Molgramostim for Autoimmune pulmonary alveolar proteinosis

Inclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- 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.\n- A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.\n- History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.\n- DLCO 70% predicted or lower at the first screening and Baseline visits\n- Change in % predicted DLCO of <15% points during the screening period.\n- 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.\n- Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the Screening visits.\n- Male or female\n- 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."}

Exclusion criteria

• {"criterion_text":"- Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.\n- 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.\n- WLL performed within 3 months prior to baseline.\n- Requirement for WLL at screening or baseline.\n- GM-CSF treatment within 6 months prior to baseline.\n- Treatment with rituximab within 6 months prior to baseline.\n- Treatment with plasmapheresis within 6 weeks months prior to baseline.\n- Treatment with any investigational medicinal product within 5 half- lives or 3 months (whichever is longer) prior to baseline.\n- Previously randomized in this trial.\n- History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution.\n- 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, including as further defined by French Health Code articles L1121-6, L1121-8, and L1121-8-1.\n- Inflammatory or autoimmune disease of a severity that necessitates significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression.\n- Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.\n- History of, or present, myeloproliferative disease or leukemia.\n- Apparent pre-existing concurrent pulmonary fibrosis, or diagnosis of interstitial lung disease other than aPAP.\n- 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.\n- Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial.\n- Physical disability or other condition that precludes safe and adequate exercise testing.\n- Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial"}

Primary endpoints

• {"endpoint_text":"- Change in % predicted DLCO from baseline to Week 24","definition_or_measurement_approach":"Change in percent predicted DLCO measured at baseline and at Week 24 (percent predicted DLCO comparison from baseline to Week 24)."}

Secondary endpoints

• {"endpoint_text":"- Change in % predicted DLCO from baseline to Week 48","definition_or_measurement_approach":"Change in percent predicted DLCO measured at baseline and at Week 48."}
• {"endpoint_text":"- Change in SGRQ Total from baseline to Week 24","definition_or_measurement_approach":"Change in St George's Respiratory Questionnaire (SGRQ) total score from baseline to Week 24."}
• {"endpoint_text":"- Change in SGRQ Activity from baseline to Week 24","definition_or_measurement_approach":"Change in SGRQ Activity domain score from baseline to Week 24."}
• {"endpoint_text":"- Change in EC (expressed as peak METs) from baseline to Week 24","definition_or_measurement_approach":"Change in exercise capacity expressed as peak metabolic equivalents (METs) from baseline to Week 24."}
• {"endpoint_text":"- Change in SGRQ Total from baseline to Week 48","definition_or_measurement_approach":"Change in SGRQ total score from baseline to Week 48."}
• {"endpoint_text":"- Change in SGRQ Activity from baseline to Week 48","definition_or_measurement_approach":"Change in SGRQ Activity domain score from baseline to Week 48."}
• {"endpoint_text":"- Change in EC (expressed as peak METs) from baseline to Week 48","definition_or_measurement_approach":"Change in exercise capacity expressed as peak METs from baseline to Week 48."}

Methods

• Recruitment brochures (digital and print) targeted to patients (documents: K1_BEL Recruitment Brochure, K1_BEL Recruitment Brochure Digital, K1_FRA Recruitment Brochure, etc.).
• Posters for patient recruitment in clinics/hospitals (K1_BEL Recruitment Poster English/Dutch/French; K1_FRA Recruitment Poster French).
• Physician 'infogetter' materials to engage other physicians for referrals (K1_BEL Recruitment Other Physician Infogetter).
• Country-specific IRB/IEC filenotes and recruitment procedure descriptions (e.g., K1_ITA IRB-IEC Filenote, K1_ROU ICF_Recruitment Placeholder-EU-CTR, Recruitment Procedure Description FILE NOTE).
• Consent navigation materials to assist informed consent discussions (K1_BEL Recruitment Other Consent Navigator).
• Country-specific translations/local materials provided (multiple country-specific ICFs and brochures).

Germany

Latest Decision Or Authorization Date

30-10-2024

Number Of Sites

2

Number Of Participants

7

Portugal

Latest Decision Or Authorization Date

04-11-2024

Number Of Sites

1

Number Of Participants

1

Ireland

Latest Decision Or Authorization Date

29-10-2024

Number Of Sites

1

Number Of Participants

1

Spain

Latest Decision Or Authorization Date

05-11-2024

Number Of Sites

1

Number Of Participants

2

Italy

Latest Decision Or Authorization Date

26-11-2024

Number Of Sites

1

Number Of Participants

9

Romania

Latest Decision Or Authorization Date

06-11-2024

Number Of Sites

1

Number Of Participants

2

Poland

Latest Decision Or Authorization Date

16-11-2024

Number Of Sites

1

Number Of Participants

3

Belgium

Latest Decision Or Authorization Date

29-10-2024

Number Of Sites

1

Number Of Participants

1

France

Latest Decision Or Authorization Date

14-05-2025

Number Of Sites

2

Number Of Participants

8

Primary sponsor

Full Name

Savara ApS

Organisation Type

Pharmaceutical company

Country Of Registered Address

Denmark

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

codes:1,10,11,12,13,2,3,6,7,8,9

Name

Klifo A/S

Responsibilities

Secondary packaging, GCP Auditing, IMP CT supply

Name

BioAgilytix Europe GmbH

Responsibilities

Anti drug antibody testing and PK analyses

Name

Cerba Research

Responsibilities

code:4

Third parties

• {"country":"Germany","full_name":"BioAgilytix Europe GmbH","duties_or_roles":"Anti drug antibody testing and PK analyses","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Cerba Research","duties_or_roles":"code:4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Denmark","full_name":"Klifo A/S","duties_or_roles":"Secondary packaging, GCP Auditing, IMP CT supply","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"codes:1,10,11,12,13,2,3,6,7,8,9","organisation_type":"Pharmaceutical company"}