [objective 7] 


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7.1.3 
Exploratory objectives 
 
• 
To investigate efficacy in subjects infected with M. abscessus complex (MABSC) and M. 
avium complex (MAC), respectively. [objective 8] 
• 
To investigate efficacy in subjects on concurrent anti-mycobacterial treatment and subjects 
not on anti-mycobacterial treatment, respectively. [objective 9] 
• 
To investigate rates of recurrence and reinfection after End of Treatment. [objective 10] 
• 
To investigate efficacy of inhaled molgramostim on bacterial co-infections. [objective 11] 
• 
To investigate efficacy of inhaled molgramostim on frequency of pulmonary exacerbations. 
[objective 12] 
• 
To investigate efficacy of inhaled molgramostim on morphologic findings on computed 
tomography (CT) scans of the lung. [objective 13] 
 
Endpoints 
 
The endpoints are numbered [a.b] where a labels the objective (numbering in section 7.1) and 
b is a numbering for the endpoint addressing the objective a. 
 
7.2.1 
Efficacy endpoints 
 
7.2.1.1 
Primary efficacy endpoint: 
 
• 
Proportion of subjects with NTM sputum culture conversion to negative (defined as at least 
three consecutive negative mycobacterial cultures collected at least 4 weeks apart during 
the Treatment period). [endpoint 1.1] 
 
7.2.1.2 
Secondary efficacy endpoints: 
 
• 
Proportion of subjects with NTM sputum culture microbiological cure (defined as multiple 
consecutive negative but no positive cultures with the causative species after last culture 
conversion and until the End of Treatment (Week 48)). [endpoint 1.2] 
• 
Time (weeks) to first NTM sputum culture conversion during the Treatment period. 
[endpoint 1.3] 
• 
Proportion of subjects with sputum smear conversion to negative (defined as at least three 
consecutive negative acid-fast bacilli (AFB) stained sputum smears on microscopy, collected 
at least 4 weeks apart in subjects who were smear positive at Baseline) during the 
Treatment period. [endpoint 2.1] 


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• 
Proportion of subjects with consistent sputum smear conversion to negative (defined as 
multiple consecutive negative but no positive smears after last smear conversion and until 
the End of Treatment (Week 48) in subjects who were smear positive at Baseline). 
[endpoint 2.2] 
• 
Time (weeks) to first NTM sputum smear conversion during the Treatment period. 
[endpoint 2.3] 
• 
Proportion of subjects with durable NTM sputum microbiological cure for the NTM 
isolate(s) treated without recurrence at Week 12 after End of Treatment. [endpoint 1.4] 
• 
Proportion of subjects with durable NTM sputum smear conversion to negative without 
subsequent positive smears at Week 12 after End of Treatment. [endpoint 2.4] 
• 
Change in semi-quantitative grade of number of NTM on microscopy of AFB stained 
sputum smears from Baseline to End of Treatment and Week 12 after End of Treatment. 
[endpoint 3.1] 
• 
Absolute change in FEV1 (percent predicted) from Baseline to End of Treatment and Week 
12 after End of Treatment. [endpoint 4.1] 
• 
Change in respiratory domain score assessed by Cystic Fibrosis Questionnaire-Revised 
(CFQ-R) from Baseline to End of Treatment and Week 12 after End of Treatment. [endpoint 
5.1] 
• 
Change in BMI from Baseline to End of Treatment and Week 12 after End of Treatment. 
[endpoint 6.1] 
 
7.2.1.3 
Exploratory Endpoints: 
 
• 
Change from Baseline in time to positivity on NTM liquid culture media at Treatment visits 
and Follow-up. [endpoint 1.5] 
• 
Change in semi-quantitative grade of sputum cultures from Baseline to Treatment visits 
and Follow-up. [endpoint 3.2] 
• 
Proportion of subjects with recurrence (re-emergence of the treated NTM species after End 
of Treatment), or reinfection (emergence of a different NTM species, after End of 
Treatment). [endpoint 10.1] 
• 
Proportion of subjects with eradication and/or reduction in bacterial load of co-infections 
in sputum. [endpoint 11.1] 
• 
Frequency of pulmonary exacerbations compared to the previous year. [endpoint 12.1] 
• 
Change in CFQ-R scores for each of the HrQoL domains (physical functioning, vitality, health 
perceptions, treatment burden, body image, eating, role functioning, emotional 
functioning, social functioning), each of the Symptoms domains, except respiratory, (weight 
and digestion)[endpoint 5.2] 


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• 
Change in CT scans of the lungs from Baseline to End of Treatment (Week 48). [endpoint 
13.1] 
 
7.2.2 
Safety endpoints 
 
• 
Number of AEs, serious adverse events (SAEs), adverse drug reactions (ADRs), severe AEs 
and AEs leading to treatment discontinuation during the trial period. [endpoint 7.1] 
• 
Change in white blood cell counts (WBC) and differentials in blood from Baseline to 
Treatment visits. [endpoint 7.2] 
• 
GM-CSF concentration levels during Treatment period. [endpoint 7.4] 
 
Derived variables 
 
7.3.1 
NTM sputum culture conversion to negative 
 
Inclusion criterion 6 requires the sputum culture to be positive for the same species (MAC) or 
subspecies (MABSC) of NTM at Screening and Baseline. Therefore, the causative 
species/subspecies is identified at Screening and confirmed at Baseline. 
A sputum culture conversion to negative is defined as having a negative result(a) on 3 or more 
consecutive on-treatment visits(b) that are at least 4 weeks apart. 
(a) A negative result is defined as being negative for the causative species/subspecies, even if 
it is positive for a non-causative species/subspecies. 
(b) Subjects may experience more than 1 conversion. The start of a conversion is the date of 
the first negative visit. The first negative visit must occur during the treatment period, i.e. 
between first dose of study drug (inclusive) to last dose of study drug (inclusive). After a 
run of at least 3 consecutive negative visits, the end of a conversion is followed by a next 
visit with positive result. The end of the conversion is the date of the last negative visit. 
(c) The criterion that each of the 3 consecutive monthly visits should be at least 4 weeks (i.e. 
within the allowed visit windows) apart will be upheld. Since visit windows are 28±7 days, 
the 3 consecutive visit duration can range from 43 to 71 days. 
The primary endpoint Sputum Culture Conversion to Negative [endpoint 1.1] is defined as 
having at least 1 sputum culture conversion to negative. 
 
7.3.2 
NTM sputum smear conversion to negative 
 
Inclusion/exclusion criteria do not require the sputum smear to have a positive acid-fast bacilli 
(AFB) stain at Screening and Baseline. Therefore, subjects can be smear negative at Baseline. 


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A sputum smear conversion to negative is defined as having a negative result(a) on 3 or more 
consecutive on-treatment visits(b) that are at least 4 weeks apart(c). in a subject who was smear 
positive at Baseline. 
(a) A negative result is defined as a negative AFB stained sputum smear on microscopy. 
(b) Subjects may experience more than 1 conversion. The start of a conversion is the date of 
the first negative visit. The first negative visit must occur during the treatment period, i.e. 
between first dose of study drug (inclusive) to last dose of study drug (inclusive). (Note, the 
baseline smear result is not considered even if the subject had a smear negative result at 
Baseline.) After a run of at least 3 consecutive negative visits, the end of a conversion is 
followed by a next visit with positive result. The end of the conversion is the date of the last 
negative visit. 
(c) The criterion that each of the 3 consecutive visits should be at least 4 weeks (within the 
allowed visit windows) apart will be upheld. Since visit windows are 28±7 days, the 3 
consecutive visit duration can range from 43 to 71 days. 
The secondary endpoint of Sputum Smear Conversion to Negative [endpoint 2.1] is defined as 
having at least 1 sputum smear conversion to negative. 
 
7.3.3 
Time to conversion 
 
Time to sputum culture conversion [endpoint 1.3] will be calculated as: 
(Date of first negative visit of the first culture conversion)-(Date of first dose)+1 
 
 
Time to sputum smear conversion [endpoint 2.3] will be calculated as: 
(Date of first negative visit of the first smear conversion)-(Date of first dose)+1 
 
7.3.4 
NTM sputum culture microbiological cure and Consistent NTM sputum smear conversion to 
negative (on-treatment) 
 
Sputum culture microbiological cure [endpoint 1.2] is defined as having all visits from the last 
culture conversion and until End of Treatment (EOT) be negative for the causative 
species/subspecies. Note, EOT (See section 8.3.2 for definition of EOT). Only subjects with 
culture conversion to negative can potentially experience microbiological cure. 
Assessment of culture microbiological cure will consider only the on-treatment scheduled and 
on-treatment unscheduled visits. 


