Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
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 48 weeks.
- 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.
- DLCO 70% predicted or lower at the screening and baseline visits.
- Change in % predicted DLCO of <15% points during the screening period.
- Demonstrated functional impairment in the treadmill exercise test (defined as a peak 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 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.
- 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.