Autoimmune Pulmonary Alveolar ProteinosisPhase 2NCT00901511
Inhaled GM-CSF Therapy of Autoimmune PAP
A Phase 2 study testing Baseline WLL, Sargramostim and Rescue WLL in people with Autoimmune Pulmonary Alveolar Proteinosis, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
Trial summary
This is a prospective, randomized, open-label, long-term, phase 2 study of inhaled granulocyte/macrophage-colony stimulating factor following whole lung lavage therapy in patients with autoimmune pulmonary alveolar proteinosis. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Autoimmune Pulmonary Alveolar Proteinosis
- What is being tested?
- Baseline WLL, Sargramostim and Rescue WLL
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteItaly
- Study dates
- Jul 2009to Jun 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Female of male 18 years of age or older
- Diagnosis of autoimmune PAP
- Able and willing to provide written informed consent
- Eligible for whole lung lavage determined as the presence of persistent or progressive respiratory failure (PaO2 at rest < 60 mm Hg) or desaturation < 90% or > 5 percentage points during standard exercise
Who cannot join
- Diagnosis with secondary PAP, congenital PAP, or hereditary PAP
- Contraindication to whole lung lavage
- Contraindication to administration of inhaled GM-CSF
- Chronic lung disease associated with already existing respiratory failure, such as emphysema or pulmonary fibrosis, chronic heart failure, ischemic heart disease, active pulmonary embolism, progressive cancer, and other severe metabolic conditions
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Inhaled GM-CSF Reduces the Need for Whole Lung Lavage and Improves Gas Exchange in Autoimmune PAP Patients
This is a prospective, randomized, open-label, long-term, phase 2 study of inhaled granulocyte/macrophage-colony stimulating factor following whole lung lavage therapy in patients with autoimmune pulmonary alveolar proteinosis.
Read the detailed description
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder of progressive surfactant accumulation and resulting hypoxemic respiratory failure caused by disruption of granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling, which alveolar macrophages require to remove pulmonary surfactant.
The current therapy of aPAP, whole lung lavage (WLL), is a procedure requiring general anesthesia, endotracheal intubation to isolate each lung, and mechanical ventilation of the untreated lung while the treated lung repeatedly filled with saline and drained while percussing the chest to loosen and emulsify the surfactant and saline to physically remove the excess surfactant.
Inhaled GM-CSF is a promising pharmacotherapeutic approach shown in case reports, small series, moderate open-label studies, and two randomized, double-blinded, placebo-controlled trials to be safe and improve the clinical, physiological, radiological, and biochemical disease manifestations in patients with mild-moderate aPAP. In contrast to the present study, prior studies were too short in duration to permit an evaluation on the requirement for WLL, which aPAP patients require a mean of every 15 months. The present study addressed the effects on WLL by studying patients with moderate-severe aPAP and by utilizing a long-term follow up period.
The study design included a screening visit (month -3) to establish eligibility, an observation period (-3 to 0 months) to establish the presence of progressive/unremitting aPAP and establish disease severity, a pre-WLL visit (-1 month), a baseline visit (month 0) during which all patients received a scheduled, baseline, bilateral WLL, a 10-month, open-label treatment period, and a 20-month follow-up period. Study visits were scheduled at months -3, -1, 0, 1, 3, 6, 10, 18, and 30 months. Patients were randomized by the statistician to the GM-CSF Group (n=9) or the Control Group (n=9). Investigators were blinded to group assignment until after the participant's baseline visit.
Patients randomized to the GM-CSF group (n=9) received inhaled GM-CSF (sargramostim (Leukine®), 250 mcg daily every other week for 12 weeks beginning 1 week after the baseline WLL - termed GM-CSF induction therapy period, followed by a 4-week washout period during which no GM-CSF was administered), and then received inhaled GM-CSF (sargramostim, 250 mcg/day on days 1 and 3 of every 14-day period for 6 months - termed GM-CSF maintenance therapy period). Inhaled GM-CSF (Leukine®) was administered using AKITA2 APIXNEB nebulizer system (Activaero, Vectura GmbH, Germany). Patients randomized to the Control Group (n=9) received no further scheduled treatment. Any patient in either group experiencing with disease progression resulting in respiratory failure (defined as peripheral artery oxygen concentration (PaO2) <60 mmHg at rest or PaO2 >60 mmHg at rest AND a peripheral blood oxygen saturation (SpO2) < 90% OR a decline in SpO2 of 5% or more during exercise), received (unscheduled) rescue WLL and were considered to have failed their assigned intervention (GM-CSF or Control).
