Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
- Conditions
- Autoimmune Pulmonary Alveolar Proteinosis
- Interventions
- Drug: Placebo
- Registration Number
- NCT04544293
- Lead Sponsor
- Savara Inc.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 160
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Subject must be ≥18 years of age, at the time of signing the informed consent (≥20 in Japan).
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A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.
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History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.
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DLCO 70% predicted or lower at the screening and baseline visits.
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Change in % predicted DLCO of <15% points during the screening period.
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Demonstrated functional impairment in the treadmill exercise test (defined as a peak MET ≤8).
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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.
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Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the screening visits.
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Male or female
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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.
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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.
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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.
- Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.
- 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.
- Physical disability or other condition that precludes safe and adequate exercise testing.
- Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial.
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo 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 96 weeks Placebo Molgramostim 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 96 weeks Molgramostim 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 96 weeks
- Primary Outcome Measures
Name Time Method Change from baseline in percentage (%) predicted diffusing capacity of the lung for carbon monoxide (DLCO) to Week 24 From Baseline 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.
- Secondary Outcome Measures
Name Time Method Change from baseline in SGRQ Activity component score to Week 24 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).
Change from baseline in alveolar-arterial oxygen difference (A-aDO2) to Week 24 (Specifically for Japan and South Korea) From Baseline to Week 24 A-aDO2 will be used as an additional measure of gas exchange.
Change from baseline in St. Georges Respiratory Questionnaire (SGRQ) Total score to Week 24 From Baseline 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).
Change from baseline in SGRQ Total score to Week 48 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).
Change from baseline in percentage (%) predicted DLCO to Week 48 From Baseline 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.
Change from baseline in EC, expressed as peak METs to Week 48 From Baseline 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.
Number of subjects with serious and non-serious adverse events From screening (6-week) until Follow-up visit (Week 100) Assessment of the safety of MOL compared to placebo
Change from baseline in exercise capacity (EC), expressed as peak metabolic equivalents (METs) to Week 24 From Baseline 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.
Change from baseline in SGRQ Activity from baseline to Week 48 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).
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 From screening (6-week) until Follow-up visit (Week 100) Assessment of the safety of MOL compared to placebo
Change in QT interval corrected by Fridericia (QTcF) From Baseline to Weeks 4 and 24 Assessment of the safety of MOL compared to placebo
Changes in Forced vital capacity (FVC) From Baseline to Weeks 24 and 48 Assessment of the safety of MOL compared to placebo
Changes in Forced expiratory volume in one second (FEV1) From Baseline to Weeks 24 and 48 Assessment of the safety of MOL compared to placebo
Trial Locations
- Locations (54)
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
🇺🇸Saint 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
🇧🇪Bruxelles, Région de Bruxelles-Capitale, 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, Quebec, Canada
Hôpital Louis Pradel
🇫🇷Bron, Auvergne-Rhône-Alpes, France
CHU Pontchaillou
🇫🇷Rennes, Bretagne, France
Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Baden-Württemberg, Germany
Asklepios Fachkliniken Muenchen-Gauting
🇩🇪Muenchen-Gauting, Bayern, Germany
Ruhrlandklinik Westdeutsches Lungenzentrum
🇩🇪Essen, Nordrhein-Westfalen, Germany
Attikon University Hospital
🇬🇷Athens, Greece
St. Vincent's University Hospital
🇮🇪Dublin, Ireland
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Lombardia, 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
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital - Yonsei University Health System - Pulmonary
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
St Antonius Hospital
🇳🇱Nieuwegein, Utrecht, Netherlands
Instytut Gruzlicy i Chorob Pluc
🇵🇱Warszawa, Mazowieckie, Poland
Hospital Pulido Valente
🇵🇹Lisboa, Portugal
Hospital São João
🇵🇹Porto, Portugal
Institutul de Pneumoftiziologie "Marius Nasta"
🇷🇴Bucuresti, Romania
Hospital Universitario de Bellvitge
🇪🇸Barcelona, Cataluña, Spain
Ege University Hospital - Department of Pulmonology
🇹🇷Bornova, Izmir, Turkey
Health Sciences University Gulhane Training and Research Hospital
🇹🇷Ankara, Turkey
Yedikule Chest Disease and Surgery Training and Research Hospital
🇹🇷Istanbul, Turkey
Royal Brompton and Harefield NHS Foundation Trust
🇬🇧London, United Kingdom