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

• ClinicalTrials.gov Identifier: NCT01511068
• Recruitment Status: Completed
• First Posted: January 18, 2012
• Results First Posted: September 1, 2020
• Last Update Posted: September 1, 2020
• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Virginia Commonwealth University; Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Children's Hospital Medical Center, Cincinnati

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hereditary Pulmonary Alveolar Proteinosis
• Intervention: Drug: Leukine
• Enrollment: 2

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Period Title: Overall Study
Started	2
Completed	2
Not Completed	0

Baseline Characteristics

Arm/Group Title		Inhaled Leukine (rhGM-CSF)
Arm/Group Description		Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Baseline Participants		2
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants
	<=18 years	2 100.0%
	Between 18 and 65 years	0 0.0%
	>=65 years	0 0.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants
	Female	2 100.0%
	Male	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants
	Hispanic or Latino	0 0.0%
	Not Hispanic or Latino	2 100.0%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	2 100.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	2 participants
		2

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Percent Change
Participant 1	17
Participant 2	33

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Percent Change
Participant 1	0
Participant 2	-2.1

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Percent Change
Participant 1	11
Participant 2	4

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Percent Change
Participant 1	0
Participant 2	50

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Hounsfield Units
Participant 1-Right Lung Baseline	-510
Participant 1- Right Lung End of Treatment	-579
Participant 1-Left Lung Baseline	-366
Participant 1-Left Lung End of Treatment	-441
Participant 2-Right Lung Baseline	-593
Participant 2-Right Lung End of Treatment	-675
Participant 2-Left Lung Baseline	-630
Participant 2-Left Lung End of Treatment	-726

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Percent Change
Participant 1 -Total Score	10.7
Participant 1 - Physical Health Score	75
Participant 1 - Psychosocial Score	-5.2
Participant 1 - Parent Score	19.6
Participant 1 - Child Score	3.1
Participant 2 - Total Score	11.7
Participant 2 - Physical Health Score	7.4
Participant 2- Psychosocial Score	14.5
Participant 2 - Parent Score	5.6
Participant 2 - Child Score	18.2

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: Percent Change
Participant 1	71
Participant 2	11

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: micrograms/ml
Participant 1-Visit 0-Baseline	0.67
Participant 1-Visit 1-Begin Low Dose Therapy	0.36
Participant 1-Visit 2	0.32
Participant 1-Visit 3	1.85
Participant 1-Visit 4	19.7
Participant 1-Visit 5-Begin High Dose Therapy	71.8
Participant 1-Visit 6	118.1
Participant 1-Visit 7	128.2
Participant 1-Visit 8 - End of Therapy	110.7
Participant 2-Baseline	0.551
Participant 2-Begin Therapy	0.358
Participant 2-Visit 2	0.299
Participant 2-Visit 3	81.04
Participant 2-Visit 4	132.52
Participant 2-Visit 5-Begin High Dose Therapy	123.66
Participant 2-Visit 6	116.82
Participant 2-Visit 7	104.36
Participant 2-Visit 8 - End of Therapy	91.92

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: picograms/ml
Participant 1-Visit 0-Baseline	43.75
Participant 1-Visit 1-Begin Low Dose Therapy	39.4
Participant 1-Visit 2	43.2
Participant 1-Visit 3	88.5
Participant 1-Visit 4	11.5
Participant 1-Visit 5-Begin High Dose Therapy	7.8
Participant 1-Visit 6	7.8
Participant 1-Visit 7	7.8
Participant 1-Visit 8 - End of Therapy	7.8
Participant 2-Baseline	26.8
Participant 2-Begin Therapy	27.9
Participant 2-Visit 2	24.8
Participant 2-Visit 3	7.8
Participant 2-Visit 4	7.8
Participant 2-Visit 5-Begin High Dose Therapy	7.8
Participant 2-Visit 6	7.8
Participant 2-Visit 7	7.8
Participant 2-Visit 8 - End of Therapy	7.8

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description:	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
Overall Number of Participants Analyzed	2
Measure Type: Number; Unit of Measure: nanograms/ml
Participant 1-Visit 0-Baseline	796.2
Participant 1-Visit 1-Begin Low Dose Therapy	619
Participant 1-Visit 2	696.4
Participant 1-Visit 3	589
Participant 1-Visit 4	697.2
Participant 1-Visit 5-Begin High Dose Therapy	536.9
Participant 1-Visit 6	642.4
Participant 1-Visit 7	495.9
Participant 1-Visit 8 - End of Therapy	673.2
Participant 2-Baseline	618.7
Participant 2-Begin Therapy	469.6
Participant 2-Visit 2	425.5
Participant 2-Visit 3	381.3
Participant 2-Visit 4	401.1
Participant 2-Visit 5-Begin High Dose Therapy	298.2
Participant 2-Visit 6	422
Participant 2-Visit 7	456.8
Participant 2-Visit 8 - End of Therapy	593

Adverse Events

Time Frame	Adverse events were collected from the time of consent until the of completion of the study, approximately 1 year.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Inhaled Leukine (rhGM-CSF)
Arm/Group Description	Inhaled recombinant human GM-CSF in individuals with Hereditary Pulmonary Alveolar Proteinosis (hPAP) due to partial dysfunction of the GM-CSF receptor Leukine: 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.
All-Cause Mortality
	Inhaled Leukine (rhGM-CSF)
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Inhaled Leukine (rhGM-CSF)
	Affected / at Risk (%)	# Events
Total	0/2 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Inhaled Leukine (rhGM-CSF)
	Affected / at Risk (%)	# Events
Total	2/2 (100.00%)
General disorders
Noseblood * 1	1/2 (50.00%)	1
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Tract Infection * 1	2/2 (100.00%)	2
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, CTCAE (3.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Bruce Trapnell
• Organization: Cincinnati Children's Hospital Medical Center
• Phone: 513636-6361
• EMail: Bruce.Trapnell@cchmc.org

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01511068
• Obsolete Identifiers: NCT01534156
• Other Study ID Numbers: 2011-0959_CCHMC_IRB
• First Submitted: December 12, 2011
• First Posted: January 18, 2012
• Results First Submitted: February 26, 2020
• Results First Posted: September 1, 2020
• Last Update Posted: September 1, 2020