A clinical trial where patients with the lung disease autoimmune Pulmonary Alveolar Proteinosis will be given the drug molgramostim by inhalation.

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2015-003878-33-GB
• Date of registration: 22/10/2015
• Prospective Registration: Yes
• Primary sponsor: Savara ApS
• Public title: A clinical trial where patients with the lung disease autoimmune Pulmonary Alveolar Proteinosis will be given the drug molgramostim by inhalation.
• Scientific title: A Randomised, Double-Blind, Placebo-Controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary AlveoLAr Proteinosis Patients - IMPALA
• Date of first enrolment: 28/01/2016
• Target sample size: 135
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003878-33
• Study type: Interventional clinical trial of medicinal product
• Study design: 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: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Spain, Switzerland, Turkey, United Kingdom, United States

Contacts

• Name: Trial director
• Affiliation: Savara ApS

• Name: Trial director
• Affiliation: Savara ApS

Key inclusion & exclusion criteria

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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
MedDRA version: 20.0 Level: LLT Classification code 10037316 Term: Pulmonary alveolar proteinosis System Organ Class: 100000004855

Intervention(s)

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

Primary Outcome(s)

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

Secondary Outcome(s)

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) and 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

Secondary ID(s)

MOL-PAP-002

Source(s) of Monetary Support

Savara ApS

Ethics review

Status: Approved
Approval date:
Contact: