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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04544293




Registration number
NCT04544293
Ethics application status
Date submitted
3/09/2020
Date registered
10/09/2020
Date last updated
6/10/2021

Titles & IDs
Public title
Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
Scientific title
A Randomized, Double-blind, Placebo-controlled Clinical Trial of Once-daily Inhaled Molgramostim Nebulizer Solution in Adult Subjects With Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
Secondary ID [1] 0 0
2020-001263-85
Secondary ID [2] 0 0
SAV006-05
Universal Trial Number (UTN)
Trial acronym
IMPALA-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autoimmune Pulmonary Alveolar Proteinosis 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 0 0 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Molgramostim
Treatment: Drugs - Placebo

Experimental: Molgramostim - Double-blind treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks, followed by open-label treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks

Placebo Comparator: Placebo - Double-blind treatment with placebo nebulizer solution once daily for 48 weeks, followed by open-label treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks


Treatment: Drugs: Molgramostim
Molgramostim 300 µg nebulizer solution

Treatment: Drugs: Placebo
Matching placebo

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change from baseline in percentage (%) predicted diffusing capacity of the lung for carbon monoxide (DLCO) to Week 24 - As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be conducted. The single-breath DLCO test will be performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing.
Timepoint [1] 0 0
From Baseline to Week 24
Secondary outcome [1] 0 0
Change from baseline in percentage (%) predicted DLCO to Week 48 - As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be conducted. The single-breath DLCO test will be performed in accordance with ATS/ERS guidelines for DLCO testing.
Timepoint [1] 0 0
From Baseline to Week 48
Secondary outcome [2] 0 0
Change from baseline in St. Georges Respiratory Questionnaire (SGRQ) Total score to Week 24 - The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).
Timepoint [2] 0 0
From Baseline to Week 24
Secondary outcome [3] 0 0
Change from baseline in SGRQ Activity component score to Week 24 - The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).
Timepoint [3] 0 0
Week 24
Secondary outcome [4] 0 0
Change from baseline in exercise capacity (EC), expressed as peak metabolic equivalents (METs) to Week 24 - As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an exercise treadmill test. EC will be expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved will be used to calculate peak METs.
Timepoint [4] 0 0
From Baseline to Week 24
Secondary outcome [5] 0 0
Change from baseline in SGRQ Total score to Week 48 - The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).
Timepoint [5] 0 0
Week 48
Secondary outcome [6] 0 0
Change from baseline in SGRQ Activity from baseline to Week 48 - The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).
Timepoint [6] 0 0
From Baseline to Week 48
Secondary outcome [7] 0 0
Change from baseline in EC, expressed as peak METs to Week 48 - As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an exercise treadmill test. EC will be expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved will be used to calculate peak METs.
Timepoint [7] 0 0
From Baseline to Week 48
Secondary outcome [8] 0 0
Change from baseline in alveolar-arterial oxygen difference (A-aDO2) to Week 24 (Specifically for Japan and South Korea) - A-aDO2 will be used as an additional measure of gas exchange.
Timepoint [8] 0 0
From Baseline to Week 24
Secondary outcome [9] 0 0
Number of subjects with serious and non-serious adverse events - Assessment of the safety of MOL compared to placebo
Timepoint [9] 0 0
From screening (6-week) until Follow-up visit (Week 100)
Secondary outcome [10] 0 0
Number of subjects with positive treatment-boosted anti Granulocyte macrophage colony stimulating factor (GM-CSF) antibody titers during 24 weeks' treatment and during 48 weeks' treatment - Assessment of the safety of MOL compared to placebo
Timepoint [10] 0 0
From screening (6-week) until Follow-up visit (Week 100)
Secondary outcome [11] 0 0
Changes in Forced vital capacity (FVC) - Assessment of the safety of MOL compared to placebo
Timepoint [11] 0 0
From Baseline to Weeks 24 and 48
Secondary outcome [12] 0 0
Changes in Forced expiratory volume in one second (FEV1) - Assessment of the safety of MOL compared to placebo
Timepoint [12] 0 0
From Baseline to Weeks 24 and 48
Secondary outcome [13] 0 0
Change in QT interval corrected by Fridericia (QTcF) - Assessment of the safety of MOL compared to placebo
Timepoint [13] 0 0
From Baseline to Weeks 4 and 24

Eligibility
Key inclusion criteria
1. Subject must be =18 years of age, at the time of signing the informed consent (=20 in
Japan).

2. A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.

3. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL)
cytology, or a high-resolution computed tomogram (HRCT) of the chest.

4. DLCO 70% predicted or lower at the screening and baseline visits.

5. Change in % predicted DLCO of <15% points during the screening period.

6. Demonstrated functional impairment in the treadmill exercise test (defined as a peak
MET =8).

7. Willing and able to come off supplemental oxygen use prior to and during the treadmill
exercise test, the DLCO assessment, and the arterial blood gas sampling.

8. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the
screening visits.

9. Male or female

10. Contraceptive use by men or women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies.

1. Male subjects: Males agreeing to use condoms during and until 30 days after last
dose of trial treatment, or males having a female partner who is using adequate
contraception as described below.

