Clinical trial NCT03531996: The Longitudinal Evaluation of Autoimmune Pulmonary Alveolar Proteinosis
Official title: The Longitudinal Evaluation of Autoimmune Pulmonary Alveolar Proteinosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Autoimmune Pulmonary Alveolar Proteinosis
Keywords: Pulmonary Surfactant
Rare Lung Disease
Registry
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2018-05-22
Enrollment: 29
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with Pulmonary Alveolar Proteinosis

Brief summary: The major goal of this study is to conduct a prospective, longitudinal study of autoimmune PAP to examine outcome measures for disease severity of potential use in clinical practice and/or clinical research studies. These results will impact the field by: 1) improving an understanding of the clinical course of autoimmune PAP, 2) providing information on various clinical outcome and quality of life outcome measures to guide patients and physicians in making treatment choices, and 3) facilitate the development of pharmaco-therapeutics for autoimmune PAP and 4) better informing PAP researchers.

Detailed description: PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure that occurs in a number of diseases classified pathogenically into three groups: primary PAP (caused by disruption of GM-CSF signaling - autoimmune PAP, hereditary PAP), secondary PAP (caused by reduction in alveolar macrophage numbers and/or functions), and surfactant dysfunction-related PAP (caused by mutations in genes required for normal surfactant production). In current clinical practice, PAP is diagnosed based on a lung biopsy; an approach that is not able to identify the PAP-causing disease in anyone. Current therapy involves the physical removal of surfactant by a procedure in which the lungs are repeatedly filled with saline and emptied - whole lung lavage, which is invasive, inefficient, and not widely available, especially for children. Importantly, research advances have elucidated the pathogenesis of diseases causing PAP in most patients and have identified new diagnostic and therapeutic approaches. Simple blood-based research tests can now identify the PAP-causing disease in about 95% of patients. Further, several promising potential disease-specific therapies are currently in development. The long-term goals of the Rare Lung Diseases Consortium include improving the diagnosis and therapy of people with PAP. A major goal of this protocol is to conduct a prospective, longitudinal study of autoimmune PAP to examine outcome measures for disease severity for potential use in clinical practice and/or clinical research studies. The investigator's central hypothesis is that a prospective, longitudinal study of autoimmune PAP patients will facilitate the identification of useful outcome measures for use in clinical practice and/or clinical research studies. The specific objectives of the study are to: 1) evaluate blood-based biomarkers of PAP lung disease over time in autoimmune PAP patients, 2) evaluate the natural history/clinical course of autoimmune PAP over time, 3) evaluate quality of life measures over time in autoimmune PAP patients, 4) evaluate physiologic measures of disease over time in autoimmune PAP patients, and 5) evaluate radiologic measures of lung disease progression over time in autoimmune PAP patients. The study design will be observational and will involve recruitment, screening, and enrollment of eligible participants and annual collection of clinical data. The experimental approach will be to assess the rate of change in GM-CSF signaling assay parameters from baseline to 24 months. GM-CSF signaling assay parameters include GM-CSF autoantibody (GMAb) level, pSTAT5-Max, STAT5-phosphorylation index (STAT5-PI), GM-CSF signaling index (GM-SI), and GM-CSF EC50. The study will also assess the progression of autoimmune PAP, including but not limited to use of treatment options, the number and types of infections and other inter-current medical issues with quality of life measures, exercise tolerance, and radiologic imaging. Experimental outcomes will evaluate SP-D, cholestenoic acid, and lipid levels. Anticipated results will establish a natural history/clinical course of autoimmune PAP to better serve patients and providers, to better inform PAP researchers, and validate outcome measures and biomarkers for use in future clinical studies of PAP. These results will impact the field by: 1) improving an understanding of the clinical course of autoimmune PAP, 2) providing information on various clinical outcome and quality of life outcome measures to guide patients and physicians in making treatment choices, and 3) facilitate the development of pharmacotherapeutics for autoimmune PAP and 4) better informing PAP researchers.

Eligibility criteria: Inclusion Criteria:

* Written informed consent must be provided by:

  * Participant if at least 18 years old -OR-
  * Parent/legal guardian if participant is less than 18 years old -AND-
  * Participant provides assent when appropriate
* History of diagnosis of autoimmune as indicated by a:

  * History of chest CT or x-ray findings compatible with PAP -AND-
  * History of a Positive (Abnormal) serum GMAb test

Exclusion Criteria:

* Individuals who have a serious medical illness that, in the opinion of the investigator, is likely to interfere with completion of the study will be excluded.

Primary outcomes:
measure: Longitudinal evaluation of GM-CSF autoantibody levels
timeFrame: Baseline, 1 year, and 2 years
measure: Longitudinal evaluation of the maximal phospho-STAT5 level after GM-CSF stimulation
timeFrame: Baseline, 1 year, and 2 years
measure: Longitudinal evaluation of the STAT5 Phosphorylation Index
timeFrame: Baseline, 1 year, and 2 years
measure: Longitudinal evaluation of the GM-CSF Signaling Index
timeFrame: Baseline, 1 year, and 2 years
measure: Longitudinal evaluation of the dose GM-CSF to stimulation 1/2 maximal STAT5 phosphorylation (EC50)
timeFrame: Baseline, 1 year, and 2 years
Secondary outcomes:
measure: Frequency of therapeutic intervention
timeFrame: Baseline, 1 year, and 2 years
measure: Concurrent infections
timeFrame: Baseline, 1 year, and 2 years
measure: Blood SP-D
timeFrame: Baseline, 1 year, and 2 years
measure: Blood cholestenoic acid
timeFrame: Baseline, 1 year, and 2 years
measure: Blood lipid levels
timeFrame: Baseline, 1 year, and 2 years
measure: Quality of Life measured by St. George Respiratory Questionnaire
timeFrame: Baseline, 1 year, and 2 years
measure: Shortness of breath measured by San Diego Dyspnea Score
timeFrame: Baseline, 1 year, and 2 years
measure: Minimum SpO2 during a standardized exercise protocol
timeFrame: Baseline, 1 year, and 2 years
measure: Time during standardized exercise protocol required for SpO2 to fall below 88%
timeFrame: Baseline, 1 year, and 2 years
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Bruce Trapnell, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol. 2010 May;135(2):223-35. doi: 10.1016/j.clim.2010.02.017. Epub 2010 Mar 25.
citation: Uchida K, Nakata K, Carey B, Chalk C, Suzuki T, Sakagami T, Koch DE, Stevens C, Inoue Y, Yamada Y, Trapnell BC. Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods. 2014 Jan 15;402(1-2):57-70. doi: 10.1016/j.jim.2013.11.011. Epub 2013 Nov 23.