Clinical trial NCT04544293: Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Autoimmune Pulmonary Alveolar Proteinosis
Lead sponsor: Savara Inc.
Sponsor class: INDUSTRY
First posted: 2020-09-10
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subject will be randomized 1:1 to treatment with inhaled molgramostim or placebo
Primary purpose: TREATMENT

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 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 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.

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. 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.

Primary outcomes:
measure: Change from baseline in percentage (%) predicted diffusing capacity of the lung for carbon monoxide (DLCO) to Week 24
timeFrame: From Baseline to Week 24
Secondary outcomes:
measure: Change from baseline in percentage (%) predicted DLCO to Week 48
timeFrame: From Baseline to Week 48
measure: Change from baseline in St. Georges Respiratory Questionnaire (SGRQ) Total score to Week 24
timeFrame: From Baseline to Week 24
measure: Change from baseline in SGRQ Activity component score to Week 24
timeFrame: Week 24
measure: Change from baseline in exercise capacity (EC), expressed as peak metabolic equivalents (METs) to Week 24
timeFrame: From Baseline to Week 24
measure: Change from baseline in SGRQ Total score to Week 48
timeFrame: Week 48
measure: Change from baseline in SGRQ Activity from baseline to Week 48
timeFrame: From Baseline to Week 48
measure: Change from baseline in EC, expressed as peak METs to Week 48
timeFrame: From Baseline to Week 48
measure: Change from baseline in alveolar-arterial oxygen difference (A-aDO2) to Week 24 (Specifically for Japan and South Korea)
timeFrame: From Baseline to Week 24
measure: Number of subjects with serious and non-serious adverse events
timeFrame: From screening (6-week) until Follow-up visit (Week 100)
measure: 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
timeFrame: From screening (6-week) until Follow-up visit (Week 100)
measure: Changes in Forced vital capacity (FVC)
timeFrame: From Baseline to Weeks 24 and 48
measure: Changes in Forced expiratory volume in one second (FEV1)
timeFrame: From Baseline to Weeks 24 and 48
measure: Change in QT interval corrected by Fridericia (QTcF)
timeFrame: From Baseline to Weeks 4 and 24
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University Of Arkansas For Medical Services
state: Arkansas
city: Los Angeles
country: United States
facility: UCLA David Geffen School of Medicine
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Raleigh
country: United States
facility: Wake Med Health & Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Perelman School of Medicine - Pulmonology
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Bruxelles
country: Belgium
facility: Hôpital Erasme
state: Région de Bruxelles-Capitale
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg - Pneumologie
state: Vlaams Brabant
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Hamilton
country: Canada
facility: St Joseph's Healthcare Hamilton Research
state: Ontario
city: Québec
country: Canada
facility: University Institute of Cardiology and Respirology of Quebec
state: Quebec
city: Bron
country: France
facility: Hôpital Louis Pradel
state: Auvergne-Rhône-Alpes
city: Rennes
country: France
facility: CHU Pontchaillou
state: Bretagne
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Muenchen-Gauting
country: Germany
facility: Asklepios Fachkliniken Muenchen-Gauting
state: Bayern
city: Essen
country: Germany
facility: Ruhrlandklinik Westdeutsches Lungenzentrum
state: Nordrhein-Westfalen
city: Athens
country: Greece
facility: Attikon University Hospital
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
state: Lombardia
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaidô
city: Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
state: Kanagawa
city: Sendai
country: Japan
facility: Tohoku University Hospital - Respiratory Tract Medicine
state: Miyagi
city: Sakai
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest medical Center
state: Osaka
city: Mitaka
country: Japan
facility: Kyorin University Hospital
state: Tokyo
city: Chiba
country: Japan
facility: Chiba University Hospital - Respiratory Medicine
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Nagakute
country: Japan
facility: Aichi Medical University Hospital
city: Saitama
country: Japan
facility: Saitama Red Cross Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital - Yonsei University Health System - Pulmonary
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Nieuwegein
country: Netherlands
facility: St Antonius Hospital
state: Utrecht
city: Warszawa
country: Poland
facility: Instytut Gruzlicy i Chorob Pluc
state: Mazowieckie
city: Lisboa
country: Portugal
facility: Hospital Pulido Valente
city: Porto
country: Portugal
facility: Hospital São João
city: Bucuresti
country: Romania
facility: Institutul de Pneumoftiziologie "Marius Nasta"
city: Barcelona
country: Spain
facility: Hospital Universitario de Bellvitge
state: Cataluña
city: Bornova
country: Turkey
facility: Ege University Hospital - Department of Pulmonology
state: Izmir
city: Ankara
country: Turkey
facility: Health Sciences University Gulhane Training and Research Hospital
city: Istanbul
country: Turkey
facility: Yedikule Chest Disease and Surgery Training and Research Hospital
city: London
country: United Kingdom
facility: Royal Brompton and Harefield NHS Foundation Trust
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Bruce Trapnell, MD
role: PRINCIPAL_INVESTIGATOR
References: