E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autoimmune Pulmonary Alveolar Proteinosis (aPAP) |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary Alveolar Proteinosis, commonly known by the acronym PAP, is a rare lung disease characterized by the build-up of proteinaceous material in the alveoli (air sacs) of the lungs.
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037316 |
E.1.2 | Term | Pulmonary alveolar proteinosis |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare efficacy of inhaled molgramostim on the Alveolar-arterial oxygen difference ((A-a)DO2) with placebo after 24-weeks treatment. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary objectives:
- To compare efficacy of inhaled molgramostim on requirement for, and time to, Whole Lung Lavage (WLL) with placebo after 24-weeks treatment
- To compare efficacy of inhaled molgramostim on Vital Capacity (VC) with placebo after 24-weeks treatment
Further Secondary objectives:
To compare efficacy of inhaled molgramostim with placebo after 24-weeks treatment on
- Diffusion Capacity of the Lung for Carbon Monoxide (DLCO), Forced Expiratory Volume in one second (FEV1), Forced Vital Capacity (FVC) and Arterial oxygen tension (PaO2)
- the categorical change of (A-a)DO2, VC , DLCO, FEV1, and PaO2
- tolerance to exercise
- dyspnoea, and cough
- disease severity by Computer Tomography (CT) scoring
- To compare safety of inhaled molgramostim with placebo in terms of reported AEs, SAEs, ADRs, severe AEs and withdrawals due to AEs during 24-weeks treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- aPAP diagnosed by CT, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by increased GM-CSF autoantibodies in serum.
- Stable or progressive aPAP (i.e. absolute VC not improved by more than 5% and/or DLCO not improved by more than 10% - assessed from medical records) during a minimum period of two months prior to the Baseline visit.
- PaO2 <75 mmHg/<10 kPa at rest, OR desaturation of >4 percentage points on the 6 Minute Walk Test (6MWT)
- An (A-a)DO2 at Screening 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
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E.4 | Principal exclusion criteria |
- Diagnosis of hereditary or secondary pulmonary alveolar proteinosis (PAP)
- WLL within two months of Baseline
- Treatment with GM-CSF within three months of Baseline
- Treatment with rituximab within six months of Baseline
- Treatment with plasmapheresis within three months of Baseline
- Treatment with any investigational medicinal product within four weeks of Screening
- Concomitant use of sputum modifying drugs such as carbocystein or ambroxol
- History of allergic reactions to GM-CSF
- Connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring immunosuppressive treatment (systemic corticosteroid 10 mg/day or less is allowed. All other immunosuppressive treatment is prohibited)
- 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
- Significant liver impairment (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level >3 times the upper normal limit) or renal impairment (estimated Glomerular Filtration Rate [eGFR] <30 mL/min/1.73m2) at Screening.
- 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 subject unsuitable for the trial
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E.5 End points |
E.5.1 | Primary end point(s) |
Absolute change from baseline of (A-a)DO2 after 24-weeks treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key Secondary Endpoints:
- Number of subjects in need of WLL during 24-weeks treatment
- Time to WLL during 24-weeks treatment
- Absolute change from baseline in VC (% predicted) after 24-weeks treatment
Further Secondary Endpoints:
- Absolute change from baseline in DLCO (% predicted), FEV1 (% predicted), FVC (% predicted) and and relative change from baseline in PaO2 after 24-weeks treatment
- Number of subjects with >5 mmHg/>0.67 kPa and number of subjects with >10 mmHg/>1.33 kPa improvement in (A-a)DO2 after 24-weeks treatment
- Number of subjects with >5 percentage points and number of subjects with >10 percentage points improvement in VC (% predicted) after 24-weeks treatment
- Number of subjects with >10 percentage points improvement in DLCO (% predicted) after 24 weeks treatment
- Number of subjects with >10 percentage points improvement in FEV1 (% predicted), FVC (% predicted) after 24-weeks treatment
- Number of subjects with >10% relative improvement in PaO2 after 24-weeks treatment
- Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m or desaturation <4 percentage points on the 6MWT) after 24-weeks treatment
- Change from baseline in dyspnoea score and cough scores after 24-weeks treatment
- Number of subjects with improved CT score after 24-weeks treatment
- Number of AEs, SAEs, ADRs, severe AEs and AEs leading to treatment discontinuation, including clinically significant changes in laboratory tests and echocardiographic (ECG) variables, during 24-weeks treatment
Exploratory Endpoints:
Double-blind treatment period
- Absolute change from baseline of (A-a)DO2, VC (% predicted), DLCO (% predicted), FEV1 (% predicted), FVC (% predicted), and relative change from baseline of PaO2 after 4 and 12-weeks treatment
- Time period during which the (A-a)DO2 level is maintained below Baseline –10mmHg
- Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m or desaturation <4 percentage points on the 6MWT) after 4 and 12-weeks treatment
- Time period during which the improvement in tolerance to exercise is maintained
- Change from baseline in dyspnoea score and cough scores after 4 and 12-weeks treatment
- Number of subjects with improved QoL (change of ≥4 units on the SGRQ/number of subjects with ‘no problems’ in EQ-5D-5L), after 4, 12, and 24-weeks treatment
- Change in serum concentration of biomarkers: Krebs von den Lungen-6 (KL-6), Carcinoembryonic antigen (CEA), Surfactant Protein A (SP-A), Surfactant Protein B (SP-B) , Surfactant Protein C (SP-C), Surfactant Protein D (SP-D), Cytokeratin 19 Fragment (Cyfra 21-1) and Lactate Dehydrogenase (LDH) after 4, 12, and 24-weeks treatment
- Levels of antibodies towards Granulocyte Macrophage Colony Stimulating Factor (anti-GM-CSF) after 12 and 24-weeks treatment
- Change in serum concentration of GM-CSF post first dose of trial drug and after 4-weeks of treatment
- Number of subjects in need for oxygen supplement therapy (PaO2 on room air <55 mmHg/<7.3 kPa) during 24-weeks treatment.
- The distribution of DSS at Screening and at Week 24
- The percentage of subjects with DSS 1 or 2 at Screening and at Week 24.
Follow-up period:
- Number of subjects requiring WLL, new treatment with GM-CSF, or other treatment for aPAP and number of treatment courses required during 48-weeks follow-up.
- Time to WLL, new treatment with GM-CSF, or other treatment for aPAP during 48-weeks follow up.
- Absolute change from baseline in (A-a)DO2 and VC (% predicted), DLCO (% predicted), FEV1 (% predicted) , FVC (% predicted), and and relative change from baseline of PaO2 after 12, 24, 36 and 48-weeks follow-up
- Number of subjects with improved tolerance to exercise (increase in distance walked ≥50 m or desaturation <4 percentage points on the 6MWT) after 12, 24, 36 and 48-weeks follow-up
- Number of AEs, severe AEs, SAEs and ADRs , including clinically significant changes in laboratory tests and ECG variables, during 48-weeks follow-up
- Levels of anti-GM-CSF after 12 and 24 weeks follow-up.
- The distribution of DSS after 24 and 48-weeks follow-up
- The percentage of subjects with DSS 1 or 2 after 24 and 48-weeks follow-up.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Denmark |
France |
Germany |
Greece |
Israel |
Italy |
Japan |
Netherlands |
Russian Federation |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |