Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)

Autoimmune Pulmonary Alveolar Proteinosis Clinical Trial

— IMPALA-2  

Official 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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04544293
• Other study ID #: SAV006-05
• Secondary ID: 2020-001263-85
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 10, 2021
• Est. completion date: June 2025

Study information

• Verified date: June 2023
• Source: Savara Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 96 weeks.

Description:

This is an interventional, randomized, double-blind, 2-arm, parallel groups, placebo-controlled, multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP. An aPAP diagnosis should be confirmed by an anti-GM-CSF auto-antibody test result, and history of PAP based on either high resolution computed tomography, lung biopsy, or bronchoalveolar lavage cytology, should be available. The trial consists of a 6-week screening period, a 48-week randomized, double-blind treatment period, a 96-week open-label treatment period, and a conditional 4-week safety follow-up period. The maximum treatment duration will be 145 weeks and the maximum trial duration will be 156 weeks. During the trial, whole lung lavage will be allowed as rescue treatment in case of worsening of aPAP.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 160
• Est. completion date: June 2025
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

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. For France only: 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.

Related Conditions & MeSH terms

• Autoimmune Diseases
• Autoimmune Pulmonary Alveolar Proteinosis
• Pulmonary Alveolar Proteinosis

Intervention

Drug:
• Molgramostim
Molgramostim 300 µg nebulizer solution
• Placebo
Matching placebo

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Belgium	Hôpital Erasme	Bruxelles	Région De Bruxelles-Capitale
Belgium	UZ Leuven - Campus Gasthuisberg - Pneumologie	Leuven	Vlaams Brabant
Canada	University of Calgary	Calgary	Alberta
Canada	St Joseph's Healthcare Hamilton Research	Hamilton	Ontario
Canada	University Institute of Cardiology and Respirology of Quebec	Québec
France	Hôpital Louis Pradel	Bron	Auvergne-Rhône-Alpes
France	CHU Pontchaillou	Rennes	Bretagne
Germany	Ruhrlandklinik Westdeutsches Lungenzentrum	Essen	Nordrhein-Westfalen
Germany	Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg
Germany	Asklepios Fachkliniken Muenchen-Gauting	Muenchen-Gauting	Bayern
Greece	Attikon University Hospital	Athens
Ireland	St. Vincent's University Hospital	Dublin
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia	Lombardia
Japan	Chiba University Hospital - Respiratory Medicine	Chiba
Japan	Kumamoto University Hospital	Kumamoto
Japan	Kyorin University Hospital	Mitaka	Tokyo
Japan	Aichi Medical University Hospital	Nagakute
Japan	Saitama Red Cross Hospital	Saitama
Japan	National Hospital Organization Kinki-Chuo Chest medical Center	Sakai	Osaka
Japan	Hokkaido University Hospital	Sapporo	Hokkaidô
Japan	Tohoku University Hospital - Respiratory Tract Medicine	Sendai	Miyagi
Japan	Kanagawa Cardiovascular and Respiratory Center	Yokohama	Kanagawa
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital - Yonsei University Health System - Pulmonary	Seoul
Netherlands	St Antonius Hospital	Nieuwegein	Utrecht
Poland	Instytut Gruzlicy i Chorob Pluc	Warszawa	Mazowieckie
Portugal	Hospital Pulido Valente	Lisboa
Portugal	Hospital São João	Porto
Romania	Institutul de Pneumoftiziologie "Marius Nasta"	Bucuresti
Spain	Hospital Universitario de Bellvitge	Barcelona	Cataluña
Turkey	Health Sciences University Gulhane Training and Research Hospital	Ankara
Turkey	Ege University Hospital - Department of Pulmonology	Bornova	Izmir
Turkey	Yedikule Chest Disease and Surgery Training and Research Hospital	Istanbul
United Kingdom	Royal Brompton and Harefield NHS Foundation Trust	London
United States	Emory University	Atlanta	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	National Jewish Health	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida Health	Gainesville	Florida
United States	University Of Arkansas For Medical Services	Little Rock	Arkansas
United States	UCLA David Geffen School of Medicine	Los Angeles	California
United States	Loyola University	Maywood	Illinois
United States	Yale University	New Haven	Connecticut
United States	University of Pennsylvania Perelman School of Medicine - Pulmonology	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Wake Med Health & Hospital	Raleigh	North Carolina
United States	Washington University in St. Louis	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Savara Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Greece,  Ireland,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Romania,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From Baseline to Week 24
Secondary	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.	From Baseline to Week 48
Secondary	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).	From Baseline to Week 24
Secondary	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).	Week 24
Secondary	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.	From Baseline to Week 24
Secondary	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).	Week 48
Secondary	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).	From Baseline to Week 48
Secondary	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.	From Baseline to Week 48
Secondary	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.	From Baseline to Week 24
Secondary	Number of subjects with serious and non-serious adverse events	Assessment of the safety of MOL compared to placebo	From screening (6-week) until Follow-up visit (Week 100)
Secondary	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	From screening (6-week) until Follow-up visit (Week 100)
Secondary	Changes in Forced vital capacity (FVC)	Assessment of the safety of MOL compared to placebo	From Baseline to Weeks 24 and 48
Secondary	Changes in Forced expiratory volume in one second (FEV1)	Assessment of the safety of MOL compared to placebo	From Baseline to Weeks 24 and 48
Secondary	Change in QT interval corrected by Fridericia (QTcF)	Assessment of the safety of MOL compared to placebo	From Baseline to Weeks 4 and 24