The primary outcome measure was time, in months, between the scheduled baseline WLL and first administration of unscheduled 'rescue' WLL (termed 'time to rescue WLL'). Key secondary outcome measures included the response in peripheral arterial oxygen concentration (PaO2), alveolar-arterial difference in oxygen concentration (A-aDO2), diffusing capacity of the lungs for carbon monoxide (DLco), vital capacity, ground glass opacification (GGO) of the lungs measured by visual scoring of chest computed tomography (CT) scans, and serum biomarkers of PAP (carcinoembryonic antigen, Krebs von-Lungren antigen, Cyfra-21.1). Other outcome measures included the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), serum GM-CSF autoantibody concentration, the peripheral white blood cell and platelet counts.
The occurrence and timing of rescue WLL administration in each group was evaluated using Kaplan-Meyer analysis. The primary end point was analyzed as the difference in median time to rescue WLL between the GM-CSF group and the Control group. Categorical outcomes were compared using Fisher's exact test. Key secondary end points were evaluated using repeated measures analysis of variance (RM-ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point. Secondary outcome measures were also evaluated by comparing the between-group mean (or median) values at each visit using Student's t-test (or Mann-Whitney test) after imputation of missing data using a last observation carried forward approach to reduce selection-type bias by comparing the corresponding group means or medians. All reported p values are two-sided and have not been adjusted for multiple testing. P values of less than 0.05 were considered to indicate statistical significance. Analysis of the primary and key secondary outcomes was performed with the use of Stata software version 14.2. Analyses of secondary outcome measures were performed with the use of Prism for Mac OS software, version 9.51.
Anticipated results were intended to compare the effects of inhaled GM-CSF following baseline WLL to those of baseline WLL alone in patients with moderate to severe aPAP.
- Being tested
- Baseline WLL, Sargramostim, Rescue WLL
- Keywords
- Whole lung lavage, GM-CSF, Sargramostim, aPAP
- Medical subject headings
- Pulmonary Alveolar Proteinosis, Acquired
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Baseline WLLProcedure or surgery
Scheduled bilateral WLL
SargramostimDrug
Also called Leukine®, recombinant granulocyte/macrophage-colony stimulating factor
Inhaled GM-CSF
Rescue WLLProcedure or surgery
Unscheduled bilateral WLL
| Study group | Role | What they receive |
|---|---|---|
| GM-CSF Group | Experimental | Scheduled Baseline WLL: All participants will receive scheduled bilateral WLL at baseline (month 0).
GM-CSF induction treatment: All participants will receive inhaled GM-CSF (250 mcg daily, 7 consecutive days every other week for 12 weeks beginning 1 week after the scheduled baseline WLL).
Washout period: All participants will not receive inhaled GM-CSF treatment for 4 weeks immediately following GM-CSF induction treatment.
GM-CSF maintenance treatment: All participants will receive inhaled GM-CSF (250 mcg daily on days 1 and 3 of every consecutive 14-day period for 6 months beginning 17 weeks after the scheduled baseline WLL).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (PaO2 at rest <60 mmHg of PaO2 > 60 mmHg at rest AND desaturation <90% at rest OR decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL. Receives: Procedure: Baseline WLL; Drug: Sargramostim; Procedure: Rescue WLL |
| Control Group | Other | Scheduled Baseline WLL: All participants will receive a scheduled bilateral WLL at baseline (month 0).
Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (defined by a resting PaO2 <60 mmHg or > 60 mmHg and desaturation <90% at rest or decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL. Receives: Procedure: Baseline WLL; Procedure: Rescue WLL |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Rescue WLL
Time (in months) between the scheduled baseline WLL (at Study Month 0) and the first administration of an unscheduled rescue WLL (during the 30-months after Study Month 0)
Measured: 30 months
Secondary outcomes (13)
Number of Patients Requiring a Rescue WLL
Number of patients requiring an unscheduled rescue WLL during the 30-months immediately following administration of the scheduled baseline WLL therapy at Study Month 0.
Measured: 30 months
Between-Group Difference in Mean Partial Pressure of Oxygen (PaO2)
Primary Analysis: Between-group difference in mean PaO2 at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in mean PaO2 at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, PaO2 is determined from lab values measured for an arterial blood gas procedure.
Measured: 30 months
Between-Group Difference in Mean Alveolar-arterial Difference in Oxygen Concentration (A-aDO2)
Primary Analysis: Between-group difference in mean A-aDO2 at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in mean A-aDO2 at each visit after imputation of missing data by the last-value carried forward method.
For both of the primary and secondary analyses, A-aDO2 is calculated from lab values measured for an arterial blood gas, the ambient atmosphere pressure, and fraction of inspired oxygen at the time of the arterial blood gas procedure.
Measured: 30 months
Between-Group Difference in Mean Diffusion Capacity of the Lungs for Carbon Monoxide (DLCO)
Primary Analysis: Between-group difference in mean DLCO at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in mean DLCO at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, DLCO is determined from pulmonary function tests.
Measured: 30 months
Between-Group Difference in Mean Vital Capacity (VC)
Primary Analysis: Between-group difference in mean VC at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in mean VC at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, VC is determined from pulmonary function tests.
Measured: 30 months
Between-Group Difference in Mean Chest Computed Tomography Ground Glass Opacification (GGO) Score
Primary Analysis: Between-group difference in median GGO Score at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in median GGO Score at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, the degree of severity of lung disease was calculated by determining the number of segments affected. The following scale was used:
Grade 1 = 1 segment affected Grade 2 = 2 - 5 segments affected Grade 3 = 6 - 9 segments affected Grade 4 = 10 - 14 segments affected Grade 5 = > 14 affected segments
Measured: 30 months
Between-Group Difference in Median Serum Carcinoembryonic Antigen (CEA) Levels
Primary Analysis: Between-group difference in median serum CEA levels at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in serum CEA levels at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, the serum CEA levels were determined via enzyme linked immunosorbent assay (ELISA).
Measured: 30 months
Between-Group Difference in Mean Serum Krebs Von-Lungren 6 Antigen (KL-6) Levels
Primary Analysis: Between-group difference in median serum KL-6 levels at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in serum KL-6 levels at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, the serum KL-6 levels were determined via enzyme linked immunosorbent assay (ELISA).
Measured: 30 months
Between-Group Difference in Mean Serum Cytokeratin-19 Fragment (Cyfra21.1) Levels
Primary Analysis: Between-group difference in mean serum Cyfra21.1 levels at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in serum Cyfra21.1 levels at each visit after imputation of missing data by the last observation carried forward method.
For both of the primary and secondary analyses, the serum Cyfra21.1 levels were determined via enzyme linked immunosorbent assay (ELISA).
Measured: 30 months
Between-Group Difference in Median Serum GM-CSF Autoantibody (GMAb) Levels
Analysis Method: Between-group difference in serum GMAb levels at each visit after imputation of missing data by the last observation carried forward method.
The serum GMAb levels were determined via enzyme linked immunosorbent assay (ELISA).
Measured: 30 months
Between-Group Difference in Mean White Blood Cell (WBC) Counts
Analysis Method: Between-group difference in WBC counts at each visit after imputation of missing data by the last observation carried forward method.
The WBC counts were determined via complete blood count.
Measured: 30 months
Between-Group Difference in Mean Platelet Counts
Analysis Method: Between-group difference in platelet counts at each visit after imputation of missing data by the last observation carried forward method.
The platelet counts were determined via complete blood count.
Measured: 30 months
Between-Group Difference in Mean 36-Item Short Form Survey (SF-36) General Health Score
Primary Analysis: Between-group difference in mean SF-36 General Health Score at each study visit after the scheduled baseline WLL was evaluated using repeated measures analysis of variance (ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point.
Secondary analysis: Between-group difference in SF-36 General Health Score at each visit after imputation of missing data by the last observation carried forward method.
The SF-36 General Health Score were determined from the RAND 36-Item Health Survey. Scoring the SF-36 questionnaire is a two-step process. First, pre-coded numeric values are recoded per the scoring key. All items are scored on a scale of 0 to 100 so that a high score defines a more favorable health state. Scores represent the percentage of total possible score achieved. In step 2, General Health is determined from the average score for questions 1, 33, 34, 35, and 36.
Measured: 30 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2009 (estimated)
- Study startJul 2009
- Primary completionJun 2016
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Autoimmune Pulmonary Alveolar ProteinosisStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Policlinico San Matteo di PaviaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Sponsor type
- University, hospital or other
- Collaborators
- Agenzia Italiana del Farmaco
- Responsible party
- Principal investigator, Ilaria Campo, Fondazione IRCCS Policlinico San Matteo di Pavia
- Investigators
- Francesca Mariani, MD, Principal investigator, Fondazione IRCCS Policlinico San Matteo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00901511
- Sponsor's protocol ID
- FARM7MCPK4
- Other IDs
- Codice Interno 19900508, EudraCT 2008-007086-23
- Status last verified
- Jul 2024
- First submitted
- 11 May 2009
- Last updated
- 12 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25;349(26):2527-39. doi: 10.1056/NEJMra023226. No abstract available.