2. Female subjects: Females who have been post-menopausal for >1 year, or females of
childbearing potential after a confirmed menstrual period using a highly
efficient method of contraception (i.e. a method with <1% failure rate such as
combined hormonal contraception, progesterone-only hormonal contraception,
intrauterine device, intrauterine hormone-releasing system, bilateral tubal
occlusion, vasectomized partner, sexual abstinence*), during and until 30 days
after last dose of trial treatment. Females of childbearing potential must have a
negative serum pregnancy test at the screening visits, and a negative urine
pregnancy test at Baseline visit (Visit 3) and must not be lactating.

11. Capable of giving signed informed consent as described in Appendix 1 which includes
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and in this protocol.

12. 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant
production.

2. WLL performed within 3 months prior to baseline.

3. Requirement for WLL at screening or baseline.

4. GM-CSF treatment within 6 months prior to baseline.

5. Treatment with rituximab within 6 months prior to baseline.

6. Treatment with plasmapheresis within 6 weeks prior to baseline.

7. Treatment with any investigational medicinal product within 5 half-lives or 3 months
(whichever is longer) prior to baseline.

8. Previously randomized in this trial.

9. History of allergic reactions to GM-CSF or any of the excipients in the nebulizer
solution.

10. Inflammatory or autoimmune disease of a severity that necessitates significant (e.g.
more than 10 mg/day systemic prednisolone) immunosuppression.

11. Previous experience of severe and unexplained side-effects during aerosol delivery of
any kind of medicinal product.

12. History of, or present, myeloproliferative disease or leukemia.

13. Apparent pre-existing concurrent pulmonary fibrosis.

14. Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise.

15. Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect
the efficacy evaluation in the trial.

16. Physical disability or other condition that precludes safe and adequate exercise
testing.

17. Any other serious medical condition which in the opinion of the Investigator would
make the subject unsuitable for the trial.

18. Pregnant, planning to become pregnant during the trial, or breastfeeding woman. For
France only: including as further defined by French Health Code L-1121-5.

19. Any subject considered to be "vulnerable" on account of, e.g., mental or physical
disability, socio-economic situation, or subjects deprived of their liberty. For
France only: including as further defined by French Health Code L1121-8-1.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arkansas
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Illinois
Country [8] 0 0
United States of America
State/province [8] 0 0
Maryland
Country [9] 0 0
United States of America
State/province [9] 0 0
Missouri
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Pennsylvania
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
Belgium
State/province [14] 0 0
Région De Bruxelles-Capitale
Country [15] 0 0
Belgium
State/province [15] 0 0
Vlaams Brabant
Country [16] 0 0
Canada
State/province [16] 0 0
Alberta
Country [17] 0 0
Canada
State/province [17] 0 0
Québec
Country [18] 0 0
France
State/province [18] 0 0
Auvergne-Rhône-Alpes
Country [19] 0 0
France
State/province [19] 0 0
Bretagne
Country [20] 0 0
Germany
State/province [20] 0 0
Baden-Württemberg
Country [21] 0 0
Germany
State/province [21] 0 0
Bayern
Country [22] 0 0
Germany
State/province [22] 0 0
Nordrhein-Westfalen
Country [23] 0 0
Greece
State/province [23] 0 0
Athens
Country [24] 0 0
Ireland
State/province [24] 0 0
Dublin
Country [25] 0 0
Italy
State/province [25] 0 0
Lombardia
Country [26] 0 0
Japan
State/province [26] 0 0
Hokkaidô
Country [27] 0 0
Japan
State/province [27] 0 0
Kanagawa
Country [28] 0 0
Japan
State/province [28] 0 0
Miyagi
Country [29] 0 0
Japan
State/province [29] 0 0
Osaka
Country [30] 0 0
Japan
State/province [30] 0 0
Tokyo
Country [31] 0 0
Japan
State/province [31] 0 0
Chiba
Country [32] 0 0
Japan
State/province [32] 0 0
Nagakute
Country [33] 0 0
Japan
State/province [33] 0 0
Saitama
Country [34] 0 0
Korea, Republic of
State/province [34] 0 0
Seoul
Country [35] 0 0
Netherlands
State/province [35] 0 0
Utrecht
Country [36] 0 0
Poland
State/province [36] 0 0
Mazowieckie
Country [37] 0 0
Portugal
State/province [37] 0 0
Lisboa
Country [38] 0 0
Portugal
State/province [38] 0 0
Porto
Country [39] 0 0
Romania
State/province [39] 0 0
Bucuresti
Country [40] 0 0
Russian Federation
State/province [40] 0 0
Sankt-Peterburg
Country [41] 0 0
Spain
State/province [41] 0 0
Cataluña
Country [42] 0 0
Turkey
State/province [42] 0 0
Izmir
Country [43] 0 0
Turkey
State/province [43] 0 0
Ankara
Country [44] 0 0
Turkey
State/province [44] 0 0
Istanbul
Country [45] 0 0
United Kingdom
State/province [45] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Savara Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
160 subjects with autoimmune pulmonary alveolar proteinosis (aPAP) will be randomized to
receive once daily treatment with inhaled molgramostim or placebo for 48 weeks. Subjects
completing the 48 week placebo-controlled period will receive open-label treatment with once
daily inhaled molgramostim for 48 weeks.
Trial website
https://clinicaltrials.gov/show/NCT04544293
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bruce Trapnell, Prof
Address 0 0
Children's Hospital Medical Center, Cincinnati
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Dhaval Desai, MD
Address 0 0
Country 0 0
Phone 0 0
+1 (512) 851-1373
Fax 0 0
Email 0 0
info@savarapharma.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04544293