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Consistent sputum smear conversion to negative [endpoint 2.2] is defined similar to sputum 
culture microbiological cure but based on sputum smear results. 
 
7.3.5 
Durable NTM sputum microbiological cure for NTM isolates & Durable NTM sputum smear 
conversion to negative (off-treatment) 
 
Durable sputum microbiological cure for NTM isolates [endpoint 1.4] is defined as having 
negative culture at EOT and negative results at all visits up to the Follow up Week 12 visit. Only 
subjects with culture conversion to negative during the treatment period (and microbiological 
cure during the remainder of the treatment period if applicable) can potentially experience 
durable microbiological cure. 
Durable sputum smear conversion to negative [endpoint 2.4] is defined similar to durable 
sputum microbiological cure for NTM isolates but based on sputum smear results. 
 
7.3.6 
Change in semi-quantitative grade 
 
Semi-quantitative grades are (negative, scant, 1+, 2+, 3+) assessed at Screening, Baseline, 
Treatment Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48/EOT, and Follow-up Weeks 4, 
12, and 24. Sputum smear data are collected using the semi-quantitative grades directly, as 
presented as follows: 
• No AFB found 
• 1+ = 2 to 18 AFB/50 fields observed 
• 2+ = 4 to 36 AFB/10 fields observed 
• 3+ = 4 to 36 AFB/fields observed 
• 4+ >36 AFB/fields observed 
Sputum culture data are categorized into the semi-quantitative grades as follows: 
• Negative = 0 colonies 
• Scant = 1-5 colonies 
• 1+ = 5-25 colonies 
• 2+ = 25-100 colonies 
• 3+ = 100-200 colonies 
• 4+ >200 colonies 


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Shifts between (negative, scant, 1+, 2+, 3+) categories will be used to describe change from 
baseline to each treatment visit and each follow-up visit in semi-quantitative grade for sputum 
smear [endpoint 3.1] and sputum culture [endpoint 3.2]. 
Categorized decrease will be defined as shift from grade (scant, 1+, 2+ or 3+) to any lower 
grade. 
 
7.3.7 
Time to positivity 
 
The time to positivity on NTM liquid culture media will be assessed for each sputum culture. 
Since this is time to event type data, the distribution of the data may not be normally 
distributed. In addition, to calculating the absolute change from baseline [endpoint 1.5], the 
fold change = (post-baseline)/(baseline) will be calculated for analysis. 
 
 
7.3.8 
FEV1% predicted 
 
Pulmonary function tests (FEV1, FVC and FEV1/FVC) are assessed at Screening, Baseline (pre- 
dose, 1.5h post-dose), Treatment Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48/EOT, 
and Follow-up Weeks 4, 12, 24. 
The absolute change from baseline in FEV1% predicted [endpoint 4.1] will be calculated. 
 
7.3.9 
Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
 
CFQ-R (Teen/Adult version) containing 50 items is assessed at Baseline, Treatment Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44 and 48/EOT, and Follow-up Weeks 4, 12, 24. The items will be 
used to derive 9 quality of life domains (physical, role, vitality, emotion, social, body image, 
eating, treatment burden, health perceptions) and 3 symptom scales (weight, respiratory, and 
digestion). The scoring instruction instructions for the domains/symptom scales are in Appendix 
section 19.1. 
Absolute change from baseline in the respiratory symptom scale [endpoint 5.1] will be analyzed 
as a secondary endpoint. 
Absolute change from baseline in the remaining domains (physical, role, vitality, emotion, 
social, body image, eating, treatment burden, health perceptions, weight, and digestion) will be 
analyzed as exploratory endpoints [endpoints 5.2]. 


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7.3.10 Body mass index 
 
Height is assessed at Screening only. Weight is assessed at Baseline, Treatment Weeks 1, 2, 4, 8, 
12, 16, 20, 24, 24, 28, 32, 36, 40, 44 and, 48/EOT, and Follow-up Weeks 4, 12, 24. BMI is 
calculated as (weight kg)/(height m)2. The absolute change from baseline in BMI [endpoint 6.1] 
will be calculated. 
 
7.3.11 Recurrence or reinfection after EOT 
 
Recurrence will be defined as having two sputum cultures positive for the causative 
species/subspecies after EOT in subjects who have achieved microbiological cure at EOT. 
Reinfection will be defined as having two sputum cultures positive for any non-causative 
species/subspecies after EOT in subjects who have achieved microbiological cure at EOT. 
The exploratory endpoint is defined as having either recurrence or reinfection [endpoint 10.1]. 
Assessment of recurrence and reinfection will consider only the follow-up visits. 
7.3.12 Eradication and/or reduction in bacterial load of co-infections 
 
Co-infection is identified as having a positive culture with non-causative bacteria (i.e. not NTM). 
Bacterial load is quantified as: 
1+ = rare growth 
2+ = light growth 
3+ = moderate growth 
4+ = heavy growth 
UNK = Unknown 
Reduction is defined as a decrease of at least 1 grade in the bacterial load. Eradication is 
defined as having no growth or organism not present. 
Therefore, the exploratory endpoint is defined as having a reduction of at least 1 grade in 
bacterial load of the non-causative organism(s). [endpoint 11.1] This will be calculated at each 
visit. 
 
7.3.13 Annual rate of pulmonary exacerbation 
 
Number of pulmonary exacerbation events within the last year prior to baseline will be 
estimated in respiratory history CRF. 


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The incidence rate (events per year) of pulmonary exacerbation events during the study will be 
calculated as the number of pulmonary exacerbation treatment-emergent adverse events 
divided by the length (years) of adverse event observation period ([date of study 
completion/early withdrawal – date of first dose + 1]/365.25). Pulmonary exacerbation events 
occurring during the treatment-emergent period will be identified using MedDRA search 
criteria (Appendix section 19.2). 
The ratio of the annual rate during the study to the annual rate last year will be constructed for 
each subject. [endpoint 11.1] 
 
7.3.14 Change in CT scan interpretation 
 
CT scan is assessed at Baseline and Week 48/EOT. Change from baseline will be described by 
shift in categories of CT scan interpretation: normal, abnormal not clinically significant (NCS), 
abnormal clinically significant (CS). 
 
7.3.15 Change in WBC and differentials 
 
WBC and differentials are assessed at Screening, Baseline*, Treatment Weeks 1*, 2*, 4*, 8, 12*, 
16, 20, 24*, 28, 32, 36*, 40, 44, 48*/EOT*, and Follow-up Weeks 4, 12, 24. At visits annotated 
with *, the WBC and differentials are assessed at pre-dose and 2h post-dose. 
Absolute change from baseline will be calculated using the Day 1 pre-dose as baseline. 
[endpoint 7.2] 
In addition, the absolute change from same day pre-dose baseline will be calculated on visits 
annotated with *. 
 
7.3.16 GM-CSF concentration 
 
GM-CSF is assessed at Baseline*, Treatment Weeks 2*, 12*, 24*, 36*, 48*/EOT* and Follow-up 
Weeks 12, 24. Visits annotated with * have GM-CSF is assessed at pre-dose and 2h post-dose. 
The following GM-CSF concentration levels are assessed: pre-dose baseline, Cmin (pre-dose 
during treatment), Cmax after dosing (2h post-dose during treatment) and at 12 and 24 weeks 
after last dose. [endpoint 7.4] 


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8 
STUDY METHODS 
 
General study design and plan 
 
This is an open-label, non-controlled, multicenter, pilot clinical trial of inhaled molgramostim in 
cystic fibrosis (CF) subjects with NTM infections. The study will include up to 34 subjects. 
The Screening period will begin up to 10 weeks prior to the Baseline visit for collection of the 
sputum sample, but the remainder of the assessments including Safety labs will be completed 
within 6 weeks of Baseline, to determine eligibility. Adult subjects with a history of CF and 
chronic pulmonary NTM infection will be considered for enrollment. Chronic pulmonary NTM 
infection will be defined by at least three positive NTM cultures (sputum or broncho-alveolar 
lavage (BAL)) for the same species/subspecies of MAC or MABSC within the 2 years prior to 
screening, with at least one positive within the past 6 months prior to screening and a minimum 
of 50% of NTM cultures positive over the past 2 years. Subjects must additionally provide a 
positive sputum culture with the same species/subspecies obtained from the central laboratory 
during the Screening period to be eligible. 
Three groups of subjects will be recruited: 
• 
Group 1: Subjects with chronic pulmonary MAC or MABSC infection who have not 
consistently achieved negative NTM sputum cultures while currently on a multidrug NTM 
guideline-based antimycobacterial regimen, which has been ongoing for at least 9 months 
prior to the Baseline visit. 
• 
Group 2: Subjects with chronic pulmonary MAC or MABSC infection 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. 
• 
Group 3: Subjects with chronic pulmonary MAC or MABSC infection not meeting 
recommendations for treatment with a multidrug NTM guideline-based antimycobacterial 
regimen based on failure to meet American Thoracic Society/Infectious Disease Society of 
America (ATS/IDSA) criteria for NTM pulmonary disease (i.e. absence of radiologic findings 
and clinical symptoms beyond what is expected from underlying CF). 
Subjects in all 3 groups will receive open-label treatment with inhaled molgramostim given at a 
dosage of 300 g once daily for 48 weeks administered via the Investigational eFlow Nebulizer 
System. 
All subjects will have a Screening, Baseline, Week 1, 2, and followed by monthly Treatment 
visits from week 4 during the Treatment period. The Treatment period will be 48 weeks. 
Following the End of Treatment, subjects will have a Follow-up visit at 4 and 12 weeks, and the 


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End of Study visit 24 weeks after the End of Treatment. At the Baseline visit, eligible subjects 
will start treatment with inhaled molgramostim. A detailed Schedule of Assessments is outlined 
in Table 1. 


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Table 1: 
Study schedule of assessments 
 
Screening 
Baseline 
Treatment Period 
End of 
Treatment 
(EOT) 
Follow-up (FU) 
End of 
Study 
Unsche 
duled 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
UV 
Study Week 
-10 to -1 d 0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
FU4 
FU12 
FU24 
a 
Day 
-70 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
Window (days) 
±3 
±3 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
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 
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 
X 
X 
X 
X 
Pregnancy test 
and 
contraceptive 
check 
X 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Physical 
exam/Brief 
Exam 
X 
Xl 
Xl 
X 
X 
X 
X 
X 
X 
(X) 


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Screening 
Baseline 
Treatment Period 
End of 
Treatment 
(EOT) 
Follow-up (FU) 
End of 
Study 
Unsche 
duled 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
UV 
Study Week 
-10 to -1 d 0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
FU4 
FU12 
FU24 
a 
Day 
-70 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
Window (days) 
±3 
±3 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
Vital signs 
X 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
X 
X 
Xj 
X 
X 
Xj 
X 
X 
Xj 
X 
X 
X 
(X) 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
PFTs b 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of 
sputum sample 
for 
microbiology 
Xc,d 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
(X) 
Laboratory 
safety sampling 
X 
Xi 
Xk 
Xk 
Xi 
X 
Xi 
X 
X 
Xi 
X 
X 
Xi 
X 
X 
Xi 
X 
X 
X 
(X) 
Samples for 
GM-CSF and 
anti-GM-CSF 
antibodies 
Xe 
Xe 
Xe 
Xe 
Xe 
X e 
X 
X 
(X) 
CTf 
X 
X 
(X) 
Questionnaire 
CFQ-R 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Subject Diary 
Dispensed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening 
Baseline 
Treatment Period 
End of 
Treatment 
(EOT) 
Follow-up (FU) 
End of 
Study 
Unsche 
duled 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
UV 
Study Week 
-10 to -1 d 0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
FU4 
FU12 
FU24 
a 
Day 
-70 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
Window (days) 
±3 
±3 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
Trial drug 
administration 
trainingg 
X 
(X) 
Trial drug 
dosing at site 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
(X) 
Dispense trial 
drug 
X 
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 
X 
X 
(X) 
Compliance 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
Abbreviations: PFT=pulmonary function test; AE=adverse event; CFQ-R= Cystic Fibrosis Questionnaire-Revised; CT= Computed tomography; ECG= 
electrocardiogram; GM-CSF=granulocyte macrophage colony stimulating factor; 
a Procedures marked with brackets should be performed as necessary. 
b Pulmonary function tests (FEV1, FVC and FEV1/FVC). At Baseline, PFTs will be performed pre-dose and post dose according to section 12.12.1. 
c Two additional sputum samples collected for NTM culture will be collected at home preferably on consecutive days and within 5 days of the site visit. 
d The screening NTM sample may be collected up to 10 weeks prior to baseline, after collection of informed consent. The remainder of screening visit should 
occur within 6 weeks of the Baseline visit. 


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e Samples for GM-CSF and anti-GM-CSF antibodies to be taken before dosing at the site. An additional sample for GM-CSF to be taken approximately 2 hours post 
dose for subjects that remain on IMP. 
f A CT scan of the lung performed up to 6 months prior to the Baseline visit is accepted. If Early End of Treatment Visit occurs prior to or at Week 12, then a CT 
scan is not required at Early End of Treatment Visit. In case of a clinically significant drop in FEV1 not responding to standard CF care, the CT scan may be 
repeated. If a chest radiograph is done information on the results will be collected. 
g Re-training can take place at all visits in the treatment period 
h Trial drug dosing should be performed after blood sampling. 
i Safety laboratory samples to be taken before dosing at the site. White blood cell count (WBC) and differentials to be repeated approximately 2 hours post dose 
for subjects that remain on IMP. 
j Repeat vital signs approximately 2 hours post dosing for subjects that remain on IMP. 
k WBC with differential will be collected pre-dose and approximately 2 hours post dose at visits 3 and 4. No additional safety laboratory assessments will be 
collected at this visit. 
l For Week 1 and 2, Brief exam of lungs and symptom oriented physical exam should be performed. 
m A urine pregnancy test will be performed for females in addition to the serum pregnancy test at the baseline visit. 


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Inclusion-exclusion criteria and general study population 
 
8.2.1 
Subject inclusion criteria 
 
1. Written informed consent obtained from participant. 
2. Confirmed diagnosis of CF according to the Cystic Fibrosis Foundation (CFF) 2017 
Consensus Guidelines. 
3. History of chronic pulmonary infection with M. avium complex (MAC) or M. abscessus 
complex (MABSC) (defined as at least three positive NTM cultures (sputum or BAL for the 
same species (MAC) or subspecies (MABSC) within the 2 years prior to the screening visit, 
with at least one positive within the past 6 months and a minimum of 50% of NTM cultures 
positive over the past 2 years) that does not demonstrate response to current treatment 
course based on decreasing NTM burden or frequency of positive cultures, and in the 
opinion of the Investigator is unlikely to resolve with current treatment course. 
4. Subject fulfills criteria for inclusion in one of the following groups: 
o 
Group 1: Subject with chronic pulmonary MAC or MABSC infection currently on a 
multidrug NTM guideline-based antimycobacterial regimen, which has been ongoing 
for at least 9 months prior to the Baseline visit. 
o 
Group 2: Subject with chronic pulmonary MAC or MABSC infection who has stopped a 
multidrug NTM guideline-based antimycobacterial regimen at least 28 days prior to 
Screening due to lack of response or intolerance. 
o 
Group 3: Subjects with chronic pulmonary MAC or MABSC infection not meeting 
recommendations for treatment with a multidrug NTM guideline-based 
antimycobacterial regimen based on failure to meet ATS/IDSA criteria for NTM 
pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond 
what is expected from underlying CF). 
5. Ability to produce sputum or be willing to undergo an induction protocol that produces 
sputum for clinical evaluation. 
6. An additional sputum culture performed by the central laboratory, which is positive for the 
same species (MAC) or subspecies (MABSC) of NTM as before the trial within 10 weeks of 
Baseline. 
7. CF which in the Investigator’s opinion is clinically stable and is not expected to require lung 
transplantation within the next year. 
8. FEV1 ≥ 30% of predicted at screening that is normalized for age, gender, race, and height, 
using the Global Lung Function Initiative (GLI) equation. 


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9. Subjects who are co-infected with a respiratory pathogen, e.g. P. aeruginosa or S. aureus, 
must either be stable on a regular suppression antibiotic regimen or must be, in the 
opinion of the Investigator, stable despite the lack of such treatment. 
10. Female or male ≥18 years of age. 
11. If female, subjects 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) during and until 30 days after 
last dose of trial treatment, having 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. 
For purposes of this study, the Sponsor defines “acceptable methods of contraception” as: 
o 
Oral birth control pills administered for at least 1 monthly cycle prior to administration 
of the study drug. 
o 
A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior 
to the study drug administration but not beyond the 4th successive year following 
insertion. 
o 
Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 monthly cycle 
prior to study drug administration. 
o 
Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1 
monthly cycle prior to administration of the study drug and continuing through 1 
month following study completion. 
o 
Hysterectomy or surgical sterilization. 
o 
Vasectomized partner. 
o 
Abstinence. 
Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive 
foam) is not considered an acceptable from of contraception. 
NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal 
contraceptive exposure, reducing the effectiveness and increasing the incidence of 
menstruation-associated adverse reactions. Hormonal contraceptives, including oral, 
injectable, transdermal, and implantable, should not be relied upon as an effective method 
of contraception when co-administered with Orkambi. 
12. If male, subjects who, if sexually active of reproductive potential and non-sterile (i.e., male 
who has not been sterilized by vasectomy for at least 6 months and not diagnosed with 
infertility through demonstration of azoospermia in a semen sample and/or absence of vas 
deferens through ultrasound) are willing to use a barrier method of contraception, or their 


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female partner must use an acceptable method of contraception, during the study and 
until 30 days after last dose of medication. 
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures specified in the protocol as judged by the Investigator. 
 