PubMed 14695413Beccaria M, Luisetti M, Rodi G, Corsico A, Zoia MC, Colato S, Pochetti P, Braschi A, Pozzi E, Cerveri I. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J. 2004 Apr;23(4):526-31. doi: 10.1183/09031936.04.00102704.
PubMed 15083749Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006 Mar;27(3):585-93. doi: 10.1183/09031936.06.00058305.
PubMed 16507860Trapnell BC, Inoue Y, Bonella F, Morgan C, Jouneau S, Bendstrup E, Campo I, Papiris SA, Yamaguchi E, Cetinkaya E, Ilkovich MM, Kramer MR, Veltkamp M, Kreuter M, Baba T, Ganslandt C, Tarnow I, Waterer G, Jouhikainen T; IMPALA Trial Investigators. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2020 Oct 22;383(17):1635-1644. doi: 10.1056/NEJMoa1913590. Epub 2020 Sep 7.
PubMed 32897035Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, Morimoto K, Tanaka T, Yamaguchi E, Takahashi A, Oda M, Ishii H, Izumi S, Sugiyama H, Nakagawa A, Tomii K, Suzuki M, Konno S, Ohkouchi S, Tode N, Handa T, Hirai T, Inoue Y, Arai T, Asakawa K, Sakagami T, Hashimoto A, Tanaka T, Takada T, Mikami A, Kitamura N, Nakata K. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019 Sep 5;381(10):923-932. doi: 10.1056/NEJMoa1816216.
PubMed 31483963
Study at a glance
From the registry record, last updated by the sponsor on 12 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inhaled GM-CSF Reduces the Need for Whole Lung Lavage and Improves Gas Exchange in Autoimmune PAP Patients
- ClinicalTrials.gov ID
- NCT00901511
- Acronym / sponsor ID
- FARM7MCPK4
- Keywords
- Whole lung lavage, GM-CSF, Sargramostim, aPAP
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di PaviaUniversity, hospital or other
- Collaborators
- Agenzia Italiana del Farmaco
- Study start
- Jul 2009 (actual)
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 13 May 2009 (estimated)
- Results
- Posted 26 Jun 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a prospective, randomized, open-label, long-term, phase 2 study of inhaled granulocyte/macrophage-colony stimulating factor following whole lung lavage therapy in patients with autoimmune pulmonary alveolar proteinosis.
Detailed description
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder of progressive surfactant accumulation and resulting hypoxemic respiratory failure caused by disruption of granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling, which alveolar macrophages require to remove pulmonary surfactant.
The current therapy of aPAP, whole lung lavage (WLL), is a procedure requiring general anesthesia, endotracheal intubation to isolate each lung, and mechanical ventilation of the untreated lung while the treated lung repeatedly filled with saline and drained while percussing the chest to loosen and emulsify the surfactant and saline to physically remove the excess surfactant.
Inhaled GM-CSF is a promising pharmacotherapeutic approach shown in case reports, small series, moderate open-label studies, and two randomized, double-blinded, placebo-controlled trials to be safe and improve the clinical, physiological, radiological, and biochemical disease manifestations in patients with mild-moderate aPAP. In contrast to the present study, prior studies were too short in duration to permit an evaluation on the requirement for WLL, which aPAP patients require a mean of every 15 months. The present study addressed the effects on WLL by studying patients with moderate-severe aPAP and by utilizing a long-term follow up period.
The study design included a screening visit (month -3) to establish eligibility, an observation period (-3 to 0 months) to establish the presence of progressive/unremitting aPAP and establish disease severity, a pre-WLL visit (-1 month), a baseline visit (month 0) during which all patients received a scheduled, baseline, bilateral WLL, a 10-month, open-label treatment period, and a 20-month follow-up period. Study visits were scheduled at months -3, -1, 0, 1, 3, 6, 10, 18, and 30 months. Patients were randomized by the statistician to the GM-CSF Group (n=9) or the Control Group (n=9). Investigators were blinded to group assignment until after the participant's baseline visit.
Patients randomized to the GM-CSF group (n=9) received inhaled GM-CSF (sargramostim (Leukine®), 250 mcg daily every other week for 12 weeks beginning 1 week after the baseline WLL - termed GM-CSF induction therapy period, followed by a 4-week washout period during which no GM-CSF was administered), and then received inhaled GM-CSF (sargramostim, 250 mcg/day on days 1 and 3 of every 14-day period for 6 months - termed GM-CSF maintenance therapy period). Inhaled GM-CSF (Leukine®) was administered using AKITA2 APIXNEB nebulizer system (Activaero, Vectura GmbH, Germany). Patients randomized to the Control Group (n=9) received no further scheduled treatment. Any patient in either group experiencing with disease progression resulting in respiratory failure (defined as peripheral artery oxygen concentration (PaO2) <60 mmHg at rest or PaO2 >60 mmHg at rest AND a peripheral blood oxygen saturation (SpO2) < 90% OR a decline in SpO2 of 5% or more during exercise), received (unscheduled) rescue WLL and were considered to have failed their assigned intervention (GM-CSF or Control).
The primary outcome measure was time, in months, between the scheduled baseline WLL and first administration of unscheduled 'rescue' WLL (termed 'time to rescue WLL'). Key secondary outcome measures included the response in peripheral arterial oxygen concentration (PaO2), alveolar-arterial difference in oxygen concentration (A-aDO2), diffusing capacity of the lungs for carbon monoxide (DLco), vital capacity, ground glass opacification (GGO) of the lungs measured by visual scoring of chest computed tomography (CT) scans, and serum biomarkers of PAP (carcinoembryonic antigen, Krebs von-Lungren antigen, Cyfra-21.1). Other outcome measures included the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), serum GM-CSF autoantibody concentration, the peripheral white blood cell and platelet counts.
The occurrence and timing of rescue WLL administration in each group was evaluated using Kaplan-Meyer analysis. The primary end point was analyzed as the difference in median time to rescue WLL between the GM-CSF group and the Control group. Categorical outcomes were compared using Fisher's exact test. Key secondary end points were evaluated using repeated measures analysis of variance (RM-ANOVA) after adjustment for baseline values, gender, age, and the number of patients at risk at each time point. Secondary outcome measures were also evaluated by comparing the between-group mean (or median) values at each visit using Student's t-test (or Mann-Whitney test) after imputation of missing data using a last observation carried forward approach to reduce selection-type bias by comparing the corresponding group means or medians. All reported p values are two-sided and have not been adjusted for multiple testing. P values of less than 0.05 were considered to indicate statistical significance. Analysis of the primary and key secondary outcomes was performed with the use of Stata software version 14.2. Analyses of secondary outcome measures were performed with the use of Prism for Mac OS software, version 9.51.
Anticipated results were intended to compare the effects of inhaled GM-CSF following baseline WLL to those of baseline WLL alone in patients with moderate to severe aPAP.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GM-CSF Group | Experimental | Procedure: Baseline WLL, Drug: Sargramostim, Procedure: Rescue WLLScheduled Baseline WLL: All participants will receive scheduled bilateral WLL at baseline (month 0). GM-CSF induction treatment: All participants will receive inhaled GM-CSF (250 mcg daily, 7 consecutive days every other week for 12 weeks beginning 1 week after the scheduled baseline WLL). Washout period: All participants will not receive inhaled GM-CSF treatment for 4 weeks immediately following GM-CSF induction treatment. GM-CSF maintenance treatment: All participants will receive inhaled GM-CSF (250 mcg daily on days 1 and 3 of every consecutive 14-day period for 6 months beginning 17 weeks after the scheduled baseline WLL). Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (PaO2 at rest <60 mmHg of PaO2 > 60 mmHg at rest AND desaturation <90% at rest OR decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL. |
| Control Group | Other | Procedure: Baseline WLL, Procedure: Rescue WLLScheduled Baseline WLL: All participants will receive a scheduled bilateral WLL at baseline (month 0). Unscheduled Rescue WLL: Any participant experiencing progression of aPAP lung disease (defined as the disease progression resulting in respiratory failure (defined by a resting PaO2 <60 mmHg or > 60 mmHg and desaturation <90% at rest or decline in SpO2 of 5% or more during exercise testing) will receive unscheduled rescue WLL. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Female of male 18 years of age or older
