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

NCT ID: NCT04544293

Last Updated: 2025-08-07

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 164 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-19
• Study Completion Date: 2027-05-30

Brief Summary

160 subjects with autoimmune pulmonary alveolar proteinosis (aPAP) will be randomized to receive once daily treatment with inhaled molgramostim (MOL) or placebo (PBO) for 48 weeks. Subjects completing the 48-week placebo-controlled period will receive open-label treatment with once daily inhaled molgramostim for 96 weeks.

Detailed 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 a Granulocyte-macrophage colony stimulating factor (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.

Conditions

Autoimmune Pulmonary Alveolar Proteinosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Molgramostim

Double-blind treatment with molgramostim nebulizer solution 300 µg once daily (Mol OD) for 48 weeks

Group Type: EXPERIMENTAL

Molgramostim

Intervention Type: DRUG

Molgramostim 300 µg nebulizer solution

Placebo

Double-blind treatment with placebo (PBO) nebulizer solution once daily for 48 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching placebo nebulizer solution

Molgramostim Open-label Extension

Open-label treatment with molgramostim nebulizer solution 300 µg once daily (Mol OD) for 96 weeks

Group Type: EXPERIMENTAL

Molgramostim Open-label

Intervention Type: DRUG

Molgramostim 300 µg nebulizer solution

Interventions

Molgramostim

Molgramostim 300 µg nebulizer solution

Intervention Type: DRUG

Placebo

Matching placebo nebulizer solution

Intervention Type: DRUG

Molgramostim Open-label

Molgramostim 300 µg nebulizer solution

Intervention Type: DRUG

Other Intervention Names

Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF); Placebo nebulizer; Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF)

Eligibility Criteria

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. A diffusing capacity for carbon monoxide of 70% predicted or lower adjusted for hemoglobin (%DLCOadj) at the screening and baseline visits.

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

6. Demonstrated functional impairment in the treadmill exercise test (defined as a peak metabolic equivalent (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 oxygen saturation (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. Whole lung lavage (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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Savara Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bruce Trapnell, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Locations

University Of Arkansas For Medical Services

Little Rock, Arkansas, United States

UCLA David Geffen School of Medicine

Los Angeles, California, United States

National Jewish Health

Denver, Colorado, United States

Yale University

New Haven, Connecticut, United States

University of Florida Health

Gainesville, Florida, United States

Emory University

Atlanta, Georgia, United States

Loyola University

Maywood, Illinois, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Washington University in St. Louis

St Louis, Missouri, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Med Health & Hospital

Raleigh, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pennsylvania Perelman School of Medicine - Pulmonology

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

Westmead Hospital

Westmead, New South Wales, Australia

Hôpital Erasme

Brussels, Brussels Capital, Belgium

UZ Leuven - Campus Gasthuisberg - Pneumologie

Leuven, Vlaams Brabant, Belgium

University of Calgary

Calgary, Alberta, Canada

St Joseph's Healthcare Hamilton Research

Hamilton, Ontario, Canada

University Institute of Cardiology and Respirology of Quebec

Québec, , Canada

Hôpital Louis Pradel

Bron, Auvergne-Rhône-Alpes, France

CHU Pontchaillou

Rennes, Brittany Region, France

Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

Asklepios Fachkliniken Muenchen-Gauting

Muenchen-Gauting, Bavaria, Germany

Ruhrlandklinik Westdeutsches Lungenzentrum

Essen, North Rhine-Westphalia, Germany

Attikon University Hospital

Athens, , Greece

St. Vincent's University Hospital

Dublin, , Ireland

Fondazione IRCCS Policlinico San Matteo

Pavia, Lombardy, Italy

Hokkaido University Hospital

Sapporo, Hokkaidô, Japan

Kanagawa Cardiovascular and Respiratory Center

Yokohama, Kanagawa, Japan

Tohoku University Hospital - Respiratory Tract Medicine

Sendai, Miyagi, Japan

National Hospital Organization Kinki-Chuo Chest medical Center

Sakai, Osaka, Japan

Kyorin University Hospital

Mitaka, Tokyo, Japan

Chiba University Hospital - Respiratory Medicine

Chiba, , Japan

Kumamoto University Hospital

Kumamoto, , Japan

Aichi Medical University Hospital

Nagakute, , Japan

Saitama Red Cross Hospital

Saitama, , Japan

St Antonius Hospital

Nieuwegein, Utrecht, Netherlands

Instytut Gruzlicy i Chorob Pluc

Warsaw, Masovian Voivodeship, Poland

Hospital Pulido Valente

Lisbon, , Portugal

Hospital São João

Porto, , Portugal

Institutul de Pneumoftiziologie "Marius Nasta"

Bucharest, , Romania

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital - Yonsei University Health System - Pulmonary

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Hospital Universitario de Bellvitge

Barcelona, Catalonia, Spain

Ege University Hospital - Department of Pulmonology

Bornova, İzmir, Turkey (Türkiye)

Health Sciences University Gulhane Training and Research Hospital

Ankara, , Turkey (Türkiye)

Yedikule Chest Disease and Surgery Training and Research Hospital

Istanbul, , Turkey (Türkiye)

Royal Brompton and Harefield NHS Foundation Trust

London, , United Kingdom

Countries

United States; Australia; Belgium; Canada; France; Germany; Greece; Ireland; Italy; Japan; Netherlands; Poland; Portugal; Romania; South Korea; Spain; Turkey (Türkiye); United Kingdom

References

Trapnell BC, Inoue Y, Bonella F, Wang T, McCarthy C, Arai T, Akasaka K, Mariani F, Mogulkoc N, Song JW, Baba T, Jouneau S, Numakura T, Ocal N, Mihaltan F, Ataya A, Bendstrup E, Campo I, Carey B, Arena R, Robinson B, Fleming R, Wasfi Y, Pratt R; IMPALA-2 Trial Investigators. Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2025 Aug 21;393(8):764-773. doi: 10.1056/NEJMoa2410542.

Reference Type: DERIVED

PMID: 40834301 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2020-001263-85

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SAV006-05

Identifier Type: -

Identifier Source: org_study_id