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    Summary
    EudraCT Number:2015-003878-33
    Sponsor's Protocol Code Number:MOL-PAP-002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-30
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-003878-33
    A.3Full title of the trial
    A Randomised, Double-Blind, Placebo-Controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary AlveoLAr Proteinosis Patients
    Sperimentazione clinica multicentrica, randomizzata, in doppio cieco, controllata con placebo, di molgramostim per via inalatoria in pazienti affetti da proteinosi polmonare alveolare autoimmune.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial where patients with the lung disease autoimmune Pulmonary Alveolar Proteinosis will be given the drug molgramostim by inhalation.
    Studio clinico nel quale i pazienti affetti da proteinosi polmonare alveolare autoimmune verrà dato il farmaco molgrastim per via inalatoria
    A.3.2Name or abbreviated title of the trial where available
    IMPALA
    A.4.1Sponsor's protocol code numberMOL-PAP-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSavara ApS
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSavara Aps
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSavara Aps
    B.5.2Functional name of contact pointTrial director
    B.5.3 Address:
    B.5.3.1Street AddressSlotsmarken 17. 2.tv.
    B.5.3.2Town/ cityHørsholm
    B.5.3.3Post code2970
    B.5.3.4CountryDenmark
    B.5.4Telephone number+45 20 48 34 30
    B.5.6E-mailinta@savarapharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberOD/106/12
    D.3 Description of the IMP
    D.3.1Product nameMolgramostim 300 mcg nebuliser solution
    D.3.4Pharmaceutical form Nebuliser solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMOLGRAMOSTIM
    D.3.9.1CAS number 99283-10-0
    D.3.9.4EV Substance CodeSUB09040MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboNebuliser solution
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
    Proteinosi polmonare alveolare autoimmune (aPAP)
    E.1.1.1Medical 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.
    la Proteinosi Polmonre alveolare, comunemente nota con l'acronimo PAP è una malattia rara del polmone caratterizzata dalla costruzionedi materiale proteico negli alveoli (sacchi di aria)nei polmoni.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10037316
    E.1.2Term Pulmonary alveolar proteinosis
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    Confrontare l'efficacia di molgramostim per via inalatoria rispetto al placebo in termini di differenza alveolo-arteriosa di ossigeno ((A-a)DO2) dopo 24 settimane di trattamento.
    E.2.2Secondary 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

    Confrontare l'efficacia di molgramostim per via inalatoria rispetto al placebo in termni di necessità di lavaggio polmonare massimo, nochè di tempo a tale procedura, dopo 24 settimane di trattamento.
    Confrontare l'efficacia di molgramostim per via inalatoria rispetto al placebo in termini di capacità vitale (CV) dopo 24 settimane di trattamento.
    Ulteriori obiettivi secondari:
    Per confrontare l'efficacia di molgramostim per via inalatoria con placebo dopo 24 settimane di trattamento
    - capacità di diffusione del polmone per monossido di carbonio (DLCO), volume espiratorio forzato in un secondo (FEV1), capacità vitale forzata (FVC)e tensione arteriosa di ossigeno (Pa02)
    la tolleranza all'esercizio
    Dispnea e tosse
    Gravità della malattia tramite punteggio di Tomografia Computerizzata (CT)
    Confrontare la sicurezza di Molgramostim per via inlatoria con placebo in termini di eventi avversi

    E.2.3Trial contains a sub-study No
    E.3Principal 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
    aPAP diagnosticata mediante uno dei seguenti metodi: TC, biopsia, lavaggio broncoalveolare (Broncho Alveolar Lavage, BAL) o aumento della concentrazione sierica di anticorpi anti-GM-CSF;

    • aPAP stabile o progressiva (ovvero miglioramento della CV assoluta non superiore al 5% e/o miglioramento della DLCO non superiore al 10% - valutati mediante le cartelle cliniche) durante un lasso di tempo minimo pari a due mesi prima della visita basale;
    • PaO2 <75 mmHg/<10 kPa a riposo OPPURE desaturazione >4 punti percentuali al test del cammino in 6 minuti (6 Minute Walk Test, 6MWT);

    • (A-a)DO2 allo screening pari almeno a 25 mmHg/3,33 kPa;

    • Soggetti di sesso maschile o femminile di età ≥18 anni;

    • Soggetti di sesso femminile in post-menopausa da almeno 1 anno o in età fertile (dopo un periodo mestruale confermato) che fanno uso di un metodo anticoncezionale altamente efficace (ovvero un metodo che riscuote un tasso di fallimento <1%, quali contraccettivi ormonali combinati, contraccettivi ormonali solo progestinici, dispositivi intrauterini, sistemi intrauterini a rilascio di ormoni, occlusione bilaterale delle tube, partner sottoposto a vasectomia, astinenza sessuale), durante e fino a 30 giorni dopo l'ultima somministrazione del trattamento sperimentale in doppio cieco. I soggetti di sesso femminile in età fertile devono presentare un test di gravidanza sul siero negativo allo screening (Visita 1) e un test di gravidanza sulle urine negativo alla somministrazione della dose al basale (Visita 2), e non devono allattare al seno;

