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    Summary
    EudraCT Number:2015-003878-33
    Sponsor's Protocol Code Number:MOL-PAP-002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-05
    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 ConcernedSpain - AEMPS
    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
    Ensayo clínico aleatorizado, doble ciego, controlado con placebo y multicéntrico de molgramostim inhalado en pacientes con proteinosis alveolar pulmonar autoinmune.
    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.
    Ensayo clínico donde los pacientes con proteinosis alveolar pulmonar autoinmune serán tratados con molgramostim inhalado.
    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+452048 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)
    Proteinosis alveolar pulmonar autoinmune
    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 proteinosis alveolar pulmonar, comúnmente conocida por PAP, es una enfermedad pulmonar rara que se caracteriza por la acumulación de material proteínico en los alvéolos de los pulmones.
    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.
    Comparar la eficacia de molgramostim inhalado frente a placebo mediante la diferencia alveolo-arterial de oxígeno [(A-a)DO2] tras 24 semanas de tratamiento.
    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
    Objetivos secundarios: Comparar tras 24 semanas de tratamiento
    La eficacia de molgramostim inhalado frente a placebo en la necesidad y el tiempo de realizar un lavado pulmonar total (TLP)
    La eficacia de molgramostim inhalado frente a placebo en la capacidad vital (CV) .
    Objetivos secundarios adicionales: Comparar tras 24 semanas de tratamiento
    La eficacia de molgramostim inhalado frente a placebo:
    en la capacidad de difusión pulmonar de monóxido de carbono (DLCO), en el volumen espiratorio forzado en el primer (1) segundo (VEMS), en la capacidad vital forzada (CVF) y en la presión parcial arterial de oxígeno (PaO2).
    en el cambio categórico de (A-a)DO2, VC, DLCO, VEMS, CVF y PaO2
    en la tolerancia al ejercicio
    en la disnea y la tos
    en la gravedad de la enfermedad mediante tomografía computarizada (TC)
    en cuanto a acontecimientos adversos declarados (AA), (AAG), (RAM), AA severos y reducciones de dosis debidas a AA durante el tratamiento de 24 semanas.
    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
    • PAP autoinmune diagnosticada mediante TC, biopsia o lavado broncoalveolar (LBA) y mediante el incremento de anticuerpos GM-CSF en suero.
    • PAP autoinmune estable o progresiva (por ejemplo, CV absoluta que no ha mejorado en más de un 5 % o DLCO que no ha mejorado en más de un 10 %, valorado a partir de informes médicos) durante un período mínimo de dos meses antes de la vista basal.
    • PaO2 <75 mmHg / <10 kPa en reposo o desaturación de >4 puntos porcentuales en la prueba de marcha de 6 minutos (PM6M).
    • Un (A-a)DO2 en la evaluación de 25 mmHg / 3,33 kPa, como mínimo.
    • Mujer u hombre ≥18 años de edad.
    • Mujeres que lleven más de 1 año con menopausia o mujeres en edad reproductiva después de un período menstrual confirmado y que utilicen un método anticonceptivo altamente eficaz durante el tratamiento experimental doble ciego y hasta 30 días después de la última dosis del mismo (por ejemplo, un método con un índice de fracaso inferior al 1 %, como un anticonceptivo hormonal combinado, un anticonceptivo de progestágeno solo, un dispositivo intrauterino, un sistema intrauterino liberador de hormonas, una obstrucción tubárica bilateral, abstinencia sexual o una pareja con vasectomía). Las mujeres en edad reproductiva deberán contar con una prueba de embarazo negativa en suero en la visita de selección (visita 1) y una prueba de embarazo negativa en orina durante la administración en la visita basal (visita 2); además, no podrán estar en período de lactancia.
    • Hombres que accedan a usar preservativo durante el tratamiento doble ciego y hasta 30 días después de la última dosis del mismo, u hombres cuyas parejas femeninas estén utilizando un método anticonceptivo adecuado, como se describe anteriormente.
    • Estar dispuestos y ser capaces de proporcionar voluntariamente el consentimiento informado .
