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    Summary
    EudraCT Number:2017-004078-32
    Sponsor's Protocol Code Number:SAV006-03
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-01-07
    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 number2017-004078-32
    A.3Full title of the trial
    AN OPEN-LABEL, NON-CONTROLLED, MULTICENTRE CLINICAL TRIAL OF INHALED MOLGRAMOSTIM IN AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS PATIENTS
    Studio multicentrico non controllato in aperto sul molgramostim per via inalatoria in pazienti con proteinosi alveolare polmonare autoimmune
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial in patients with the lung disease, autoimmune pulmonary alveolar proteinosis, to assess continued treatment with molgramostim by inhalation
    Studio clinico su pazienti affetti da patologia polmonare, proteinosi alveolare polmonare autoimmune, per valutare il trattamento continuato con molgramostim per via inalatoria.
    A.3.2Name or abbreviated title of the trial where available
    IMPALA-EX
    IMPALA-EX
    A.4.1Sponsor's protocol code numberSAV006-03
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03482752
    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 Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressSlotsmarken 17, 1.th
    B.5.3.2Town/ cityHørsholm
    B.5.3.3Post code2970
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4524885979
    B.5.5Fax number+4569884967
    B.5.6E-mailmette.vinge@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 Nebuliser solution 300 mcg
    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
    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 Alveolare Polmonare 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 Alveolare Polmonare è una rara malattia polmonare caratterizzata da dall'accumulo di una sostanza proteica negli alveoli (spazi aerei) del polmone.
    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 20.0
    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 investigate safety of long term use of inhaled molgramostim.
    Valutare la sicurezza dell'uso a lungo termine di Molgramostim per via inalatoria
    E.2.2Secondary objectives of the trial
    • To investigate effects of long term use of inhaled molgramostim on oxygenation.
    • To investigate effects of long term use of inhaled molgramostim on exercise capacity.
    • To investigate effects of long term use of inhaled molgramostim on respiratory quality of life.
    • To investigate frequency of need for WLL during long term use of inhaled molgramostim.
    • To investigate effects of long term use of inhaled molgramostim on lung function.
    • To investigate maintenance of effect after discontinuation of inhaled molgramostim.
    • Valutare gli effetti dell'uso a lungo termine di Molgramostim per via inalatoria sull'ossigenazione.
    • Valutare gli effetti dell'uso a lungo termine di Molgramostim per via inalatoria sulla capacità di esercizio.
    • Valutare gli effetti dell'uso a lungo termine di Molgramostim per via inalatoria sulla qualità respiratoria della vita.
    • Valutare il requisito per il lavaggio polmonare totale durante l'uso a lungo termine di Molgramostim per via inalatoria.
    • Valutare gli effetti dell'uso a lungo termine di Molgramostim per via inalatoria sulla funzione polmonare.
    • valutare il mantenimento dell'effetto dopo la sospensione di Molgramostim per via inalatoria.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Completer of the IMPALA trial.
    2. 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 where inhibition of ovulation is the primary mode of action, 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 urine pregnancy test at Baseline, or at start of treatment if treatment is not dispensed at Baseline, and must not be lactating during and until 30 days after last dose of trial treatment*.
    3. 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.
    4. Willing and able to provide signed informed consent.
    * Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the female trial participant of child bearing potential and that the vasectomised partner has received medical assessment of the surgical success. 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 study 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
    1. Soggetti che hanno completato lo studio IMPALA.
    2. Donne in post menopausa da più di 1 anno, o donne in età fertile che stanno utilizzando un metodo contraccettivo altamente efficace (cioè un metodo con tasso di fallimento <1% come contraccezione ormonale combinata, solo contraccezione ormonale a progesterone che abbia come meccanismo d’azione principale l’inibizione dell’ovulazione, dispositivo intrauterino, sistema di rilascio di ormone intrauterino, occlusione tubarica bilaterale, partner vasectomizzato, astinenza sessuale*), durante e fino a 30 giorni dopo l'ultima dose del farmaco in studio. Le donne in età fertile devono avere un test di gravidanza urinario negativo al basale o all'inizio del trattamento se il trattamento non viene dispensato al basale e non devono essere in allattamento durante e fino a 30 giorni dopo l'ultima dose del farmaco in studio*.