- Diagnosis of autoimmune PAP
- Able and willing to provide written informed consent
- Eligible for whole lung lavage determined as the presence of persistent or progressive respiratory failure (PaO2 at rest < 60 mm Hg) or desaturation < 90% or > 5 percentage points during standard exercise
Key exclusion criteria (4 listed)
- Diagnosis with secondary PAP, congenital PAP, or hereditary PAP
- Contraindication to whole lung lavage
- Contraindication to administration of inhaled GM-CSF
- Chronic lung disease associated with already existing respiratory failure, such as emphysema or pulmonary fibrosis, chronic heart failure, ischemic heart disease, active pulmonary embolism, progressive cancer, and other severe metabolic conditions
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Baseline WLLScheduled bilateral WLL | Procedure or surgery | Control Group, GM-CSF Group |
| SargramostimAlso: Leukine®, recombinant granulocyte/macrophage-colony stimulating factorInhaled GM-CSF | Drug | GM-CSF Group |
| Rescue WLLUnscheduled bilateral WLL | Procedure or surgery | Control Group, GM-CSF Group |
Primary outcome
Time to Rescue WLL
Time frame: 30 months
Time (in months) between the scheduled baseline WLL (at Study Month 0) and the first administration of an unscheduled rescue WLL (during the 30-months after Study Month 0)
13 secondary outcomes
Number of Patients Requiring a Rescue WLL
Time frame: 30 months
Between-Group Difference in Mean Partial Pressure of Oxygen (PaO2)
Time frame: 30 months
Between-Group Difference in Mean Alveolar-arterial Difference in Oxygen Concentration (A-aDO2)
Time frame: 30 months
Between-Group Difference in Mean Diffusion Capacity of the Lungs for Carbon Monoxide (DLCO)
Time frame: 30 months
Between-Group Difference in Mean Vital Capacity (VC)
Time frame: 30 months
Between-Group Difference in Mean Chest Computed Tomography Ground Glass Opacification (GGO) Score
Time frame: 30 months
Between-Group Difference in Median Serum Carcinoembryonic Antigen (CEA) Levels
Time frame: 30 months
Between-Group Difference in Mean Serum Krebs Von-Lungren 6 Antigen (KL-6) Levels
Time frame: 30 months
Between-Group Difference in Mean Serum Cytokeratin-19 Fragment (Cyfra21.1) Levels
Time frame: 30 months
Between-Group Difference in Median Serum GM-CSF Autoantibody (GMAb) Levels
Time frame: 30 months
Between-Group Difference in Mean White Blood Cell (WBC) Counts
Time frame: 30 months
Between-Group Difference in Mean Platelet Counts
Time frame: 30 months
Between-Group Difference in Mean 36-Item Short Form Survey (SF-36) General Health Score
Time frame: 30 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 14695413Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25;349(26):2527-39. doi: 10.1056/NEJMra023226. No abstract available.
- Background: PubMed 15083749Beccaria M, Luisetti M, Rodi G, Corsico A, Zoia MC, Colato S, Pochetti P, Braschi A, Pozzi E, Cerveri I. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J. 2004 Apr;23(4):526-31. doi: 10.1183/09031936.04.00102704.
- Background: PubMed 16507860Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006 Mar;27(3):585-93. doi: 10.1183/09031936.06.00058305.
- Background: PubMed 32897035Trapnell BC, Inoue Y, Bonella F, Morgan C, Jouneau S, Bendstrup E, Campo I, Papiris SA, Yamaguchi E, Cetinkaya E, Ilkovich MM, Kramer MR, Veltkamp M, Kreuter M, Baba T, Ganslandt C, Tarnow I, Waterer G, Jouhikainen T; IMPALA Trial Investigators. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2020 Oct 22;383(17):1635-1644. doi: 10.1056/NEJMoa1913590. Epub 2020 Sep 7.
- Background: PubMed 31483963Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, Morimoto K, Tanaka T, Yamaguchi E, Takahashi A, Oda M, Ishii H, Izumi S, Sugiyama H, Nakagawa A, Tomii K, Suzuki M, Konno S, Ohkouchi S, Tode N, Handa T, Hirai T, Inoue Y, Arai T, Asakawa K, Sakagami T, Hashimoto A, Tanaka T, Takada T, Mikami A, Kitamura N, Nakata K. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019 Sep 5;381(10):923-932. doi: 10.1056/NEJMoa1816216.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Francesca Mariani, MD principal investigator
Fondazione IRCCS Policlinico San Matteo
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Baseline WLL, Sargramostim and Rescue WLL in people with Autoimmune Pulmonary Alveolar Proteinosis, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jun 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Rescue WLL (time frame: 30 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00901511, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jul 2024; AzTrials last refreshed its copy on 7 Nov 2026.