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 | 21.1 |
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 |
Investigate the efficacy of Molgramostim 300 µg nebulizer solution compared to placebo |
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E.2.2 | Secondary objectives of the trial |
- Investigate the safety of MOL compared to placebo - Investigate the safety of MOL compared to placebo after 96-week treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in % predicted DLCO from baseline to Week 24 |
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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) |
Change in % predicted DLCO from baseline to Week 48 • 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 SGRQ Total from baseline to Week 48 • Change in SGRQ Activity from baseline to Week 48 • Change in EC (expressed as peak METs) from baseline to Week 48
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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 | Yes |
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) | No |
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 | Yes |
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 | 2 |
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 | 12 |
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 |
Australia |
Canada |
Japan |
Korea, Republic of |
United States |
France |
Poland |
Netherlands |
Romania |
Spain |
Germany |
Greece |
Italy |
Belgium |
Ireland |
Portugal |
Turkey |
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 | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |