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

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.

Inclusion criteria

• 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.

Exclusion criteria

• 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.
• 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.