efficacy and safety of inhaled molgramostim (rhgm-csf) in autoimmune pulmonary alveolar proteinosis

Conditions: Autoimmune Pulmonary Alveolar Proteinosis

Summary: this study evaluates inhaled molgramostim (recombinant human granulocyte macrophage-colony stimulating factor \[rhgm-csf\]) in the treatment of autoimmune pulmonary alveolar proteinosis (apap) patients. a third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks.

the trial is a phase 2, randomized, double-blind, placebo-controlled multicentre clinical trial investigating efficacy and safety of inhaled molgramostim (rhgm-csf) in patients with apap. the trial will include 2 periods; a double-blind treatment period consisting of up to 8 trial visits (screening, baseline, and at weeks 4, 8,12, 16, 20 and 24 after randomisation) and a open-label follow-up period consisting of up to 5 trial visits (at weeks 4, 12, 24, 36 and 48 post-treatment). in the double-blind treatment period, eligible subjects will be randomised to treatment for up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily (mol-od), 2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (7 days on and 7 days off) (mol-int) or 3) inhaled placebo once daily (pbo). during the follow-up period, all participants will receive inhaled molgramostim intermittently (7 days on, 7 days off). during the trial, whole lung lavage (wll) may be applied as rescue therapy in case of significant clinical worsening.

Eligibility criteria:
inclusion criteria: * apap diagnosed by computed tomography, or by biopsy, or by broncho alveolar lavage (bal), and by increased gm-csf autoantibodies in serum. * stable or progressive apap during a minimum period of 2 months prior to the baseline visit. * arterial oxygen tension (pao2) \ 4 percentage points on the 6mwt * an alveolar-arterial oxygen difference \[(a-a)do2\] of minimum 25 mmhg/3.33 kpa * female or male ≥18 years of age * 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, vasectomised partner, sexual abstinence), during and until 30 days after last dose of double-blind trial treatment. females of childbearing potential must have a negative serum pregnancy test at screening (visit 1) and a negative urine pregnancy test at dosing at baseline (visit 2) and must not be lactating * males agreeing to use condoms during and until 30 days after last dose of double-blind medication, or males having a female partner who is using adequate contraception as described above * willing and able to provide signed informed consent * 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 * wll within 1 month of baseline * treatment with gm-csf within 3 months of baseline * treatment with rituximab within 6 months of baseline * treatment with plasmapheresis within 3 months of baseline * treatment with any investigational medicinal product within 4 weeks of screening * concomitant use of sputum modifying drugs such as carbocysteine or ambroxol * history of allergic reactions to gm-csf * connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring treatment associated with significant immunosuppression, e.g. more than 10 mg/day systemic prednisolone * previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product * history of, or present, myeloproliferative disease or leukaemia * known active infection (viral, bacterial, fungal or mycobacterial) * apparent pre-existing concurrent pulmonary fibrosis * any other serious medical condition which in the opinion of the investigator would make the participant unsuitable for the trial