Pulmonary alveolar proteinosis (PAP) is a syndrome of surfactant accumulation, respiratory failure, and innate immune deficiency for which therapy remains limited to whole lung lavage (WLL), an invasive physical procedure to remove surfactant unavailable at most medical centers. While PAP occurs in multiple diseases affecting men, women, and children of all ages and ethnic origins, in 85% of patients, it occurs as an idiopathic disease associated with neutralizing GM-CSF autoantibodies. Basic science and translational research has shown that idiopathic PAP is an autoimmune disease in which disruption of GM-CSF signaling impairs the ability of alveolar macrophages to clear surfactant and perform host defense functions.
Recently, it has been shown that cholesterol toxicity drives pathogenesis in alveolar macrophages from GM-CSF deficient (Csf2-/-) mice and patients with autoimmune PAP. Loss of GM-CSF signaling reduces PU.1/CEBP-mediated expression of PPARγ and its downstream target ABCG1 (a cholesterol exporter important in macrophages). The cell responds by esterifying and storing cholesterol in vesicles to reduce toxicity. Eventually, vesicles fill the cell, impair intracellular transport and reduce uptake and clearance of surfactant from the lung surface resulting in disease manifestations. Recent data indicates that pioglitazone, a PPARγ agonist currently approved by the FDA for human use, increases cholesterol/surfactant clearance by alveolar macrophages from autoimmune PAP patients and Csf2-/- mice. Importantly, pioglitazone significantly reduced the severity of PAP lung disease in Csf2-/- mice after several months of therapy. Together, these observations suggest pioglitazone could be 'repurposed' as pharmacologic therapy for PAP.
Who can participate
Age range
18 Years – 80 Years
Sex
ALL
See this in plain English?
AI-rewrites the medical criteria so a patient or caregiver can understand them. Always confirm with the trial site.
Inclusion Criteria:
* Male or female
* Age ≥ 18 years and ≤ 80 years
* Able to understand and willing to sign a written informed consent document
* Able and willing to complete administration of study drug at home
* Able and willing to adhere to study visit schedule and study procedures
* Diagnosis of aPAP determined by:
* History of a diagnosis of PAP with or without supporting lung histology or BAL/cytology and
* Abnormal serum GM-CSF autoantibody test (GMAb ELISA Test) and
* Chest CT findings compatible with a diagnosis of aPAP
* Evidence of impaired GM-CSF signaling demonstrated by an abnormal STAT5 phosphorylation index (STAT5-PI) test measured in heparinized whole blood at the time screening
* A-aDO2 ≥ 25 mm Hg
Exclusion Criteria:
* Diagnosis of any other PAP-causing disease
* aPAP complicated by:
* Severe disease at screening/enrollment (A-aD02\<55)
* Clinically significant pulmonary fibrosis
* History of any clinically significant:
* Other lung disease
* Cardiovascular disease
* Disease requiring use of systemic steroids in past year
* History of Diabetes Mellitus
* History of untreated osteoporosis
* History of bladder cancer
* Active / serious lung or systemic infection
* Persistent or unexplained fever \>101oF within 2 months of study
* Treatment with an investigational therapeutic agent for aPAP within 3 months prior to enrollment, which includes inhaled GM-CSF
* Abnormal clinical and/or laboratory parameters at screening
* Wo…
Questions worth asking your doctor
Bring these to your next appointment. They're a starting point for a shared conversation — not a sign you qualify or a recommendation to enrol.
1Based on my diagnosis and history, is this trial worth exploring for me — or is there a standard treatment we should try first?
2What does this trial's phase tell us about how much is already known about its safety and benefit?
3What would taking part actually involve for me — visits, tests, time, and travel?
4What are the known and possible risks or side effects I should weigh, and how would they be monitored?
5If this trial isn't the right fit, what other options or trials would you suggest I look into?
Generated to help you prepare — always confirm anything about your own eligibility and care with the study team and your doctor.
Questions for the trial coordinator
The trial coordinator is the person who runs the study day to day. These cover the practical side — logistics, costs, and what taking part would actually mean for your life. The study team confirms whether you meet the criteria; these are questions to ask, not a sign you qualify.
1What does taking part actually involve week to week — how many visits, where, and how long does each one take?
2What costs are covered by the study, and what might I have to pay for myself, including travel, parking, or time off work?
3What happens during screening, and what happens if the study team confirms I don't meet the criteria after those tests?
4Who pays for the scans, blood work, and other tests the trial requires — the study, my insurance, or me?
5How will being in the trial affect my regular care, and will my own doctor stay informed and involved?
6Can I leave the trial at any point if I change my mind, and what would happen to my care if I do?
A starting point for the conversation — always confirm anything about your own eligibility, costs, and care with the study team and your doctor.
What they're measuring
1
Occurrence of any treatment-emergent adverse events and serious adverse events
Timeframe: 1 year
Trial details
NCT IDNCT03231033
SponsorChildren's Hospital Medical Center, Cincinnati