8.2.2 
Subject exclusion criteria 
 
1. Use of non-maintenance antibiotic for a concurrent pulmonary or extrapulmonary infection 
within 28 days prior to the Baseline visit. 
2. Use of a maintenance antibiotic regimen containing azithromycin for a concurrent non- 
NTM pulmonary infection within 28 days prior to the Baseline visit. For subjects in Group 1, 
azithromycin is allowed if part of ongoing multidrug NTM guideline-based 
antimycobacterial regimen. 
3. Prior therapy with inhaled or systemic granulocyte macrophage colony stimulating factor 
(GM-CSF). 
4. Subjects with hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to Screening. 
5. Life expectancy of less than 6 months according to Investigator’s judgement. 
6. History of, or present, myeloproliferative disease, leukemia or other hematological 
malignancy. 
7. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring 
chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during 
the study period. 
8. Active autoimmune disorder or other condition requiring therapy associated with 
significant immunosuppression, e.g., such as systemic corticosteroids at a dose equivalent 
of 10 mg/day or more of prednisolone, or other significant immunosuppressant 
medication, within 3 months prior to Screening or anticipated during the study period. 
Inhaled or topical corticosteroids, or brief courses (< 14 days) of systemic corticosteroids 
for pulmonary exacerbations or other self-limited conditions are permitted. 
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications, 
or changes in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, 
within 28 days prior to the Baseline visit. 
10. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening. 
11. History of human immunodeficiency virus (HIV) infection or other disease associated with 
significant immunodeficiency. 
12. History of lung or other solid organ transplantation or currently on the list to receive lung 
or other solid organ transplantation. 
13. History of congestive heart failure (CHF) New York Heart Association (NYHA) Class III or 
greater in severity. 


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14. History of cardiovascular ischemic event within 6 months of Baseline. 
15. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to 
Screening. 
16. Treatment with any investigational medicinal product within 28 days of Screening. 
17. Previous experience of severe and unexplained side-effects during aerosol delivery of any 
kind of medicinal product. 
18. Any other condition that, in the opinion of the Investigator, would preclude informed 
consent or assent, make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives. 


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Study variables 
 
8.3.1 
Study day 
 
Study day of assessments or events is calculated as: 
• 
Date of assessment – date of first dose + 1, if date of assessment ≥ date of first dose. 
• 
Date of assessment – date of first dose, if date of assessment < date of first dose. 
8.3.2 
End of treatment (EOT) visit 
 
For subjects treated up to Week 48, end of treatment (EOT) visit is the assessment at the 
Treatment Week 48 visit. 
For subjects who discontinued study drug prior to Week 48, EOT is the assessment at the 
last on-treatment scheduled or unscheduled visit. 
In summary tables, 
• 
Week 48 will display data occurring at the planned Week 48 time point for subjects who 
complete a full 48-week treatment period. 
• 
EOT visit will be display data for subjects with early end of treatment as well as subjects 
who complete a full 48-week treatment period. 
 
8.3.3 
Treatment period and Follow-up period 
 
The treatment period starts from date of first dose of study drug and ends on date of last 
dose. The follow-up period starts from date of last dose + 1 day and ends at the last follow- 
up visit. 
 
8.3.4 
Visit windows 
 
Please reference Table 1 for scheduled visit windows and corresponding study days. 
If an assessment occurs outside of these scheduled visit windows and a visit name/number 
has not been provided in the raw data, then the assessment should be mapped to the 
nearest visit (which does not already have a corresponding assessment) that occurred either 
immediately before or after the assessment’s study day. 
If multiple assessments occur within the same assessment time window, then the 
assessment nearest to the scheduled visit date will be retained for analysis. If there is a tie, 
the later visit will be retained. 
 
8.3.5 
Baseline value 
 
Baseline will be defined as the last non-missing value prior to administration of first dose of 
study drug. 


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9 
SAMPLE SIZE 
A minimum of 30 subjects will be enrolled. No formal sample size calculation was done as 
this is an initial pilot study. To be able to assess response in each of the three groups, a 
minimum of 8 subjects with MAC or MABSC will be enrolled in each group, and a minimum 
of 30 subjects will be enrolled across all 3 groups. The maximum number of subjects 
enrolled into each group will be 12, and the maximum number of subjects enrolled into the 
study will be 34. The sample size consideration by group is summarized in Table 2. 
Table 2: 
Number of Subjects 
 
Organism 
Group 1 
Group 2 
Group 3 
Total 
MAC/MABSC 
8-12 
8-12 
8-12 
30-34 
 
10 
GENERAL CONSIDERATIONS 
 
Analysis Populations 
 
The All Subjects analysis set will include all subjects with informed consent. 
The Safety Analysis Set (SAF) will include all subjects who received at least 1 dose of study 
drug. 
The Pharmacokinetic Analysis Set (PKAS) will include all subjects who received at least 1 
dose of study drug for whom at least 1 quantifiable plasma concentration of GM-CSF with 
known sample date and time is obtained. 
 
Covariates and Subgroups 
 
There subgroup variables are numbered [a.b] where a labels the objective (numbering in 
section 7.1) and b is a numbering for the subgroup variable addressing the objective a. 
The following subgroup variables will be defined: 
• 
Causative species (MABSC, MAC). [subgroup 8.1] 
• 
Any concurrent anti-mycobacterial medication during the treatment period (Yes, No). 
[subgroup 9.1] 
A concurrent anti-mycobacterial medication during the treatment period is a medication 
with standard medication name (CMDECOD) listed in Appendix section 19.3 and having at 
least one dose taken between the date of first dose (inclusive) and the last dose of study 
drug (inclusive). 
 
Missing Data 
 
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and medication (described below). The 
imputed dates will be used to determine whether an AE is treatment emergent, and 


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whether a medication is prior and/or concomitant. Listings of the AEs and concomitant 
medications will present the actual partial dates; imputed dates will not be shown. 
 
10.3.1 Imputation of Adverse Start Event Dates 
 
Missing or partial AE start dates will be imputed with consideration of start of the treatment 
period: 
1. If AE start date is missing day element: 
• 
If available AE start MONYEAR = study treatment start month/year then: 
○ 
If AE stop date contains a complete date and stop date is before study 
treatment start date then set AE start date = 01MONYEAR. 
○ 
If AE stop date is (complete stop date is on or after study treatment start date) 
or (partial stop month/year is on or after study treatment start month/year) or 
(partial stop year is on or after study treatment start year) or (missing entire 
stop date) then set AE start date = study treatment start date. 
• 
If available AE start MONYEAR  study treatment start month/year then set AE start 
date = 01MONYEAR. 
2. If AE start date is missing day and month elements: 
• 
If available AE start YEAR = study treatment start year then: 
○ 
If AE stop date (complete stop date is before study treatment start date) or 
(partial stop month/year is before study treatment start month/year) then set 
AE start date = 01JANYYYY. 
○ 
If AE stop date is (complete stop date is on or after study treatment start date) 
or (partial stop date MONYYYY is on or after study treatment start MONYYYY) or 
(partial stop date YYYY is on or after study treatment start YYYY) or (missing 
entire stop date) then set AE start date = study treatment start date. 
• 
If available AE start YEAR  study treatment start year then set AE start date = 
01JANYEAR. 
3. If AE start date is missing day, month and year elements: 
• 
If AE stop date (complete stop date is before study treatment start date) or (partial stop 
month/YEAR is before study treatment start month/year) or (partial stop YEAR is before 
study treatment start year) then set AE start date = 01JAN of the stop YEAR. 
• 
If AE stop date is (complete stop date is on or after study treatment start date) or 
(partial stop date month/year is on or after study treatment start month/year) or 
(partial stop date year is on or after study treatment start year) or (missing entire stop 
date) then set AE start date = study treatment start date. 
The imputation algorithm for AE start dates is summarized in Table 3. 