    • Estar dispuestos y ser capaces de cumplir con las visitas programadas, el plan de tratamiento, las pruebas de laboratorio y otros procedimientos del ensayo especificados en el protocolo, según los criterios del investigador.
    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
    • Diagnóstico de proteinosis alveolar pulmonar (PAP) hereditaria o secundaria.
    • TLP durante los dos meses previos a la visita basal.
    • Tratamiento con GM-CSF durante los tres meses previos a la visita basal.
    • Tratamiento con rituximab durante los seis meses previos a la visita basal.
    • Tratamiento con plasmaféresis durante los tres meses previos a la visita basal.
    • Tratamiento con cualquier producto en fase de investigación clínica durante las cuatro semanas previas a la selección.
    • Uso concomitante de medicamentos mucolíticos como la carbocisteína y el ambroxol.
    • Antecedentes de reacciones alérgicas a GM-CSF.
    • Enfermedad del tejido conectivo, enfermedad inflamatoria intestinal u otro trastorno autoinmune que necesite un tratamiento inmunosupresor (se permite el uso de 10 mg al día de un corticosteroide sistémico, pero se prohíbe el uso de cualquier otro tratamiento inmunosupresor).
    • Antecedentes previos de efectos secundarios graves e inexplicados durante la administración por aerosol de cualquier tipo de producto farmacéutico.
    • Antecedentes o presencia de una enfermedad mieloproliferativa o leucemia.
    • Insuficiencia hepática importante (nivel de aspartato transaminasa [AST] o alanina transaminasa [ALT] >3 veces el límite superior normal) o insuficiencia renal (tasa estimada de filtración glomerular [TFG estimada] <30 mL / min / 1,73 m2) durante la selección.
    • Infección activa conocida (vírica, bacteriana, micótica o microbacteriana).
    • Fibrosis pulmonar concurrente, evidente y preexistente.
    • Cualquier otro problema médico grave que según la opinión del investigador volvería al sujeto inadecuado para el ensayo.
    E.5 End points
    E.5.1Primary end point(s)
    Absolute change from baseline of (A-a)DO2 after 24-weeks treatment
    Cambio absoluto respecto a los valores de referencia de (A-a)DO2 tras 24 semanas de tratamiento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 24-weeks treatment
    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.
    Criterios de valoración secundarios fundamentales:
    Número de sujetos que necesitan un TLP durante el tratamiento de 24 semanas.
    Tiempo transcurrido hasta el TLP durante el tratamiento de 24 semanas.
    Cambio absoluto respecto a los valores de referencia de la CV (% pronosticado) tras el tratamiento de 24 semanas.
    Criterios de valoración adicionales:
    Cambio absoluto respecto a los valores de referencia de DLCO (% pronosticado), VEMS (% pronosticado) y CVF (% pronosticado), así como el cambio relativo respecto a los valores de referencia de PaO2 tras 24 semanas de tratamiento.
    Número de sujetos:
    con una mejora de >5 mmHg / >0,67 kPa y de >10 mmHg / >1,33 kPa en (A-a)DO2 tras 24 semanas de tratamiento.
    con una mejora de >5 y de >10 en los puntos porcentuales de la CV (% pronosticado) tras 24 semanas de tratamiento.
    con una mejora de >10 en los puntos porcentuales de DLCO (% pronosticado) tras 24 semanas de tratamiento.
    con una mejora de >10 en los puntos porcentuales de VEMS (% pronosticado) y CVF (% pronosticado) tras 24 semanas de tratamiento.
    con una mejora relativa de >10 % en PaO2 tras 24 semanas de tratamiento.
    con una tolerancia al ejercicio mejorada (aumento de la distancia recorrida ≥50 m o puntos porcentuales de desaturación <4 en la prueba PM6M) tras 24 semanas de tratamiento.
    con una evaluación mejorada de la TC tras 24 semanas de tratamiento.
    Cambio respecto a los valores de referencia en las evaluaciones de la disnea y de la tos tras 24 semanas de tratamiento.
