Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)

Study Overview
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Brief Summary
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160 subjects with autoimmune pulmonary alveolar proteinosis (aPAP) will be randomized to receive once daily treatment with inhaled molgramostim or placebo for 48 weeks. Subjects completing the 48 week placebo-controlled period will receive open-label treatment with once daily inhaled molgramostim for 96 weeks.

Detailed Description
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This is an interventional, randomized, double-blind, 2-arm, parallel groups, placebo-controlled, multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP. An aPAP diagnosis should be confirmed by an anti-GM-CSF auto-antibody test result, and history of PAP based on either high resolution computed tomography, lung biopsy, or bronchoalveolar lavage cytology, should be available. The trial consists of a 6-week screening period, a 48-week randomized, double-blind treatment period, a 96-week open-label treatment period, and a conditional 4-week safety follow-up period. The maximum treatment duration will be 145 weeks and the maximum trial duration will be 156 weeks. During the trial, whole lung lavage will be allowed as rescue treatment in case of worsening of aPAP.

Official Title
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A Randomized, Double-blind, Placebo-controlled Clinical Trial of Once-daily Inhaled Molgramostim Nebulizer Solution in Adult Subjects With Autoimmune Pulmonary Alveolar Proteinosis (aPAP)

Conditions
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Autoimmune Pulmonary Alveolar Proteinosis

Intervention / Treatment
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* Drug: Molgramostim
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be ≥18 years of age, at the time of signing the informed consent (≥20 in Japan). A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest. DLCO 70% predicted or lower at the screening and baseline visits. Change in % predicted DLCO of <15% points during the screening period. Demonstrated functional impairment in the treadmill exercise test (defined as a peak MET ≤8). Willing and able to come off supplemental oxygen use prior to and during the treadmill exercise test, the DLCO assessment, and the arterial blood gas sampling. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the screening visits. Male or female Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male subjects: 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 below. Female subjects: 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, vasectomized 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 the screening visits, and a negative urine pregnancy test at Baseline visit (Visit 3) and must not be lactating. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 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, or a metabolic disorder of surfactant production. WLL performed within 3 months prior to baseline. Requirement for WLL at screening or baseline. GM-CSF treatment within 6 months prior to baseline. Treatment with rituximab within 6 months prior to baseline. Treatment with plasmapheresis within 6 weeks prior to baseline. Treatment with any investigational medicinal product within 5 half-lives or 3 months (whichever is longer) prior to baseline. Previously randomized in this trial. History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution. Inflammatory or autoimmune disease of a severity that necessitates significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product. History of, or present, myeloproliferative disease or leukemia. Apparent pre-existing concurrent pulmonary fibrosis. Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise. Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial. Physical disability or other condition that precludes safe and adequate exercise testing. Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial. Pregnant, planning to become pregnant during the trial, or breastfeeding woman. For France only: including as further defined by French Health Code L-1121-5. For France only: Any subject considered to be vulnerable on account of, e.g., mental or physical disability, socio-economic situation, or subjects deprived of their liberty. For France only: including as further defined by French Health Code L1121-8-1.

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
Interventional Model Description: Subject will be randomized 1:1 to treatment with inhaled molgramostim or placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molgramostim<br>Double-blind treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks, followed by open-label treatment with molgramostim nebulizer solution 300 µg once daily for 96 weeks | Drug: Molgramostim<br>* Molgramostim 300 µg nebulizer solution<br>* Other names: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF);|
| Placebo Comparator: Placebo<br>Double-blind treatment with placebo nebulizer solution once daily for 48 weeks, followed by open-label treatment with molgramostim nebulizer solution 300 µg once daily for 96 weeks | Drug: Molgramostim<br>* Molgramostim 300 µg nebulizer solution<br>* Other names: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF);Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in percentage (%) predicted diffusing capacity of the lung for carbon monoxide (DLCO) to Week 24 | As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be conducted. The single-breath DLCO test will be performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing. | From Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in percentage (%) predicted DLCO to Week 48 | As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be conducted. The single-breath DLCO test will be performed in accordance with ATS/ERS guidelines for DLCO testing. | From Baseline to Week 48 | 
| Change from baseline in St. Georges Respiratory Questionnaire (SGRQ) Total score to Week 24 | The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good). | From Baseline to Week 24 | 
| Change from baseline in SGRQ Activity component score to Week 24 | The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good). | Week 24 | 
| Change from baseline in exercise capacity (EC), expressed as peak metabolic equivalents (METs) to Week 24 | As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an exercise treadmill test. EC will be expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved will be used to calculate peak METs. | From Baseline to Week 24 | 
| Change from baseline in SGRQ Total score to Week 48 | The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good). | Week 48 | 
| Change from baseline in SGRQ Activity from baseline to Week 48 | The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good). | From Baseline to Week 48 | 
| Change from baseline in EC, expressed as peak METs to Week 48 | As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an exercise treadmill test. EC will be expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved will be used to calculate peak METs. | From Baseline to Week 48 | 
| Change from baseline in alveolar-arterial oxygen difference (A-aDO2) to Week 24 (Specifically for Japan and South Korea) | A-aDO2 will be used as an additional measure of gas exchange. | From Baseline to Week 24 | 
| Number of subjects with serious and non-serious adverse events | Assessment of the safety of MOL compared to placebo | From screening (6-week) until Follow-up visit (Week 100) | 
| Number of subjects with positive treatment-boosted anti Granulocyte macrophage colony stimulating factor (GM-CSF) antibody titers during 24 weeks' treatment and during 48 weeks' treatment | Assessment of the safety of MOL compared to placebo | From screening (6-week) until Follow-up visit (Week 100) | 
| Changes in Forced vital capacity (FVC) | Assessment of the safety of MOL compared to placebo | From Baseline to Weeks 24 and 48 | 
| Changes in Forced expiratory volume in one second (FEV1) | Assessment of the safety of MOL compared to placebo | From Baseline to Weeks 24 and 48 | 
| Change in QT interval corrected by Fridericia (QTcF) | Assessment of the safety of MOL compared to placebo | From Baseline to Weeks 4 and 24 |