A clinical trial where patients with the lung disease autoimmunePulmonary Alveolar Proteinosis will be given the drug molgramostim nebulizer solution by inhalation.

Phase 1

Conditions: Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
MedDRA version: 21.1Level: LLTClassification code 10037316Term: Pulmonary alveolar proteinosisSystem Organ Class: 100000004855
Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Registration Number: EUCTR2020-001263-85-DE

Lead Sponsor: Savara ApS

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 160

Inclusion Criteria

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 first Screening and Baseline visits.
5. Change in % predicted DLCO of <15% points during the screening period.
6. 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.
7. Resting SpO2 >85% during 15 minutes without use of supplemental
oxygen at the Screening visits.
8. Male or female
9. 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 Screening (Visit 1) and a
negative urine pregnancy test at baseline (Visit 3) and must not be
lactating.
*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.
10. 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.
11. 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 140
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion Criteria

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 months 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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Investigate the efficacy of Molgramostim 300 µg nebulizer solution<br>compared to placebo<br>;Secondary Objective: - Investigate the safety of MOL compared to placebo<br>- Investigate the safety of MOL compared to placebo after 96-week<br>treatment<br>;Primary end point(s): Change in % predicted DLCO from baseline to Week 24;Timepoint(s) of evaluation of this end point: Week 24

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Change in % predicted DLCO from baseline to Week 48<br>• Change in SGRQ Total from baseline to Week 24<br>• Change in SGRQ Activity from baseline to Week 24<br>• Change in EC (expressed as peak METs) from baseline to<br>Week 24<br>• Change in SGRQ Total from baseline to Week 48<br>• Change in SGRQ Activity from baseline to Week 48<br>• Change in EC (expressed as peak METs) from baseline to<br>Week 48<br>;Timepoint(s) of evaluation of this end point: Week 24

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