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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037316 |
E.1.2 | Term | Pulmonary alveolar proteinosis |
E.1.2 | System Organ Class | 100000015560 |
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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 tolerance to exercise with placebo after 24-weeks of treatment - To compare efficacy of inhaled molgramostim on respiratory disease-related quality of life with placebo after 24-weeks of treatment - To compare efficacy of inhaled molgramostim based on time to Whole Lung Lavage (WLL) with placebo during 24-weeks of treatment. - To compare safety of inhaled molgramostim with placebo in terms of reported adverse events (AEs), serious adverse events (SAEs), adverse drug reactions (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 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 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 trial treatment, 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 one month 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 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 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: - Change from baseline in 6-minute walking distance (6MWD) after 24-weeks treatment - Change from baseline in SGRQ total score after 24-weeks treatment - Time to WLL during 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
Further Secondary Endpoints: - Absolute change from baseline in VC (% predicted), 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) and 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
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 4, 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, or other treatment for aPAP and number of treatment courses required during 24-weeks or 48-weeks follow-up. - Time to WLL, or other treatment for aPAP during 24-weeks or 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 24-weeks or 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 | 15 |
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 |
Korea, Republic of |
Netherlands |
Poland |
Portugal |
Russian Federation |
Slovakia |
Spain |
Switzerland |
Turkey |
United Kingdom |
United States |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 19 |