Efficacy and Safety of Inhaled Molgramostim (rhGM-CSF) in Autoimmune Pulmonary Alveolar Proteinosis

Study Overview
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Brief Summary
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This study evaluates inhaled molgramostim (recombinant human granulocyte macrophage-colony stimulating factor [rhGM-CSF]) in the treatment of autoimmune pulmonary alveolar proteinosis (aPAP) patients. A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks.

Detailed Description
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The trial is a phase 2, randomized, double-blind, placebo-controlled multicentre clinical trial investigating efficacy and safety of inhaled molgramostim (rhGM-CSF) in patients with aPAP. The trial will include 2 periods; a double-blind treatment period consisting of up to 8 trial visits (Screening, Baseline, and at Weeks 4, 8,12, 16, 20 and 24 after randomisation) and a open-label follow-up period consisting of up to 5 trial visits (at Weeks 4, 12, 24, 36 and 48 post-treatment). In the double-blind treatment period, eligible subjects will be randomised to treatment for up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily (MOL-OD), 2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (7 days on and 7 days off) (MOL-INT) or 3) inhaled placebo once daily (PBO). During the follow-up period, all participants will receive inhaled molgramostim intermittently (7 days on, 7 days off). During the trial, whole lung lavage (WLL) may be applied as rescue therapy in case of significant clinical worsening.

Official Title
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A Randomised, Double-blind, Placebo-controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients

Conditions
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Autoimmune Pulmonary Alveolar Proteinosis

Intervention / Treatment
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* Drug: Molgramostim
* Drug: Placebo
* Device: PARI eFlow nebulizer system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aPAP diagnosed by computed tomography, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by increased GM-CSF autoantibodies in serum. Stable or progressive aPAP during a minimum period of 2 months prior to the Baseline visit. Arterial oxygen tension (PaO2) <75 mmHg/<10 kilo Pascal (kPa) at rest, OR desaturation of >4 percentage points on the 6MWT An alveolar-arterial oxygen difference [(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 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 Exclusion Criteria: Diagnosis of hereditary or secondary PAP WLL within 1 month of Baseline Treatment with GM-CSF within 3 months of Baseline Treatment with rituximab within 6 months of Baseline Treatment with plasmapheresis within 3 months of Baseline Treatment with any investigational medicinal product within 4 weeks of Screening Concomitant use of sputum modifying drugs such as carbocysteine 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 participant unsuitable for the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind molgramostim once daily<br>Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks | Drug: Molgramostim<br>* 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation<br>* Other names: rhGM-CSF;Device: PARI eFlow nebulizer system<br>* PARI eFlow nebulizer system<br>|
| Experimental: Double-blind molgramostim intermittent<br>Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles) | Drug: Molgramostim<br>* 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation<br>* Other names: rhGM-CSF;Device: PARI eFlow nebulizer system<br>* PARI eFlow nebulizer system<br>|
| Placebo Comparator: Double-blind placebo<br>Inhalation of placebo nebuliser solution once daily for 24 weeks | Drug: Placebo<br>* Placebo nebulizer solution for inhalation<br>Device: PARI eFlow nebulizer system<br>* PARI eFlow nebulizer system<br>|
| Experimental: Open-label molgramostim intermittent<br>Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period | Drug: Molgramostim<br>* 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation<br>* Other names: rhGM-CSF;Device: PARI eFlow nebulizer system<br>* PARI eFlow nebulizer system<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment | Measurement of (A-a)DO2 was done by blood gas analysis. An arterial blood sample was collected in the supine position, after resting for at least 10 minutes (or longer if required to achieve stable oxygen saturation). The sample was analyzed for arterial oxygen tension (PaO2) and partial pressure of carbon dioxide (PaCO2). The calculation of (A-a)DO2 was done centrally by using a formula described in the protocol. | From baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment | The 6MWD was assessed by the use of 6-minute walking test (6MWT). The 6MWT was performed in accordance with the 2014 ATS/ERS guideline field walking tests in chronic respiratory disease (Holland et al. 2014) by technicians with documented training and experience. Where possible, the test was conducted with the participant breathing ambient atmospheric air. If the participant required oxygen supplementation at rest, a titration procedure was carried out as part of the 6MWT at screening in order to determine the oxygen flow rate required for the participant to complete the test. This flow rate was to be used during subsequent tests, if possible. | From baseline to 24 weeks | 
| Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment | The SGRQ is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It consists of two parts, where Part 1 covers the participants' recollection of their symptoms over the preceding period (1 month recall used in this trial, Symptoms component) and Part 2 addresses the participants' current state in terms of disturbances to their daily physical activity (Activity component) and a wide range of disturbances of psycho-social function (Impact component). A total score as well as individual component scores were calculated. Scores (total and component) range from 0 to 100, with higher scores indicating more limitations. | From baseline to 24 weeks | 
| Number of Whole Lung Lavage During 24 Weeks of Treatment | In all versions of the protocol (no participants were recruited under version 1.0), whole lung lavage (single lung or both lungs) was applied as rescue therapy. In protocol version 2.0, the criterion for performing whole lung lavage was an increase in (A-a)DO2 by more than 10 mmHg/1.33 kilopascal compared to baseline. In protocol version 3.0 onwards, the criterion for performing whole lung lavage was clinical worsening of aPAP based on symptoms, reduced exercise capacity and/or findings of hypoxemia or desaturation according to the investigator's judgement. In protocol versions 2.0 and 3.0, participants undergoing whole lung lavage during the double-blind period were to discontinue double-blind treatment, encouraged to continue to follow the same visit schedule and, if required, receive further whole lung lavage at the investigator's discretion. In protocol version 4.0 and 5.0, participants undergoing whole lung lavage were to continue double-blind treatment. | From baseline to 24 weeks | 
| Number of Adverse Events (AEs) During 24 Weeks of Treatment | Treatment-emergent adverse events (AEs) were assessed on or after the first dose of trial drug to 28 days after last dose. Information about AEs was collected by the investigator by a non-leading question such as have you experienced any new health problems or worsening of existing conditions and by reporting events directly observed or spontaneously volunteered by participants (e.g., in the Subject Diary Card, where subjects were asked to record any AEs and answer questions regarding lung toxicity and known systemic effects). Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. All AEs were assessed by the investigator for severity (mild, moderate, severe), outcome (recovered, not recovered, recovered with sequelae, fatal, unknown) and causality (unlikely, possible, probable, not applicable) according to current regulatory standards. | From baseline to 24 weeks | 
| Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment | SAEs are defined as any untoward medicinal occurrence or effect that at any dose: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Is a congenital anomaly or birth defect May jeopardise the subject or may require intervention to prevent one or more of the other outcomes listed above (Important Medical Events) | From baseline to 24 weeks | 
| Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment | All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as ADRs. The expression reasonable causal relationship means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility i.e. the relationship cannot be ruled out. | From baseline to 24 weeks | 
| Number of Severe AEs During 24 Weeks of Treatment | All AEs were assessed by the investigator for severity (mild, moderate, severe) according to current regulatory standards: Mild: The AE is easily tolerated and does not interfere with daily activity. Moderate: The AE interferes with daily activity, but the subject is still able to function. Medical intervention may be considered. Severe: The AE is incapacitating and requires medical intervention. | From baseline to 24 weeks | 
| Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment | Participants could be discontinued from treatment and assessments at any time, if deemed necessary by the investigator. Potential reasons for discontinuation of treatment included e.g. unacceptable AE. | From baseline to 24 weeks |