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

Once-daily inhaled molgramostim nebulizer solution in aPAP.

Desai Dhaval

Savara Pharmaceuticals

Bee Cave Road, Building 3, Suite 200, Austin, TX 78746, USA

dhaval.desai@savarapharma.com

Rosario Chikako

PAREXEL International

Kayabacho Tower, 1-21-2, Shinkawa, Chuo-ku, Tokyo

+81-80-8929-3137

Clinicaltrial-registration@parexel.com

Recruiting

July. 02, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Subject must be >=18 years of age, at the time of signing the informed consent. Specific for Japan; Subject must be >=20 years of age, at the time of signing the informed consent.
2. A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.
3. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.
4. DLCO 70% predicted or lower at the screening and baseline visits.
5. Change in % predicted DLCO of <15% points during the screening period.
6. Demonstrated functional impairment in the treadmill exercise test (defined as a peak MET =<8).
7. 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.
8. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the screening visits.
9. Male or female
10. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. 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.
b. 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.
11. 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.
12. 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.

1. Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.
2. WLL performed within 3 months prior to baseline.
3. Requirement for WLL at screening or baseline.
4. GM-CSF treatment within 6 months prior to baseline.
5. Treatment with rituximab within 6 months prior to baseline.
6. Treatment with plasmapheresis within 6 weeks prior to baseline.
7. Treatment with any investigational medicinal product within 5 half-lives or 3 months (whichever is longer) prior to baseline.
8. Previously randomized in this trial.
9. History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution.
10. Inflammatory or autoimmune disease of a severity that necessitates significant (e.g., more than 10 mg/day systemic prednisolone) immunosuppression.
11. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.
12. History of, or present, myeloproliferative disease or leukemia.
13. Apparent pre-existing concurrent pulmonary fibrosis, or diagnosis of interstitial lung disease other than aPAP.
14. Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise or confound assessment of the primary endpoint: including presence of pulmonary edema,or diagnosis of chronic obstructive pulmonary disease (COPD), pulmonary vasculitis, or pulmonary hypertension.
15. Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial.
16. Physical disability or other condition that precludes safe and adequate exercise testing.
17. Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial.
18. 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.
19. Any subject considered to be "vulnerable" on account of, e.g., mental or physical disability, socio-economic situation, or subjects deprived of their liberty.

Both

Autoimmune Pulmonary Alveolar Proteinosis(aPAP)

During the 48-week double-blind treatment period, subjects will be treated once daily with either MOL or PBO. All subjects who complete the double-blind treatment period will continue into the open-label treatment period where they will receive 48-week open-label once-daily treatment with MOL.

Change in % predicted DLCO from baseline to Week 24

- Change in SGRQ Total from baseline to Week 24
- Change in SGRQ Activity from baseline to Week 24
- Change in EC (expressed as peak METs) from baseline to Week 24
- Change in A-aDO2 from baseline to Week 24

+81-72-252-3021

Nov. 13, 2020

No

Belgium/Canada/Germany/France/England/Ireland/Italy/Korea/Netherlands/Poland/Romania/Turkey/America/Australia/Portugal/Spain/Greece