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

NCT04544293 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 2 other identifiers: SAV006-052020-001263-85
• Study Type: interventional
• Target: 164
• Locations: 18 countries
• Sites: 54

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.

Conditions

Autoimmune Pulmonary Alveolar Proteinosis

Keywords

aPAP

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Percent (%) Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Adjusted for Hemoglobin Concentration to Week 24

  As a measure of pulmonary gas transfer, a standardized lung function test, DLCO, was conducted. The single-breath DLCO test was performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing. Results reported as % predicted DLCO adjusted for hemoglobin concentration (%predicted DLCOadj).

  From Baseline to Week 24

Secondary Outcomes (13)

• Change From Baseline in Percent (%) Predicted DLCO Adjusted for Hemoglobin Concentration (%DLCOadj) to Week 48

  From Baseline to Week 48

• Change From Baseline in St. Georges Respiratory Questionnaire (SGRQ) Total Score to Week 24

  From Baseline to Week 24

• Change From Baseline in SGRQ Activity Component Score to Week 24

  From Baseline to Week 24

• Change From Baseline in Exercise Capacity (EC), Expressed as Peak Metabolic Equivalents (METs) to Week 24

  From Baseline to Week 24

• Change From Baseline in SGRQ Total Score to Week 48

  From Baseline to Week 48

Study Arms (3)

Molgramostim

EXPERIMENTAL

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

Drug: Molgramostim

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Molgramostim Open-label Extension

EXPERIMENTAL

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

Drug: Molgramostim Open-label

Interventions

Molgramostim DRUG

Molgramostim 300 µg nebulizer solution

Also known as: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF)

Molgramostim

Placebo DRUG

Matching placebo nebulizer solution

Also known as: Placebo nebulizer

Placebo

Molgramostim Open-label DRUG

Molgramostim 300 µg nebulizer solution

Also known as: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF)

Molgramostim Open-label Extension

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be ≥18 years of age, at the time of signing the informed consent (≥20 in Japan).
• A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.
• History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.
• A diffusing capacity for carbon monoxide of 70% predicted or lower adjusted for hemoglobin (%DLCOadj) at the screening and baseline visits.
• Change in %DLCO adj of \<15% points during the screening period.
• Demonstrated functional impairment in the treadmill exercise test (defined as a peak metabolic equivalent (MET) ≤8).
• 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.
• Resting oxygen saturation (SpO2) \>85% during 15 minutes without use of supplemental oxygen at the screening visits.
• Male or female
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• 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.
• 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.
• 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.
• 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.

You may not qualify if:

• Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.
• Whole lung lavage (WLL) performed within 3 months prior to baseline.
• Requirement for WLL at screening or baseline.
• GM-CSF treatment within 6 months prior to baseline.
• Treatment with rituximab within 6 months prior to baseline.
• Treatment with plasmapheresis within 6 weeks prior to baseline.
• Treatment with any investigational medicinal product within 5 half-lives or 3 months (whichever is longer) prior to baseline.
• Previously randomized in this trial.
• History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution.
• Inflammatory or autoimmune disease of a severity that necessitates significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression.
• Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.
• History of, or present, myeloproliferative disease or leukemia.
• Apparent pre-existing concurrent pulmonary fibrosis.
• Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise.
• Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial.

Sponsors & Collaborators

• Savara Inc.: lead

Study Sites (54)

University Of Arkansas For Medical Services

Little Rock, Arkansas, 72205, United States

Location

UCLA David Geffen School of Medicine

Los Angeles, California, 90095, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

University of Florida Health

Gainesville, Florida, 32610, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Loyola University

Maywood, Illinois, 60153, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Wake Med Health & Hospital

Raleigh, North Carolina, 27610, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania Perelman School of Medicine - Pulmonology

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Royal Prince Alfred Hospital

Camperdown, New South Wales, 2050, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Hôpital Erasme