    • I soggetti di sesso maschile devono acconsentire ad usare il preservativo durante e fino a 30 giorni dopo l'ultima somministrazione del farmaco in doppio cieco, oppure devono avere una partner che faccia uso dei metodi anticoncezionali adeguati sopra descritti;

    • Volontà e capacità di fornire il consenso informato scritto;

    • Volontà e capacità di rispettare le visite programmate, il piano terapeutico, i test di laboratorio e le altre procedure della sperimentazione indicate nel protocollo, in base al parere dello sperimentatore
    E.4Principal 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
    Diagnosi di proteinosi alveolare polmonare (PAP) secondaria o ereditaria;

    • Esecuzione di un WLL entro due mesi dal basale;

    • Trattamento a base di GM-CSF entro tre mesi dal basale;

    • Trattamento a base di rituximab entro sei mesi dal basale;

    • Trattamento con plasmaferesi entro tre mesi dal basale;

    • Trattamento con qualsiasi medicinale sperimentale entro quattro settimane dallo screening;

    • Uso concomitante di farmaci modificanti l'espettorato, come carbocisteina o ambroxolo;

    • Anamnesi di reazioni allergiche a GM-CSF;

    • Malattia dei tessuti connettivi, malattia infiammatoria intestinale o altri disturbi autoimmuni che richiedono un trattamento immunosoppressivo (è ammesso l'uso di corticosteroidi sistemici fino alla dose di 10 mg/die; tutte le altre terapie immunosoppressive sono invece vietate);
    Precedenti di effetti indesiderati gravi e inspiegabili durante la somministrazione aerosolica di qualsiasi tipo di prodotto medicinale;

    • Anamnesi o presenza di malattia mieloproliferativa o leucemia;

    • Danno epatico significativo (livello di aspartato aminotransferasi [AST] o di alanina aminotransferasi [ALT] >3 volte il limite superiore della norma) o danno renale (tasso stimato di filtrazione glomerulare [estimated Glomerular Filtration Rate, eGFR] <30 ml/min/1,73 m2) allo screening;

    • Presenza accertata di infezione attiva (virale, batterica, micotica o micobatterica);