    Número de AA, AAG, RAM y AA severos que llevaron a una interrupción del tratamiento antes de las 24 semanas, incluyendo cambios clínicos importantes en las pruebas de laboratorio y en las variables del electrocardiograma (ECG).
    Criterios de valoración de la exploración
    Período de tratamiento doble ciego
    Cambio absoluto respecto a los valores de referencia de (A-a)DO2, CV (% pronosticado), DLCO (% pronosticado), VEMS (% pronosticado) y CVF (% pronosticado), así como el cambio relativo respecto a los valores de referencia de PaO2 tras 4 y 12 semanas de tratamiento.
    Período de tiempo durante el cual el nivel de (A-a)DO2 se mantiene debajo de los valores de base (10 mmHg).
    Número de sujetos con una tolerancia al ejercicio mejorada (aumento de la distancia recorrida ≥50 m o puntos porcentuales de desaturación <4 en la prueba PM6M) tras 4 y 12 semanas de tratamiento.
    Período de tiempo durante el que se mantiene la mejora en la tolerancia al ejercicio.
    Cambio respecto a los valores de referencia en las evaluaciones de la disnea y de la tos tras 4 y 12 semanas de tratamiento.
    Número de sujetos con una CDV mejorada (cambio de ≥4 unidades en el SGRQ / número de sujetos «sin problemas» en el EQ-5D-5L) tras 4, 12 y 24 semanas de tratamiento.
    Cambio en la concentración de marcadores biológicos en suero: Krebs von den Lungen-6 (KL-6), antígeno carcinoembrionario (CEA), proteína surfactante A (SP-A), proteína surfactante B (SP-B), proteína surfactante C (SP-C), proteína surfactante D (SP-D), fragmentos de citoqueratina 19 (Cyfra 21-1) y lactato deshidrogenasa (LDH) tras 4, 12 y 24 semanas de tratamiento.
    Niveles de anticuerpos contra el factor estimulante de colonias de granulocitos y macrófagos (anti GM-CSF) tras 12 y 24 semanas de tratamiento.
    Cambio en la concentración en suero del GM-CSF después de la primera dosis del medicamento experimental y tras 4 semanas de tratamiento.
    Número de sujetos que necesitan una terapia con suplementación de oxígeno (PaO2 en aire ambiental <55 mmHg / <7,3 kPa) durante el tratamiento de 24 semanas.
    La distribución de la DSS en el momento de la selección y en la semana 24.
    El porcentaje de sujetos con DSS 1 o 2 en el momento de la selección y en la semana 24.
    Período de seguimiento
    Número de sujetos que necesiten un TLP, un tratamiento nuevo con GM-CSF u otro tratamiento para la PAP autoinmune, así como el número de tratamientos requeridos durante el seguimiento de 48 semanas.
    Tiempo transcurrido hasta el TLP, el nuevo tratamiento con GM-CSF u otro tratamiento para la PAP autoinmune durante el seguimiento de 48 semanas.
    Cambio absoluto respecto a los valores de referencia de (A-a)DO2, CV (% pronosticado), DLCO (% pronosticado), VEMS (% pronosticado) y CVF (% pronosticado), así como el cambio relativo respecto a los valores de referencia de PaO2 tras 12, 24, 36 y 48 semanas de seguimiento.
    Número de sujetos con una tolerancia al ejercicio mejorada (aumento de la distancia recorrida ≥50 m o puntos porcentuales de desaturación <4 en la prueba PM6M) tras 12, 24, 36 y 48 semanas de seguimiento.
    Número de AA, AA severos, AAG y RAM, incluyendo cambios clínicos importantes en las pruebas de laboratorio y en las variables del ECG, durante el seguimiento de 48 semanas.
    Niveles de anti GM-CSF tras 12 y 24 semanas de seguimiento.
    La distribución de la DSS tras 24 y 48 semanas de seguimiento.
    El porcentaje de sujetos con DSS 1 o 2 tras 24 y 48 semanas de seguimiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See 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.
    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 Decision2016-10-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-27
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