A randomized, double-blind, placebo-controlled clinical trial of once-daily inhaled molgramostim nebulizer solution in adult subjects with autoimmune pulmonary alveolar proteinosis

Data from a completed phase 2/3 trial, MOL-PAP-002, suggested that molgramostim, an inhaled form of the recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF), improves lung pathology, pathophysiology, and health status in subjects with aPAP in a dose-frequency dependent fashion. The present confirmatory phase 3 trial will be conducted to further investigate the efficacy and safety of molgramostim in subjects with aPAP.

1. Subject must be _> 18 years of age, at the time of signing the informed consent.

Type of Subject and Disease Characteristics

1. A serum anti- GM-CSF autoantibody test result confirming autoimmune PAP.
2. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.
3. DLCO 70% predicted or lower at the first screening and baseline visits.
4. Change in % predicted DLCO of < 15% points during the screening period.
5. 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.
6. Resulting SpO2> 95% during 15 minutes without use of supplemental oxygen at the screening visits.

Sex

1. Male or female
2. 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.

*Post-menopausal is defined as no menses for at least 12 months without any alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. ** A female is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. ***Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

Informed Consent

1. 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.
2. 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.