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Table 3 Imputation of AE start dates 
 
Start Date 
Stop Date 
Complete: 
DDMONYEAR 
Partial: MONYEAR 
Partial: YEAR 
Missing 
< 1st dose 
≥ 1st dose 
< 1st dose 
MONYEAR 
≥ 1st dose 
MONYEAR 
< 1st 
dose 
YEAR 
≥ 1st 
dose 
YEAR 
Partial: 
MONYEAR 
= 1st dose 
MONYEAR 
B 
A 
na 
A 
na 
A 
A 
≠ 1st dose 
MONYEAR 
B 
B 
B 
B 
B 
B 
Partial: 
YEAR 
= 1st dose 
YEAR 
C 
A 
C 
A 
na 
A 
A 
≠ 1st dose 
YEAR 
C 
C 
C 
C 
C 
Missing 
D 
A 
D 
A 
D 
A 
A 
A = Impute AE start date as the date of first dose; B = Impute AE start date as the first of the month; 
C = Impute AE start date as 01 January of the year; D = Impute AE start date as 01 January of the stop year; 
na = Missing data case is not applicable. 
 
10.3.2 Imputation of Adverse Event Stop Dates 
 
Missing or partial AE stop dates will be imputed with consideration of end of the treatment 
period: 
1. If AE stop date is missing day element: Impute as min(Last day of that month, Date of 
end of treatment period). 
2. If AE stop date is missing day and month elements: Impute as min(31 December of that 
year, Date of end of treatment period). 
3. If AE stop date is entirely missing: Impute as Date of end of treatment period. 
 
10.3.3 Imputation of Start and End Dates for Prior/Concomitant Medication and Surgical 
Procedures 
 
Missing or partial medication start and stop dates of medications and surgical procedures 
will be imputed with consideration of the start of the baseline period and end of the 
treatment period: 
If start date is missing or partial: 
• 
If day is missing, use the first day of the month under consideration. 
• 
If month is missing, use January. 
• 
If year is missing, use year of the informed consent date. 
• 
If entire date is missing, use informed consent date. 
If stop date is missing or partial and medication is not ongoing: 
• 
if day is missing, use the last day of the month under consideration. 


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• 
if month is missing, use December. 
• 
if year or the entire date is missing, set to 31 December 2099 
If the imputed start date is after the stop date, then the imputed start date will be revised to 
be one day prior to the stop date. If the medication is indicated as ongoing, the stop date 
will remain 
 
Interim Analyses and Data Monitoring 
 
No interim analyses are planned. 
A data review will be conducted by a safety review committee comprised of the lead 
Investigators and sponsor representatives after the first 6 subjects have completed 12 
weeks of treatment. If safety concerns or poor tolerability are identified in this review, the 
review committee may decide on less frequent dosing for subsequent subjects in the study. 
Additional safety reviews will be conducted at regular intervals thereafter. Any changes to 
the conduct of the study such as change of dose regimen will be documented in a protocol 
amendment. The statistical methodology and outputs for these data review meetings are 
defined in the SDRC charter. 
 
Multiple Testing 
 
There will be no hypothesis tests performed and no comparisons statistics estimated 
between the patient groups. All analyses are descriptive within each patient group. 
Consequently, no adjustments for multiplicity will be required. 
 
11 
SUMMARY OF STUDY DATA 
All continuous variables will be summarized using the following descriptive statistics: n (non- 
missing sample size), mean, standard deviation (SD), median, 25th percentile (Q1), 75th 
percentile (Q3), minimum and maximum. The frequency and percentages (based on the 
non-missing sample size) of observed levels will be reported for all categorical measures. 
Data listings will show all recorded data, sorted by group (Group 1, Group 2, Group 3 who 
were treated and then Group 1, Group 2, Group 3 screen failures) and subject and visit 
(when relevant). 
All summary tables will be structured with a column for each group (Group 1, Group 2, 
Group 3) and overall (All Subjects) and will include in the header the total population size 
relevant to that table/treatment, including any missing observations. 
 
Subject Disposition 
 
The subject disposition will be summarized by group and overall based on All Subjects for 
the number of subjects who were screened, failed screening, were treated, discontinued 


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treatment, completed the study, discontinued from the study, and reasons for 
discontinuation. 
A by-subject data listing of study completion information including the reason for study 
discontinuation will be presented for All Subjects. 
 
Protocol Deviations 
 
Protocol deviations will be presented in a by-subject data listing for All Subjects who have at 
least 1 protocol deviation. Since analysis groups are defined based on NTM infection 
characteristics, protocol deviations will not have an impact on which subjects are included in 
each group, as defined in section 10.1. 
 
Demographic and Baseline Variables 
 
Demographic characteristics including age at informed consent, sex, ethnicity, race, and 
smoking status will be summarized by group and overall for SAF. 
Baseline characteristics including causative species (MABSC, MAC) [subgroup 8.1] and 
causative subspecies (MABSC subspecies: M. abscessus subsp. abscessus, M. abscessus 
subsp. massiliense, M. abscessus subsp. bolletii, Unknown; MAC subspecies: M. 
intracellulare, M. avium, Other MAC, Unknown) will also be summarized. 
A by-subject data listing of demographic and baseline characteristics will also be presented 
for All Subjects. 
 
Concurrent Illnesses and Medical Conditions 
 
Medical History events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary 22.1 or later. These events will be presented in a by-subject 
data listing for All Subjects. 
 
Prior and Concurrent Medications 
 
Prior and concomitant medications will be coded using WHO drug dictionary version Mar 
2019 or later. 
Medications can only be flagged as prior or concurrent: 
Prior medication is defined as any medication with a stop date prior to the date of first dose 
of study drug. Concurrent medication during the treatment period is defined as medication 
with stop date between the date of first dose (inclusive) of study medication and the last 
dose of treatment (inclusive).Prior and concomitant medications will be summarized by 
therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred 
WHO name by group and overall for SAF. Patients taking the same medication multiple 
times will be counted once per medication and investigational period. In case a medication 


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is classified into several chemical and/or therapeutic subgroups, it will be presented in all 
chemical and therapeutic subgroups. 
In addition, any concurrent anti-mycobacterial medication during the treatment period (Yes, 
No) [subgroup 9.1] will be summarized by group and overall for SAF. 
A by-subject data listing will be presented for all prior and concurrent medications for All 
Subjects. 
 
Treatment Compliance 
 
Treatment compliance will be calculated at Treatment Weeks 𝑥=4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and,48 (EOT is not applicable), as well as overall. 
Number of used vials 
Number of non-returned vials 
Compliance 
( 
) + ( 
returned at Week 𝑥 
) 
at Week 𝑥 
= ( 
at Week 𝑥 
Number of days between 
) × 100% 
( 
treatment visits 
) 
 
Number of used vials 
Number of non-returned vials 
Overall 
( 
) + ( 
returned in total 
) 
in total 
Compliance = ( 
(Number of days between first IP) 
administration and last IP return 
) × 100% 
 
 
Treatment compliance will be summarized for SAF by presenting the number of vials 
dispensed and vials used (sum of returned and lost) at each regularly scheduled visit and 
presenting the % compliance at each regularly scheduled post-baseline visit. The number of 
vials dispensed, vials used (returned and lost), and % compliance will also be totaled across 
all visits. 
Number of vials dispensed, used vials returned, unused vials returned, used vials lost, 
unused vials lost, and the weekly and overall compliance will be listed for SAF. 
 
12 
EFFICACY ANALYSES 
Each group (Group 1, Group 2 and Group 3) and the overall group will be analyzed 
separately. Data will be presented descriptively and using 95% CIs. Statistical summaries 
comparing post-treatment values with Baseline will be conducted for selected endpoints. 
For the time until sputum culture and smear conversion, Kaplan-Meier survival curves will 
be prepared. 
Frequency of pulmonary exacerbations will be compared with frequency in the year prior to 
the trial. 


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Primary Efficacy Analysis 
 
The proportion of subjects with sputum culture conversion to negative [endpoint 1.1] 
(number of subjects who convert to negative out of the number per group) will be 
presented with 95% exact binomial confidence intervals. This proportion will be calculated 
by group and overall for SAF. 
 
Secondary Efficacy Analyses 
 
12.2.1 Overall Response Variables 
 
The number (%) of subjects and 95% exact binomial confidence interval for the proportion 
will be calculated by group and overall for SAF for the following endpoints: 
• 
Sputum smear conversion to negative [2.1]*. 
• 
NTM sputum culture microbiological cure [endpoint 1.2] 
• 
Consistent sputum smear conversion to negative [endpoint 2.2]*. 
• 
Durable NTM sputum microbiological cure for the NTM isolates [endpoint 1.4]. 
• 
Durable NTM sputum smear conversion to negative [endpoint 2.4]*. 
 
*Sputum smear conversion to negative is only possible provided subjects were sputum 
smear positive at baseline. 
 