    • Apparente fibrosi polmonare concomitante pre-esistente;
    • Qualsiasi altra condizione medica grave che, secondo il parere dello sperimentatore, renderebbe il soggetto non idoneo per la sperimentazione.
    E.5 End points
    E.5.1Primary end point(s)
    Absolute change from baseline of (A-a)DO2 after 24-weeks treatment
    Variazione assoluta della (A-a)DO2 rispetto al basale dopo 24 settimane di trattamento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 24-weeks treatment
    Dopo 24 settimane di trattamento
    E.5.2Secondary 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.
    Numero di soggetti per i quali è necessario ricorrere al WLL durante le 24 settimane di trattamento; Tempo al WLL durante le 24 settimane di trattamento;Variazione assoluta del CV (% prevista) rispetto al basale dopo 24 settimane di trattamento
    Endpoints esplorativi: Variazione assoluta rispetto al basale in termini di DLCO (% prevista), FEV1 (% prevista), CVF (% prevista), nonché variazione relativa della PaO2 rispetto al basale dopo 24 settimane di trattamento;Numero di soggetti con miglioramento della (A-a)DO2 >5 mmHg/>0,67 kPa e >10 mmHg/>1,33 kPa dopo 24 settimane di trattamento;
    Numero di soggetti con miglioramento della CV (% prevista) >5 punti percentuali e >10 punti percentuali dopo 24 settimane di trattamento;
    Numero di soggetti con miglioramento della DLCO (% prevista) >10 punti percentuali dopo 24 settimane di trattamento. Numero di soggetti con miglioramento del FEV1 (% prevista) e della CVF (% prevista) >10 punti percentuali dopo 24 settimane di trattamento; Numero di soggetti con miglioramento relativo della PaO2 >10% dopo 24 settimane di trattamento;Numero di soggetti con miglior tolleranza all'attività fisica (aumento della distanza percorsa camminando ≥50 m o desaturazione <4 punti percentuali al test 6MWT) dopo 24 settimane di trattamento;Variazioni rispetto al basale del punteggio relativo alla dispnea e dei punteggi concernenti la tosse dopo 24 settimane di trattamento;Numero di soggetti con miglioramento del punteggio ottenuto alla TC dopo 24 settimane di trattamento;Numero di AE, SAE, ADR, AE gravi e AE che provocano l'interruzione del trattamento, ivi comprese variazioni clinicamente significative delle variabili ecocardiografiche (ECG) e relative ai test di laboratorio, durante le 24 settimane di trattamento
    Endpoint esplorativi:Periodo di trattamento in doppio cieco, Variazione assoluta rispetto al basale in termini di (A-a)DO2, CV (% prevista), DLCO (% prevista), FEV1 (% prevista), CVF (% prevista), nonché variazione relativa della PaO2 rispetto al basale dopo 4 e 12 settimane di trattamento;
    Lasso temporale durante il quale il livello di (A-a)DO2 rimane al di sotto del livello al basale – 10mmHg; Numero di soggetti con miglior tolleranza all'attività fisica (aumento della distanza percorsa camminando ≥50 m o desaturazione <4 punti percentuali al test 6MWT) dopo 4 e 12 settimane di trattamento; Lasso temporale durante il quale il miglioramento della tolleranza all'attività fisica rimane stabile;
    Variazioni rispetto al basale del punteggio relativo alla dispnea e dei punteggi concernenti la tosse dopo 4 e 12 settimane di trattamento;
    Numero di soggetti con miglioramento del QoL (variazione ≥4 unità al SGRQ/numero di soggetti che non riportano problemi nell'EQ-5D-5L), dopo 4, 12 e 24 settimane di trattamento; Variazione della concentrazione sierica dei seguenti biomarcatori: Krebs von den Lungen-6 (KL-6), antigene carcino-embrionale (Carcinoembryonic Antigen, CEA); proteina A del surfattante (Surfactant Protein A, SP-A), proteina B del surfattante (Surfactant Protein B, SP-B), proteina C del surfattante (Surfactant Protein C, SP-C), proteina D del surfattante (Surfactant Protein D, SP-D), frammento 19 della citocheratina (cyfra 21-1) e lattato deidrogenasi (Lactate Dehydrogenase, LDH) dopo 4, 12 e 24 settimane di trattamento; Livelli di anticorpi anti-GM-CSF dopo 12 e 24 settimane di trattamento; Variazione della concentrazione sierica di GM-CSF dopo la prima somministrazione del farmaco in studio e dopo 4 settimane di trattamento; Numero di soggetti per i quali si rende necessaria l'ossigenoterapia (PaO2 in aria ambiente <55 mmHg/<7,3 kPa) durante le 24 settimane di trattamento;
    Distribuzione del DSS allo screening e alla Settimana 24;Percentuale di soggetti con DSS pari a 1 o 2 allo screening e alla Settimana 24.
    Periodo di follow-up, Numero di soggetti per i quali si rende necessario il WLL, un nuovo trattamento con GM-CSF o un'altra cura per l'aPAP, nonché il numero di cicli di trattamento necessari durante il follow-up di 48 settimane;Tempo al WLL, al nuovo trattamento con GM-CSF o a un'altra cura per l'aPAP durante le 48 settimane di follow-up; Variazione assoluta rispetto al basale in termini di (A-a)DO2, CV (% prevista), DLCO (% prevista), FEV1 (% prevista), CVF (% prevista), nonché variazione relativa rispetto al basale in termini di PaO2, dopo 12, 24, 36 e 48 settimane di follow-up;Numero di soggetti con miglior tolleranza all'attività fisica (aumento della distanza percorsa camminando ≥50 m o desaturazione <4 punti percentuali al test 6MWT) dopo 12, 24, 36 e 48 settimane di follow-up;
    Numero di AE, AE gravi, SAE e ADR, ivi comprese variazioni clinicamente significative delle variabili dell'ECG e dei test di laboratorio, durante le 48 settimane di follow-up;Livelli di anticorpi anti-GM-CSF dopo 12 e 24 settimane di follow-up; Distribuzione del DSS dopo 24 e 48 settimane di follow-up; Percentuale di soggetti con DSS pari a 1 o 2 dopo 24 e 48 settimane di follow-up
    E.5.2.1Timepoint(s) of evaluation of this end point
    See E.5.2
    vedere sezione E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Denmark
    France
    Germany
    Greece
    Israel
    Italy
    Japan
    Netherlands
    Russian Federation
    Spain
    Switzerland
    United Kingdom
    E.8.7Trial 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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 38
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 51
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the 24 weeks Double-blind treatment period, patients will enter a post treatment Follow–up period of up to 48 weeks to investigate long term outcomes following double-blind treatment.
    During the Follow-up period and post trial, subjects will be treated at the investigator’s discretion and molgramostim will be available as one of the treatment options. The data from the Follow-up period will be analysed descriptively and reported separately.
    Dopo il periodo di trattamento in doppio cieco di 24 settimane, i pazienti entreranno in periodo di FU post trattamento fino a 48 settimane per osservare i risultati a lungo termine dopo il trattamento in doppio cieco. Durante il periodo di FU e dopo la fine dello studio, i soggetti saranno trattati a discrezione del medico di studio e molgramostim sarà disponibile come una delle opzioni di trattamento. I dati del periodo di FU saranno utilizzati, descritti e riportati separatamente.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-27
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