Brussels, Brussels Capital, 1070, Belgium

Location

UZ Leuven - Campus Gasthuisberg - Pneumologie

Leuven, Vlaams Brabant, 3000, Belgium

Location

University of Calgary

Calgary, Alberta, T2N 4N1, Canada

Location

St Joseph's Healthcare Hamilton Research

Hamilton, Ontario, L8N 4A6, Canada

Location

University Institute of Cardiology and Respirology of Quebec

Québec, G1V 4G5, Canada

Location

Hôpital Louis Pradel

Bron, Auvergne-Rhône-Alpes, 69500, France

Location

CHU Pontchaillou

Rennes, Brittany Region, 35033, France

Location

Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, 69126, Germany

Location

Asklepios Fachkliniken Muenchen-Gauting

Muenchen-Gauting, Bavaria, 82131, Germany

Location

Ruhrlandklinik Westdeutsches Lungenzentrum

Essen, North Rhine-Westphalia, 45239, Germany

Location

Attikon University Hospital

Athens, 12462, Greece

Location

St. Vincent's University Hospital

Dublin, DO4 T6F4, Ireland

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, Lombardy, 27100, Italy

Location

Hokkaido University Hospital

Sapporo, Hokkaidô, 060-8648, Japan

Location

Kanagawa Cardiovascular and Respiratory Center

Yokohama, Kanagawa, 236-0051, Japan

Location

Tohoku University Hospital - Respiratory Tract Medicine

Sendai, Miyagi, 980-8574, Japan

Location

National Hospital Organization Kinki-Chuo Chest medical Center

Sakai, Osaka, 591-8555, Japan

Location

Kyorin University Hospital

Mitaka, Tokyo, 181-8611, Japan

Location

Chiba University Hospital - Respiratory Medicine

Chiba, 260-8677, Japan

Location

Kumamoto University Hospital

Kumamoto, 860-8556, Japan

Location

Aichi Medical University Hospital

Nagakute, 480-1195, Japan

Location

Saitama Red Cross Hospital

Saitama, 330-8553, Japan

Location

St Antonius Hospital

Nieuwegein, Utrecht, 3435CM, Netherlands

Location

Instytut Gruzlicy i Chorob Pluc

Warsaw, Masovian Voivodeship, 01-138, Poland

Location

Hospital Pulido Valente

Lisbon, 1769-001, Portugal

Location

Hospital São João

Porto, 4200-319, Portugal

Location

Institutul de Pneumoftiziologie "Marius Nasta"

Bucharest, 050159, Romania

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital - Yonsei University Health System - Pulmonary

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Hospital Universitario de Bellvitge

Barcelona, Catalonia, 08907, Spain

Location

Ege University Hospital - Department of Pulmonology

Bornova, İzmir, 35100, Turkey (Türkiye)

Location

Health Sciences University Gulhane Training and Research Hospital

Ankara, 6010, Turkey (Türkiye)

Location

Yedikule Chest Disease and Surgery Training and Research Hospital

Istanbul, 34020, Turkey (Türkiye)

Location

Royal Brompton and Harefield NHS Foundation Trust

London, SW3 6NP, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 40834301 DERIVED

MeSH Terms

Conditions

Pulmonary Alveolar Proteinosis, Acquired

Interventions

molgramostim; Colony-Stimulating Factors; regramostim

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Raymond D Pratt, MD FACP
• Organization: Savara Inc.

ray.pratt@savarapharma.com

512 614 1848

Study Officials

• Bruce Trapnell, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subject will be randomized 1:1 to treatment with inhaled molgramostim or placebo

Study Record Dates

• First Submitted: September 3, 2020
• First Posted: September 10, 2020
• Study Start: May 19, 2021
• Primary Completion: November 30, 2023
• Study Completion (Estimated): May 30, 2027
• Last Updated: August 7, 2025
• Results First Posted: August 7, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3); TU (3); DE (3); JP (9); US (16); PT (2); RO (1); IE (1); BE (2); GR (1); KR (4); ES (1); IT (1); GB (1); PL (1); NL (1); AU (2); FR (2)