Back to resultsInhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP) (FAMPAP)
Primary Purpose
Hereditary Pulmonary Alveolar Proteinosis
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Leukine
Sponsored by
About this trial
This is an interventional treatment trial for Hereditary Pulmonary Alveolar Proteinosis focused on measuring PAP
Eligibility Criteria
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
Sites / Locations
- Cincinnati Children's Hospital Medical Center
- Virginia Commonwealth University
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Inhaled Leukine (rhGM-CSF)
Arm Description
Inhaled recombinant human GM-CSF in individuals with hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor
Outcomes
Primary Outcome Measures
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%.
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%.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
Change in Serum Biomarkers - GM-CSF
Serum GM-CSF was measured via a commercial ELISA kit from R & D Systems.
Change in Serum Biomarkers - Surfactant Protein D
Surfactant protein D (SP-D) was measured via a commercial ELISA kit from Biovender.
Full Information
NCT ID
NCT01511068
First Posted
December 12, 2011
Last Updated
August 28, 2023
Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Virginia Commonwealth University, Genzyme, a Sanofi Company
1. Study Identification
Unique Protocol Identification Number
NCT01511068
Brief Title
Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)
Acronym
FAMPAP
Official Title
Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
August 2012 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
July 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Virginia Commonwealth University, Genzyme, a Sanofi Company
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Pulmonary Alveolar Proteinosis
Keywords
PAP
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Inhaled Leukine (rhGM-CSF)
Arm Type
Experimental
Arm Description
Inhaled recombinant human GM-CSF in individuals with hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor
Intervention Type
Drug
Intervention Name(s)
Leukine
Other Intervention Name(s)
GM-CSF [Leukine (Sargramostim)]
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Time (Minutes) to Discontinuation of Exercise During a Standardized Treadmill Exercise Test
Description
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%.
Time Frame
Baseline, 7 months
Title
Change in Minimum Pulse Oximetry During a Standardized Treadmill Exercise Test
Description
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%.
Time Frame
Baseline, 7 months
Secondary Outcome Measure Information:
Title
Change in Diffusion Capacity for Carbon Monoxide
Description
Routine full pulmonary function testing, including spirometry, lung volumes, and DLCO, were performed according to American Thoracic Society guidelines.
Time Frame
Baseline, 7 months
Title
Change in Minimum Pulse Oximetry During a Standardized Exercise Protocol Oximetry
Description
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.
Time Frame
Baseline, 7 months
Title
Change in Radiographic Evidence of PAP Lung Disease
Description
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.
Time Frame
Baseline, 7 months
Title
Change in Quality of Life
Description
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.
Time Frame
Baseline, 7 months
Title
Change in Dyspnea Symptom Score
Description
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.
Time Frame
Baseline, 7 months
Title
Change in Serum Anti-GM-CSF Antibodies Levels
Description
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.
Time Frame
Baseline and monthly up to 7 months
Title
Change in Serum Biomarkers - GM-CSF
Description
Serum GM-CSF was measured via a commercial ELISA kit from R & D Systems.
Time Frame
Baseline and monthly up to 7 months
Title
Change in Serum Biomarkers - Surfactant Protein D
Description
Surfactant protein D (SP-D) was measured via a commercial ELISA kit from Biovender.
Time Frame
Baseline and monthly up to 7 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
8 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce Trapnell, MD
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Bruce Rubin, MD, FRCPC
Organizational Affiliation
Virginia Commonwealth University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298-0646
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)
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