12.2.2 By-Visit Response Variables 
 
For semi-quantitative grading of the number of NTM on microscopy of AFB stained sputum 
smears [endpoint 3.1], a shift table displaying the number (%) of subjects with shifts from 
Baseline in 5 categories (negative, scant, 1+, 2+, or 3+) will be summarized for treatment 
visits (Weeks, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48*, EOT*) and follow-up visits 
(Follow-up Weeks 4, 12*, 24) by group and overall for SAF. 
*These time points being of specific interest. 
The number (%) of subjects with categorized decrease in semi-quantitative grading of 
sputum smear will be summarized at each visit by group and overall for SAF. A 95% exact 
binomial confidence interval will be presented for the proportion of subjects with 
categorized decrease. 
 
12.2.3 Time to Event Variables 
 
The “time to event” endpoints will be summarized by Kaplan-Meier survival plots. The event 
will be regarded as having occurred at the time of the first consecutive negative culture: 
• 
Time to first NTM sputum culture conversion during the Treatment period. [endpoint 
1.3] 
• 
Time to first NTM sputum smear conversion during the Treatment period. [endpoint 
2.3] 


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12.2.4 Continuous Variables 
 
The following continuous endpoints will be presented using mean, SD, median, Q1, Q3, min 
and max at baseline and each assessment visit; and mean, SD, median, min and max change 
from Baseline to each assessment visit by group for SAF: 
• 
Absolute change in FEV1% predicted from Baseline (pre-dose) to 1.5h post-dose, 
Treatment Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and, 48*, EOT*, and 
Follow-up Weeks 4, 12*, 24. [endpoint 4.1] 
• 
Absolute change in CFQ-R respiratory symptom scale from Baseline to Treatment 
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and, 48*, EOT*, and Follow-up Weeks 4, 
12*, 24. [endpoint 5.1] 
• 
Absolute change in BMI from Baseline to Treatment Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44 and 48*, EOT*, and Follow-up Weeks 4, 12*, 24. [endpoint 6.1] 
*These time points being of specific interest. 
 
Exploratory Efficacy Analyses 
 
12.3.1 Overall Response 
 
The number (%) of subjects will be presented by group and overall for SAF for any 
recurrence or reinfection after EOT. 
 
12.3.2 By-Visit Response 
 
For semi-quantitative grading of sputum culture [endpoint 3.2], a shift table displaying the 
number (%) of subjects with shifts from Baseline in 5 categories (negative, scant, 1+, 2+, or 
3+) will be summarized for treatment visits (Weeks, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 
and, 48, EOT) and follow-up visits (Follow-up Weeks 4, 12, 24) by group and overall for SAF. 
The number (%) of subjects with categorized decrease in semi-quantitative grading of 
sputum culture will be summarized at each visit by group and overall for SAF. A 95% exact 
binomial confidence interval will be presented for the proportion of subjects with 
categorized decrease. 
The number (%) of subjects with eradication and/or reduction in bacterial load of co- 
infections in sputum will be summarized at each visit by group and overall for SAF. 
The number (%) of subjects with Normal, Abnormal NCS, Abnormal CS interpretation and 
shift from Baseline to Week 48 and EOT will be summarized by group and overall for SAF. 
 
12.3.3 Continuous Variables 
 
The following continuous endpoints will be presented as mean, SD, median, Q1, Q3, min 
and max at baseline and each assessment visit; and mean, SD, median, min and max change 
from Baseline to each assessment visit by group for SAF: 


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• 
Absolute change and fold change from Baseline in time to positivity on NTM liquid 
culture media at Treatment visits and Follow-up. 
• 
Absolute change in CFQ-R domains scores for physical functioning, vitality, health 
perceptions, treatment burden, role functioning, emotional functioning, and social 
functioning. 
 
The following continuous endpoint will be presented as mean, SD, median, Q1, Q3, min and 
max by group for SAF: 
• 
Frequency of pulmonary exacerbations in the previous year, annual rate of pulmonary 
exacerbations during the study, rate ratio. 
 
13 
SAFETY ANALYSES 
 
Extent of Exposure 
 
13.1.1 Inhaled molgramostim 
 
Duration (days) of exposure to inhaled molgramostim is calculated as (date of last dose of 
study drug)-(date of first dose of study)+1. Exposure duration will be categorized into 12 
4-week intervals: 1 to 28 days, 29 to 56 days, ..., 281 to 308 days, ≥309 days (the last interval 
is open-ended to allow for maximum duration exceeding 336 days). Exposure duration 
(continuous and categorical) will be summarized by group and overall and listed for SAF. 
 
13.1.2 Antimycobacterial therapy 
 
Subjects in Group 1 will have concomitant antimycobacterial treatment. The 
antimycobacterial therapy should preferably not change during the treatment period except 
in case of drug toxicity or adverse reactions. All changes in antimycobacterial treatment will 
be recorded including planned daily dosing and actual daily drug intake, physician- 
prescribed modification and interruptions, and reasons for each change in 
antimycobacterial treatment. 
Antimycobacterial therapy variables will be listed only. 
 
Adverse Events, Serious Adverse Events, Deaths, and other Significant Adverse 
Events 
 
AEs will be recorded from the time written informed consent is signed until 30 days after 
the last dose of study drug. AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary 22.1 or later. It will be used to summarize AEs by 
system organ class (SOC) and preferred term (PT). 
Treatment-emergent AE (TEAE) is defined as any AE that started or worsened in severity on 
or after the date of first dose of study drug until 30 days after the last dose or until the last 
follow-up visit, whichever is longer. AEs are considered treatment-emergent irrespective of 


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hour or minute of onset (if recorded). Imputed AE start dates are allowed for determination 
of treatment-emergence. 
Related TEAE will be defined as any TEAE with “possible” or “probably” relationship to study 
treatment as assessed by the investigator or with “not applicable” or missing assessment of 
the causal relationship. AEs with start date before or after the 
There are currently no AEs of special interest identified due to limited previous experience 
of Savara’s molgramostim. 
Key guidelines for counting incidence proportions of AEs are as follows: 
• 
When a patient has the same AE reported multiple times during an analysis period 
based on MedDRA terminology (SOC or PT), the patient will only be counted once 
within a level of MedDRA in an AE incidence table. 
• 
When assessing investigator reported relationship to study drug of the AEs, if an AE 
reported multiple times changes in causal relationship during an analysis period for a 
patient, the event with highest relatedness will be presented. Related AEs will include 
those reported as “possible” or “probably” by the investigator and those with a “not 
applicable” or missing relationship. However, in the summary of AEs by relationship, 
AEs with “not applicable” or missing relationship will be separate categories to be 
tabulated. 
• 
When summarizing severity of the AEs (mild, moderate, severe), if there are multiple 
AEs of the same preferred term but different severity, during an analysis period for a 
patient, the AE with the maximum severity will be reported. If the AE term (SOC and PT) 
is reported more than once, one of them with missing severity, and at least another 
with non-missing severity, the maximum severity will be chosen from the non-missing 
severity and the missing severity can be ignored. If all are of missing severity, then the 
AE severity will be summarized with an additional “Missing” category. In summary of 
severe AEs, missing severity will be included in severe category following conservative 
approach. 
• 
When summarizing severity for related AEs, only related AEs will be used in the analysis. 
If a patient has the same AE reported multiple times during an analysis period for a 
related AE, the AE with the maximum severity will be chosen. 
In summaries by SOC and PT, AEs will be sorted alphabetically for SOC and descending 
frequency for PT in total patients. Summaries will include only TEAEs. All AEs, all SAEs and 
TEAEs leading to study drug discontinuation will be listed for SAF. Individual-subject 
narratives written for all SAEs. 
 
13.2.1 Overview of TEAEs 
 
An overview of AEs will summarize the number (%) of patients and number of events for the 
following details by group and overall for SAF: 
• 
TEAEs 
• 
Related TEAEs (i.e. adverse drug reactions (ADRs)) 
• 
Serious TEAEs 


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• 
Severe TEAEs 
• 
TEAEs leading to study drug discontinuation 
• 
Deaths 
13.2.2 TEAEs by SOC and PT 
 
The number (%) of patients with TEAEs classified by SOC and PT will be summarized by 
group and overall for SAF. Summaries will be provided for: 
• 
TEAEs 
• 
Related TEAEs 
• 
Serious TEAEs 
• 
Severe TEAEs 
• 
TEAEs leading to study drug discontinuation 
 
Pregnancies 
 
Serum pregnancy test will be assessed at screening, day 1 (including urine pregnancy test), 
treatment week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and EOT, and follow-up week 
4. 
A by-subject data listing will be provided for pregnancy data including if the pregnancy test 
was performed, result of the test (if performed), reason for test not performed, visit, and 
date/time of test. 
 
Clinical Laboratory Evaluations 
 
Details of laboratory assessments performed by the central laboratory are provided in 
Table 4. Hematology, biochemistry and urinalysis will be assessed at scheduled visits and 
optionally at unscheduled study visits. 


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Table 4: Safety laboratory tests 
 
Test 
Scheduled visit 
Parameters to be analyzed 
Hematology 
V1/Screening; 
Pre-dose on V2/D1, V5/W4, 
V6/W8, ..., V15/W44, V16/W48; 
V17/FU4, V18/FU12, V19/FU19 
Hemoglobin, RBC count, red blood cell distribution 
width (RDW), hematocrit (PCV/EVF), mean cell volume 
(MCV), mean cell hemoglobin (MCH), mean cell 
hemoglobin concentration 
(MCHC), platelet count, and prothrombin time 
international normalized ratio (PT-INR). 
Pre-dose and 2 hours post-dose 
on V2/D1, V3/W1, V4/W2, 
V5/W4, V7/W12, V10/W24, 
V13/W36, V16/W48; 
Otherwise only pre-dose on the 
other scheduled visits 
WBC count, and white cell differentials absolute count: 
neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, 
Biochemistry 
V1/Screening; 
Pre-dose on V2/D1, V5/W4, 
V6/W8, ..., V15/W44, V16/W48; 
V17/FU4, V18/FU12, V19/FU19 
Aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma glutamyl 
transpeptidase (GGT), alkaline phosphatase, amylase, 
bilirubin, blood urea nitrogen (BUN), creatinine, 
estimated glomerular filtration rate (eGFR), creatine 
phosphokinase (CPK), potassium, sodium, calcium, 
chloride, bicarbonate, phosphate, magnesium, total 
protein, albumin, lactate dehydrogenase (LDH), C- 
reactive protein (CRP), and glucose (non-fasting). 
Urinalysis 
V1/Screening; 
Pre-dose on V2/D1, V5/W4, 
V6/W8, ..., V15/W44, V16/W48; 
V17/FU4, V18/FU12, V19/FU19 
pH, specific gravity, bilirubin, glucose, ketones, RBCs, 
WBCs, protein, microalbuminuria, and microscopic 
elements. 
For laboratory safety continuous variables, values recorded as “<X” or “<=X” or “>Y” or 
“>=Y” will be imputed by “X” and “Y” respectively for descriptive statistics. This will be 
documented in a footnote in all output where such a replacement was performed. 
Continuous clinical laboratory observed values and absolute change from baseline (for all 
hematology and biochemistry parameters and pH value and specific gravity from the 
urinalysis panel) at baseline and scheduled post-baseline visits (including EOT) and time 
points will be summarized by visit, treatment group and overall for SAF. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. The number (%) of subjects below 
and above reference range will be summarized by visit, treatment group and overall for SAF. 
Categorical urinalysis variables will be summarized for the number (%) of subjects in each of 
the categories by visit, treatment group and overall for SAF. 
All laboratory parameters will be presented in a by-subject data listing for SAF and will 
include the lab category, lab test, unit of measurement, test result, reference range 
indicator (e.g., normal, high, low), visit, date, time point (pre-dose, post-dose), and reason 


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test not performed (if applicable). All visits, including screening and unscheduled, will be 
included in the data listing. 
 
13.4.1 Change from same visit baseline 
 
For WBC count and white cell differentials, the change from same visit baseline to same visit 
2-hour post-dose value will be calculated and summarized at treatment week 1, 2, 4, 12, 24, 
36, 48. 
 
Other Safety Measures 
 
13.5.1 Pulmonary Function Test (PFT) 
 
PFT including FEV1, FVC and FEV1% will be assessed at screening, pre-dose on day 1, and at 
1.5 hours post-dose on day 1, treatment week 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 
and, 48, and follow-up week 4, 12, 24. 
FEV1% predicted and absolute change from baseline will be summarized by visit (including 
EOT), treatment group and overall for SAF. 
All PFT parameters will be presented in a by-subject data listing for SAF and will include 
FEV1, FVC, FEV1% and FEV1% predicted, visit, date, time point, and reason test not 
performed (if applicable). All visits, including screening and unscheduled, will be included in 
the data listing. 
 
13.5.2 Vital signs 
 
Vital signs including SBP (mmHg), DBP (mmHg), heart rate (beats per minute), respiration 
rate (breaths per minute), body temperature (C) will be assessed at screening, pre-dose 
and 2 hours post-dose on day 1, treatment week 1, 2, 4, 12, 24, 36, 48, and pre-dose only on 
other scheduled visits. 
Vital signs parameters, body weight and BMI (section 7.3.10) observed value and absolute 
change from baseline will be summarized by visit (including EOT), treatment group and 
overall for SAF. 
In addition, for vital signs parameters, absolute change from same visit baseline will be 
summarized at treatment week 1, 2, 4, 12, 24, 36, 48. 
All vital sign parameters will be presented in a by-subject data listing for SAF and will include 
the vital sign, unit of measurement, test result, visit, date, time point (pre-dose, post-dose), 
and reason test not performed (if applicable). Body weight and BMI will be similarly listed. 
All visits, including screening and unscheduled, will be included in the data listing. 
 
13.5.3 Electrocardiogram (ECG) 
 
12-lead ECGs continuous parameters include heart rate, QRS, PR, QT and QTcF intervals, and 
ECG interpretation (normal, abnormal NCS (not clinically significant), abnormal CS (clinically 


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significant)) will be assessed at screening, day 1, treatment week 4, 12, 24, 36, 48, and 
follow-up week 24. 
ECG continuous parameter observed values and absolute change from baseline will be 
summarized by visit (including EOT), treatment group and overall for SAF. 
ECG interpretation will be summarized for the number (%) of subjects in each of the 
categories by visit (including EOT), treatment group and overall for SAF. Shifts in categories 
(normal, abnormal NCS, abnormal CS) from baseline to post-baseline visits will be 
summarized by visit, treatment group and overall for SAF. 
All ECG parameters will be presented in a by-subject data listing for SAF and will include the 
ECG parameter, unit of measurement, test result, visit, date, and reason test not performed 
(if applicable). All visits, including screening and unscheduled, will be included in the data 
listing. 
 
13.5.4 Computed Tomography (CT) 
 
CT scans of the lung will be assessed at day 1 and treatment week 48. CT interpretation will 
be summarized for the number (%) of subjects in each of the categories by visit, treatment 
group and overall for SAF. Shifts in categories (normal, abnormal NCS, abnormal CS) from 
baseline to week 48 will be summarized by visit (EOT*), treatment group and overall for SAF. 
*If Early End of Treatment Visit occurs prior to or at Week 12, then a CT scan is not required 
at Early End of Treatment Visit. 
All CT values will be presented in a by-subject data listing for SAF and will include the test 
result (normal/abnormal), clinical significance indicator for abnormal results (NCS/CS), 
description of abnormality -, visit, date, and reason test not performed (if applicable). All 
visits will be included in the data listing. 
 
13.5.5 Physical examination (PE) 
 
PE will be assessed at screening, treatment week 1, 2, 4, 12, 24, 48. PE data will be listed 
only for SAF and will include the body system, exam result, clinical significance, description 
of abnormality, visit, date, and reason test not performed (if applicable). All visits, including 
screening and unscheduled, will be included in the data listing. 
 
14 
PHARMACOKINETICS 
 
GM-CSF Concentration 
 
Plasma concentrations of GM-CSF [endpoint 7.4] will be summarized at Baseline (pre-dose), 
post-dose 2h, and at pre-dose and 2h post-dose at Treatment Weeks 2, 12, 24, 36, 48, EOT 
and at Follow up Weeks 12, 24 by group and overall for PKAS using descriptive statistics 
including the mean, SD, median, Q1, Q3, min, and max. Concentration values below limit of 
quantification (BLQ) or less than the limit of quantification (<LLOQ) will be set to 0. 


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15 
FIGURES 
 
Efficacy 
 
The “time to event” endpoints will be summarized by Kaplan-Meier survival plots. The event 
will be regarded as having occurred at the time of the first consecutive negative culture: 
• 
Time to first NTM sputum culture conversion during the Treatment period. 
• 
Time to first NTM sputum smear conversion during the Treatment period. 
 
