Brief description of trial (Data source: BASEC)
Savara ApS, a développé une solution pour l'inhalation du produit connu molgramostim dans le cadre du traitement de la PAP. Le molgramostim contient la substance active suivante : le facteur de stimulation des colonies de granulocytes-macrophages (GM-CSF) humain recombinant.
Le GM-CSF est une protéine présente naturellement dans l'organisme humain : elle fait partie du système immunitaire. Les patients atteints de PAP présentent des taux accrus d'anticorps luttant contre cette protéine spécifique. Ces anticorps se lient au GM-CSF du patient et bloquent son fonctionnement. De ce fait, une substance riche en protéines s'accumule dans les alvéoles pulmonaires, rendant difficile le transfert de l'oxygène en direction du sang. Il a été suggéré que le molgramostim en inhalation pourrait permettre au système immunitaire des poumons de se débarrasser de cette substance, et ainsi permettre à l'oxygène de pénétrer dans le sang.
On considère qu'à l'avenir, le molgramostim pourrait être utilisé comme alternative au grand lavage pulmonaire, qui constitue de nos jours le traitement standard de la PAPa. Le grand lavage pulmonaire est une procédure complexe, nécessitant une anesthésie générale prolongée et présentant des comorbidités. De plus, un seul grand lavage pulmonaire n’est pas efficace chez tous les patients. Il est donc nécessaire de proposer des traitements plus efficaces et moins invasifs aux patients atteints de PAP. De nombreuses preuves cliniques montrent que le molgramostim inhalé (GM-CSF) est efficace et sûr chez les patients atteints de PAP et constitue une solution de traitement plus pratique et moins invasive pour les patients atteints de PAP, en remplacement du grand lavage pulmonaire ou en association.
Health conditions investigated(Data source: BASEC)
la protéinose alvéolaire pulmonaire auto-immune (PAPa)
Health conditions
(Data source: WHO)
Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
MedDRA version: 20.0
Level: LLT
Classification code 10037316
Term: Pulmonary alveolar proteinosis
System Organ Class: 100000004855
Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]
Rare disease
(Data source: BASEC)
No
Intervention investigated (e.g. drug, therapy or campaign)
(Data source: BASEC)
Médicament à l’essai : Molgramostim, solution pour inhalation par nébuliseur
Substance active : Molgramostim, facteur de croissance des granulocytes et macrophages humain recombinant (rhGM-CSF)
Forme pharmaceutique : Solution pour inhalation par nébuliseur
Voie d'administration : Inhalation
Dosage et durée : 300 microgrammes une fois par jour pendant 24 semaines/300 microgrammes une fois par jour toutes les deux semaines pendant 24 semaines.
Interventions
(Data source: WHO)
Product Name: Molgramostim 300 mcg nebuliser solution
Pharmaceutical Form: Nebuliser solution
INN or Proposed INN: MOLGRAMOSTIM
CAS Number: 99283-10-0
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Nebuliser solution
Route of administration of the placebo: Inhalation use
Criteria for participation in trial
(Data source: BASEC)
- PAP diagnostiquée par tomodensitométrique, biopsie ou lavage broncho-alvéolaire et sur la base d'une augmentation des auto-anticorps anti-GM-CSF dans le sérum
- PAP stable ou progressive sur un minimum de deux mois avant la visite d'inclusion.
- La pression artérielle en oxygène < 75 mmHg/10 kPa au repos OU désaturation de > 4 points de pourcentage lors du test de marche de 6 minutes
- Sujet de sexe féminin ou masculin, âgé de ≥ 18 ans
Exclusion criteria
(Data source: BASEC)
- Grand lavage pulmonaire thérapeutique réalisé dans les deux mois précédant l'inclusion
- Atteinte hépatique significative (taux d'aspartate aminotransférase ou d'alanine aminotransférase > 3 fois la limite supérieure de la normale) ou atteinte rénale significative (débit de filtration glomérulaire estimé < 30 mL/min/1,73 m2) lors de la sélection
- Présence simultanée d'une fibrose pulmonaire préexistante apparente
- Toute autre affection médicale grave qui, de l'avis de l'investigateur, rend inadéquate la participation du sujet à l'étude
Inclusion/Exclusion Criteria
(Data source: WHO)
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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 35
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
-
Further information on trial
Date trial registered
Nov 11, 2015
Incorporation of the first participant
Feb 22, 2016
Recruitment status
Not Recruiting
Academic title
(Data source: WHO)
A Randomised, Double-Blind, Placebo-Controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary AlveoLAr Proteinosis Patients - IMPALA
Type of trial
(Data source: WHO)
Interventional clinical trial of medicinal product
Design of the trial
(Data source: WHO)
Controlled: yes
Randomised: yes
Open: no
Single blind: no
Double blind: yes
Parallel group: no
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: yes
Other: no
Number of treatment arms in the trial: 3
Phase
(Data source: WHO)
Human pharmacology (Phase I): no
Therapeutic exploratory (Phase II): yes
Therapeutic confirmatory - (Phase III): yes
Therapeutic use (Phase IV): no
Primary end point
(Data source: WHO)
Main Objective: To compare efficacy of inhaled molgramostim on the Alveolar-arterial oxygen difference ((A-a)DO2) with placebo after 24-weeks treatment.
Timepoint(s) of evaluation of this end point: After 24-weeks treatment
Primary end point(s): Absolute change from baseline of (A-a)DO2 after 24-weeks treatment
Secondary Objective: 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
Secundary end point
(Data source: WHO)
Secondary end point(s): Key Secondary Endpoints:
- Change from baseline in 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 electrocardiogram (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), 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 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.
Timepoint(s) of evaluation of this end point: See E.5.2
Contact information
(Data source: WHO)
Savara ApS
Trial results
(Data source: WHO)
Results summary
no information available yet
Link to the results in the primary register
no information available yet
Information on the availability of individual participant data
no information available yet
Trial sites
Trial sites in Switzerland
(Data source: BASEC)
Lausanne
Countries
(Data source: WHO)
Australia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Korea, Netherlands, Poland, Portugal, Republic of, Russian Federation, Slovakia, Spain, Switzerland, Turkey, United Kingdom, United States
Contact for further information on the trial
Details of contact in Switzerland
(Data source: BASEC)
Esther Schmid
+41 71 227 1188
es@schmidconsult.com
Authorisation by the ethics committee (Data source: BASEC)
Name of the authorising ethics committee (for multicentre studies only the lead committee)
Commission
cantonale d’Éthique de la Recherche sur l’être humain Vaud (CER-VD)
Date of authorisation by the ethics committee
27.04.2016
Further trial identification numbers
Trial identification number of the ethics committee (BASEC-ID)
(Data source: BASEC)
2016-00013
Secondary ID (Data source: WHO)
MOL-PAP-002
2015-003878-33-GB
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