Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the therapeutic efficacy of inhaled recombinant human GM-CSF in individuals with hereditary Pulmonary Alveolar Proteinosis (PAP) due to partial dysfunction of the GM-CSF receptor.

Official Title
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Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)

Conditions
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Hereditary Pulmonary Alveolar Proteinosis

Intervention / Treatment
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* Drug: Leukine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of PAP caused by bi-allelic mutations in CSF2RA or CSF2RB associated with impaired GM-CSF-R-alpha or GM-CSF-R-beta function, respectively, resulting in reduced but non-zero GM-CSF signaling Able and willing to give written informed consent / assent as necessary Clinically stable Exclusion Criteria: Confirmed diagnosis of a disorder of surfactant production caused by bi-allelic mutations in ABCA3, SFTPB, or SFTPC Confirmed diagnosis of autoimmune PAP caused by a high level of GM-CSF autoantibody Confirmed diagnosis of secondary PAP caused by an underlying clinical disorder known to be associated with the development of PAP, e.g., inhalation of silica or titanium; myelodysplasia and others Treatment with any investigational agent in the 3 months prior to enrollment History of severe allergic or anaphylactic reactions to GM-CSF or other yeast-derived products History of asthma or other reactive airways disease Known active, viral, fungal, mycobacterial, or other infection A serious medical condition which, in the opinion of the investigator or data and safety monitoring committee, would make the patient unsuitable for the study