    3. Uomini che accettano di usare il preservativo durante e fino a 30 giorni dopo l'ultima dose del farmaco in studio, o uomini che hanno una partner che sta usando una contraccezione adeguata come descritto sopra.
    4. Soggetti capaci di comprendere e firmare il consenso informato.
    * la vasectomia del partner è un metodo contrraccettivo estremamente efficace purchè questi sia l’unico partner sessuale del soggetto di sesso femminile in età fertile che partecipi alla sperimentazione e che la riuscita dell’intervento di vasectomia del partner sia confermata da valutazione medica. L’astinenza sessuale è considerata un metodo contraccettivo estremamente efficace solo se definita come asssenza di rapporti eterosessuali durante l’intero periodo di rischio associato al trattamento in studio. L’affidabilità dell’astinenza sessuale deve essere valutata in base alla durata della sperimentazione e allo stile di vita del soggetto.
    E.4Principal exclusion criteria
    1. Treatment with GM-CSF products other than molgramostim nebuliser solution within three months of Baseline.
    2. Treatment with any IMP other than inhaled molgramostim within four weeks of Baseline.
    3. History of allergic reactions to GM-CSF.
    4. 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.
    5. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.
    6. History of, or present, myeloproliferative disease or leukaemia.
    7. Apparent pre-existing concurrent pulmonary fibrosis.
    8. Any other serious medical condition which in the opinion of the investigator would make the subject unsuitable for the trial.
    1. Trattamento con i prodotti che vanno ad agire sul GM CSF diversi dalla soluzione per nebulizzatore di Molgramostim entro tre mesi dalla visita basale.
    2. Trattamento con qualsiasi medicinale sperimentale diverso da Molgramostim per via inalatoria entro quattro settimane dalla visita basale.
    3. Storia di reazioni allergiche ai prodotti contenenti GM CSF.
    4. Malattia del tessuto connettivo, malattia infiammatoria intestinale o altra malattia autoimmune che richiede un trattamento associato ad una significativa immunosoppressione, per es. più di 10 mg/die di prednisolone per via sistemica
    5. Esperienza precedente di effetti collaterali gravi e inspiegabili durante la somministrazione di aerosol di qualsiasi tipo di medicinale.
    6. Anamnesi concomitante, recente o passata di malattia mieloproliferativa o leucemia.
    7. Fibrosi polmonare concomitante preesistente.
    8. Qualsiasi altra condizione medica grave che, secondo il parere dello sperimentatore, renderebbe il soggetto inadatto alla partecipazione allo studio.
    E.5 End points
    E.5.1Primary end point(s)
    Number of AEs, SAEs, adverse drug reactions (ADRs), and AEs leading to treatment discontinuation.
    Numero di eventi avversi gravi, eventi avversi gravi (SAE), reazioni avverse al farmaco (ADR) e eventi avversi che portano all'interruzione del trattamento durante lo studio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of trial
    Fine dello studio
    E.5.2Secondary end point(s)
    • (A-a)DO2 during the trial
    • 6MWD during the trial
    • SGRQ total score during the trial
    • Frequency of WLL during the trial
    • DLCO (% predicted), FEV1 (% predicted), and FVC (% predicted) during the trial
    • PaO2 and disease severity score (DSS) during the trial
    • Need for oxygen supplement therapy during the trial
    • Number of subjects not requiring treatment for aPAP and time off treatment after discontinuation of inhaled molgramostim
    • Gradiente alveolo-arterioso di ossigeni (A-aDO2) durante lo studio.
    • Test 6 minute walking distance (6MWD) durante studio.
    • Punteggio totale del questionario respiratorio St Georges (SGRQ) durante lo studio.
    • Frequenza del lavaggio polmonare totale durante lo studio.
    • Capacità di diffusione del polmone per il monossido di carbonio (DLCO), volume espiratorio forzato in 1 secondo (FEV1) e capacità vitale forzata (FVC) durante lo studio, tutti espressi come percentuale predetta.
    • Tensione arteriosa dell'ossigeno (PaO2) e punteggi di gravità della malattia (DSS) durante lo studio.
    • Necessità di terapia con supplemento di ossigeno durante lo studio.
    • Numero di soggetti che non richiedono trattamento per aPAP e sospensione del trattamento dopo la sospensione di Molgramostim inalato
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of trial
    Fine dello studio
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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
    Netherlands
    Russian Federation
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 90
    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)
    None
    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 Decision2019-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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