Safety 
 
All safety figures will graphically present Box Plots summarizing change from baseline values 
for all regularly scheduled post-baseline visits. These will include both pre-dose and post- 
dose (or pre-PFT and post-PFT) values when applicable. Laboratory parameters will also be 
presented in spaghetti plots summarizing individual values for all regularly scheduled visits. 
The following parameters will be graphically displayed: 
• 
Laboratory: hematology leukocytes, eosinophils, basophils, neutrophils, monocytes, and 
lymphocytes 
• 
PFT: FEV1, FVC, and FEV1/FVC 
• 
Vital Signs: HR, SBP, DBP, and BMI 
• 
ECG: PR Interval, QRS Interval, QT Interval, QTc Interval, and HR 
 
16 
REPORTING CONVENTIONS 
The mean, median, Q1, Q3, minimum and maximum will be reported to one more decimal 
place than the raw value. The standard deviation will be reported to two more decimal 
places. 
Count data will be presented as an integer and percentages will be presented to one 
decimal place. 
 
17 
REFERENCES 
Cowman S, Burns K, Benson S, Wilson R, Loebinger MR. The antimicrobial susceptibility of 
non-tuberculous mycobacteria. J Infect 2016;72(3):324-331. 
Field SK, Fisher D and Cowie RL. Mycobacterium avium complex pulmonary disease in 
patients without HIV infection. Chest 2004; 126(2): 566-81. 
Griffith DE, Aksamit TR. Understanding nontuberculous mycobacterial lung disease: it's been 
a long time coming. F1000Res 2016; 5:2797. 
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. 


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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. 
Lee BY, Kim S, Hong Y, Lee SD, Kim WS, Kim DS, et al. Risk factors for recurrence after 
successful treatment of Mycobacterium avium complex lung disease. Antimicrob Agents 
Chemother 2015; 59(6): 2972-7. 
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. 
Stout JE, Koh WJ, Yew WW. Update on pulmonary disease due to non-tuberculous 
mycobacteria. Int J Infect Dis 2016; 45:123-134. 
Wallace RJ, Jr., Brown-Elliott BA, McNulty S, Philley JV, Killingley J, Wilson RW, et al. (2014). 
Macrolide/Azalide therapy for nodular/bronchiectatic mycobacterium avium complex lung 
disease. Chest 146(2): 276-282. 
Xu HB, Jiang RH and Li L (2014). Treatment outcomes for Mycobacterium avium complex: a 
systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis 2014; 33(3): 347-58. 
Zhao X, Wang Y, Pang Y. Antimicrobial susceptibility and molecular characterization of 
Mycobacterium intracellulare in China. Infect Genet Evol 2014;27:332-338 


18 
LISTING OF TABLES, LISTINGS AND FIGURES 
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Please see “SAV008-02 SAP V1.0 Mock TLF Shells” document for full list and mock shells for tables, 
listings, and figures. Minor changes to TLF shells will not necessarily result in an SAP amendment. 


19 
APPENDICES 
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CFQ-R Teen/Adult Version Scoring Instructions 
 
19.1.1 General Scoring Instructions 
 
For ease of interpretation, the questions on the CFQ-R are labeled according to the number on the 
questionnaire and the domain they are designed to measure. The domain label precedes the question 
number. For example, the first question on the questionnaire is designed to measure a physical 
symptom and its label is “Phys1.” The complete labeling for each version of the CFQ-R is presented 
under the section entitled “Question Labels”. 
The following scoring codes were written to be used with CFQ-R data that was entered into a 
database/spreadsheet where each question is a unique variable. The variable names should match the 
question labels listed in the “Question Labels” section. Values for each question range from 1 to 4. For 
questions with responses listed horizontally (left to right) the left response category should be assigned 
a value of 1, the second category should be assigned a 2, the third a 3, and the rightmost category 
should be assigned a 4. 
Here is an example. 
1. Performing vigorous activities such as running or playing sports……. 
1 
2 
3 
4 
 
For questions that are listed vertically (top to bottom), the top category should be assigned a value of 
1, the next a 2, the third a 3, and the bottom category a 4. 
Here is an example. 
13. To what extent do you have difficulty walking? Scoring Values 
1. You can walk a long time without getting tired 
(1) 
2. You can walk a long time, but you get tired 
(2) 
3. You cannot walk a long time because you get tired quickly 
(3) 
4. You avoid walking whenever possible because it’s too tiring for you 
(4) 
 
It is important that you assign the values according to these rules for each question. Some of the 
questions will be phrased in a positive direction (like Question 13 listed above) and the values may 
seem inappropriate. The scoring codes reverse the ordering for these positively phrased questions. Do 
not reverse the coding when you are entering the scores into your database/spreadsheet. We have 
found it to be more accurate to let the scoring procedures address the reverse coding. 
 
Please note that question 43 (resp43) on the Teen/Adult version and question 37 (resp37) on the 
Parent version have one extra category (don’t know) we typically assign a value of 5 to that category. 
This question is not included in the scoring of the respiratory scale. 


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19.1.2 SAS Program Codes for Scoring the CFQ-R Teen/Adult Version 
 
/*This scoring program requires that the data be imported into a SAS table 
titled "CFQR_TA" and that the variable names in the table match those listed 
below.*/ 
 
Data CFQR_TA; set CFQR_TA; 
 
/* Recoding Some Variables */ 
 
vital6 
= 
5-vital6; 
vital10 
= 
5-vital10; 
phys13 
= 
5-phys13; 
treat15 
= 
5-treat15; 
treat17 
= 
5-treat17; 
health18 
= 
5-health18; 
social23 
= 
5-social23; 
social28 
= 
5-social28; 
social30 
= 
5-social30; 
health32 
= 
5-health32; 
health34 
= 
5-health34; 
role35 
= 
5-role35; 
resp43 
= 
5-resp43; 
 
/* Calculating Scores */ 
 
if nmiss (phys1, phys2, phys3, phys4, phys5, phys13, phys19, phys20) <= 4 
then 
physical = (mean (phys1, phys2, phys3, phys4, phys5, phys13, phys19, 
phys20)-1)/3*100; 
 
if nmiss (role35, role36, role37, role38) <= 2 then 
role = (mean (role35, role36, role37, role38)-1)/3*100; 
 
if nmiss (vital6, vital9, vital10, vital11) <= 2 then 
vitality = (mean (vital6, vital9, vital10, vital11)-1)/3*100; 
 
if nmiss (emot7, emot8, emot12, emot31, emot33) <= 2 then 
emotion = (mean (emot7, emot8, emot12, emot31, emot33)-1)/3*100; 
 
if nmiss (social22, social23, social27, social28, social29, social30) <= 3 
then 
social = (mean (social22, social23, social27, social28, social29, social30)- 
1)/3*100; 
 
if nmiss (body24, body25, body26) <= 1 then 
body = (mean (body24, body25, body26)-1)/3*100; 


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if nmiss (eat14, eat21, eat50) <= 1 then 
eat = (mean (eat14, eat21, eat50)-1)/3*100; 
 
if nmiss (treat15, treat16, treat17) <= 1 then 
treat = (mean (treat15, treat16, treat17)-1)/3*100; 
 
if nmiss (health18, health32, health34) <= 1 then 
health = (mean (health18, health32, health34)-1)/3*100; 
 
if nmiss (weight39) = 0 then 
weight= (mean (weight39)-1)/3*100; 
 
if nmiss (resp40, resp41, resp42, resp44, resp45, resp46) <= 3 then 
respirat = (mean (resp40, resp41, resp42, resp44, resp45, resp46)-1)/3*100; 
 
if nmiss (digest47, digest48, digest49) <= 1 then 
digest = (mean (digest47, digest48, digest49)-1)/3*100; 
run; 


 
 
Pulmonary Exacerbation MedDRA Search List 
 
 
 
MedDRA term 
MedDRA code 
MedDRA level (qualifier) 
Infective pulmonary 
exacerbation of cystic fibrosis 
10070608 
PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Anti-Mycobacterial Medication WHO Drug Dictionary Search List 
 
WHO Drug term 
WHO Drug code 
WHO Drug level (qualifier) 
AMIKACIN 
00391001001 
PT 
AZITHROMYCIN 
00944301001 
PT 
CEFOXITIN 
00454701001 
PT 
CLARITHROMYCIN 
00984601001 
PT 
CLOFAZIMINE 
00224701001 
PT 
CO-TRIMOXAZOLE 
13286701802 
PT 
ETHAMBUTOL 
00022301001 
PT 
IMIPENEM 
00788801001 
PT 
LINEZOLID 
01436301001 
PT 
MOXIFLOXACIN 
01453201001 
PT 
MINOCYCLINE 
00232401001 
PT 
RIFAMPICIN 
00146901005 
PT 
RIFABUTIN 
851201001 
PT 
STREPTOMYCIN 
00051001001 
PT 
TIGECYCLINE 
05505301002 
PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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