Ages Eligible for Study
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Minimum Age: 8 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Leukine (rhGM-CSF)<br>Inhaled recombinant human GM-CSF in individuals with hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor | Drug: Leukine<br>* Participants will receive inhaled rhGM-CSF (Sargramostim, Leukine) at the dose of 250 mcg one time per week for 12 weeks. Following an interim safety evaluation, participants may be entered into a second 12 week treatment period where participants will receive either 250 mcg or 500 mcg once weekly. At the end of any treatment period, participants will be followed for 12 additional weeks in the absence of inhaled rhGM-CSF to evaluate safety and efficacy.<br>* Other names: GM-CSF [Leukine (Sargramostim)];|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Time (Minutes) to Discontinuation of Exercise During a Standardized Treadmill Exercise Test | A modified Bruce protocol stress test was used to evaluate improvement in blood oxygen saturation (SpO2). A pulse-oximeter was placed on the participant's finger with the participant at rest while sitting in a chair. Leads for the electrocardiograph were placed on the chest wall. The treadmill was started at 1.7 miles per hour (mph) and a grade of 0%. At three minute intervals, the speed increased as follows: 1.7 mph, 1.7 mph, 1.7 mph, 2.5 mph, 3.4 mph, 4.2 mph, 5.0 mph, 5.5 mph, 6.0 mph, 6.5 mph, 7.0 mph, and 7.5 mph. The participant stopped the test due to intolerable dyspnea or if the SpO2 fell below 88%. | Baseline, 7 months | 
| Change in Minimum Pulse Oximetry During a Standardized Treadmill Exercise Test | A modified Bruce protocol stress test was used to evaluate improvement in blood oxygen saturation (SpO2). A pulse-oximeter was placed on the participant's finger with the participant at rest while sitting in a chair. Leads for the electrocardiograph were placed on the chest wall. The treadmill was started at 1.7 miles per hour (mph) and a grade of 0%. At three minute intervals, the speed increased as follows: 1.7 mph, 1.7 mph, 1.7 mph, 2.5 mph, 3.4 mph, 4.2 mph, 5.0 mph, 5.5 mph, 6.0 mph, 6.5 mph, 7.0 mph, and 7.5 mph. The participant stopped the test due to intolerable dyspnea or if the SpO2 fell below 88%. | Baseline, 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Diffusion Capacity for Carbon Monoxide | Routine full pulmonary function testing, including spirometry, lung volumes, and DLCO, were performed according to American Thoracic Society guidelines. | Baseline, 7 months | 
| Change in Minimum Pulse Oximetry During a Standardized Exercise Protocol Oximetry | Standardized exercise pulse oximetry (SEPO) was used to measure SpO2 at the participant's home on a weekly basis between clinic visits. Briefly, a pulse-oximeter was placed on the finger with the participant at rest sitting in a chair. Three baseline (resting) readings were taken over a period of 1 minute to measure the SpO2 at rest. The participant then began stepping onto and off of the first step of a staircase in the home while holding onto the handrail for safety. Stepping was started by placing the bottom of one foot onto the stair followed by the other foot and then removal of one foot from the stair to the floor followed by the other foot. This procedure was repeated at a frequency of 1 cycle per second for a total of 5 minutes. The participant's parent assisted by noting the saturation data at 1-minute intervals during the test onto the weekly exercise form in the participant's Diary. The participant's saturation data continued to be recorded for 3 minutes after the test. | Baseline, 7 months | 
| Change in Radiographic Evidence of PAP Lung Disease | High resolution computed tomography (HRCT) scans were performed using an interval technique, a 1 mm slice was obtained every 20 mm. The slice series were placed so that images were obtained from the pulmonary apices to the lung bases with one of the images located at the level of the carina. The CT parameters were performed at full inspiration and required a lower dose than usual clinical CT scans; 1 mm slices at 20 mm intervals,120 kVp, 60 mAs, rotation time 0.5 second. Images were reconstructed with lung and soft tissue reconstruction kernels (B35F and B60F). The primary analysis was performed using the B60F kernel. Images were read and reported according to Radiology Department protocol. The raw data was recorded on a DVD and sent to CCHMC for centralized reading and lung attenuation analysis. | Baseline, 7 months | 
| Change in Quality of Life | The PedsQL quality of life questionnaire is a modular approach to measure health-related quality of life in healthy children and those with acute and chronic health conditions. It is self-administered and completed in less than 5 minutes. It contains 23 items divided into 4 domains: physical functioning, emotional functioning, social functioning, and school functioning. To reverse score, transform the 0-4 scale items to 0-100 as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Higher scores indicate a better Health-Related Quality of Life.To create the Psychosocial Health Summary Score, the mean is computed as the sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales. The Physical Health Summary Score is the same as the Physical Functioning Scale Score. To create the Total Scale Score, the mean is computed as the sum of all the items over the number of items answered on all the Scales. | Baseline, 7 months | 
| Change in Dyspnea Symptom Score | The dyspnea visual analogue scales were used by the patient to record the level of dyspnea by a single mark on a linear scale. The dyspnea scale ranged from 0 to 10, with short of breath all the time equal to 0 and never short of breath equal to 10. A higher score indicated a better dyspnea score. | Baseline, 7 months | 
| Change in Serum Anti-GM-CSF Antibodies Levels | Serum GM-CSF autoantibody was measured as follows: microtiter plates were incubated (4°C, overnight) with rhGM-CSF, washed in PBS and Tween-20, and incubated (room temperature (RT), 1 hour) with blocking solution. Serum samples were diluted with dilution buffer and aliquots of diluted serum or standard were pipetted into adjacent microtiter wells, incubated at RT for 40 minutes, and then washed with wash buffer. Horseradish peroxidase-conjugated secondary antibody was diluted with dilution buffer and pipetted into each well. Plates were incubated (RT, 0.5 hour) and then washed with wash buffer. Substrate solution was added to each well, plates were incubated (RT, 15 min), and color development was stopped with sulfuric acid. Absorbance at 450 nm was measured using a Benchmark® ELISA plate reader. | Baseline and monthly up to 7 months | 
| Change in Serum Biomarkers - GM-CSF | Serum GM-CSF was measured via a commercial ELISA kit from R & D Systems. | Baseline and monthly up to 7 months | 
| Change in Serum Biomarkers - Surfactant Protein D | Surfactant protein D (SP-D) was measured via a commercial ELISA kit from Biovender. | Baseline and monthly up to 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAP