Ignite Creation Date:
2024-05-06 @ 10:21 AM
Last Modification Date:
2024-10-26 @ 12:28 PM
Study NCT ID:
NCT03231033
Status:
COMPLETED
Last Update Posted:
2020-01-18
First Post:
2017-06-19
Brief Title:
Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis Autoimmune Pulmonary Alveolar Proteinosis
Sponsor:
Childrens Hospital Medical Center Cincinnati
Organization:
Childrens Hospital Medical Center Cincinnati
Study Overview
Official Title:
First in Human Study of Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis
Status:
COMPLETED
Status Verified Date:
2019-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PioPAP
Brief Summary:
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 PU1CEBP-mediated expression of PPARĪ³ 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 PPARĪ³ agonist currently approved by the FDA for human use increases cholesterolsurfactant 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
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 PU1CEBP-mediated expression of PPARĪ³ 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 PPARĪ³ agonist currently approved by the FDA for human use increases cholesterolsurfactant 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
Detailed Description:
PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure that occurs in multiple diseases that can be classified on the basis of pathogenesis 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 andor functions and metabolic disorders of surfactant production-related PAP caused by mutations in genes required for normal surfactant production Blood tests are capable of identifying the PAP-causing disease in about 95 of patients
Research has demonstrated that aPAP is caused by a high level of GM-CSF autoantibodies which block GM-CSF signaling Normally alveolar macrophages clear remove about half of the used surfactant from air sacs alveoli in the lungs Without GM-CSF alveolar macrophages have a reduced ability to clear surfactant which builds up in the alveoli and the blocks delivery of oxygen into the blood resulting in a low blood oxygen level and a reduced oxygen delivery to tissues of the body This macrophage defect is thought to occur because loss of GM-CSF stimulation causes reduced activity of PPAR-gamma a molecule present within alveolar macrophages that they require to simulate the ability to clear surfactant the reduction in PPAR-gamma activity cause a functional impairment of surfactant clearance by alveolar macrophages
Currently no pharmacologic agent has been FDA-approved as therapy aPAP it is currently treated by whole lung lavage a procedure requiring general anesthesia and a breathing machine the lungs are individually filled with saline and drained repeatedly to physically remove the excess surfactant Recent research has shown that pioglitazone a drug that activates PPAR-gamma is able to increase the ability of cultured macrophages to clear surfactant in the laboratory and that oral administration is able to reduce lung disease severity and be well-tolerated in a mouse model of aPAP Currently pioglitazone is approved by the FDA for treatment of increased blood sugar in patients with diabetes
This study is a pilot phase III human clinical trial of oral pioglitazone as therapy for autoimmune PAP The target population is adults with aPAP who have measurable clinically significant disease satisfying all of the inclusion and exclusion criteria The study design will involve recruitment screening and enrollment of participants into a phase I open-label dose-escalating single site study Oral pioglitazone will be administered to autoimmune PAP patients with a personalized dose escalation plan beginning at 15 mg per day advancing to 30 mg per day and then 45 mg per day if tolerated in 12 week increments Adverse events AEs serious AEs SAEs and pharmacodynamics PD parameters will be evaluated The experimental approach will evaluate 1 safety of oral pioglitazone by documenting occurrence of treatment-emergent AEs and SAEs 2 physiological effects of oral pioglitazone by measuring changes in the physiological clinical and quality of life parameters and 3 biochemical effects of pioglitazone on the transcriptome phenotype and function of mononuclear phagocytes alveolar macrophages and monocytes from autoimmune PAP patients Anticipated results will determine the safety efficacy and biochemical effects of oral pioglitazone in patients with autoimmune PAP These results will impact the field by 1 monitoring safety of oral pioglitazone in autoimmune PAP patients 2 translating existing preclinical data in humans and 3 demonstrating the results of pioglitazone in a personalized treatment plan with dose escalation in a pilot trial to evaluate the efficacy of oral pioglitazone for aPAP
Research has demonstrated that aPAP is caused by a high level of GM-CSF autoantibodies which block GM-CSF signaling Normally alveolar macrophages clear remove about half of the used surfactant from air sacs alveoli in the lungs Without GM-CSF alveolar macrophages have a reduced ability to clear surfactant which builds up in the alveoli and the blocks delivery of oxygen into the blood resulting in a low blood oxygen level and a reduced oxygen delivery to tissues of the body This macrophage defect is thought to occur because loss of GM-CSF stimulation causes reduced activity of PPAR-gamma a molecule present within alveolar macrophages that they require to simulate the ability to clear surfactant the reduction in PPAR-gamma activity cause a functional impairment of surfactant clearance by alveolar macrophages
Currently no pharmacologic agent has been FDA-approved as therapy aPAP it is currently treated by whole lung lavage a procedure requiring general anesthesia and a breathing machine the lungs are individually filled with saline and drained repeatedly to physically remove the excess surfactant Recent research has shown that pioglitazone a drug that activates PPAR-gamma is able to increase the ability of cultured macrophages to clear surfactant in the laboratory and that oral administration is able to reduce lung disease severity and be well-tolerated in a mouse model of aPAP Currently pioglitazone is approved by the FDA for treatment of increased blood sugar in patients with diabetes
This study is a pilot phase III human clinical trial of oral pioglitazone as therapy for autoimmune PAP The target population is adults with aPAP who have measurable clinically significant disease satisfying all of the inclusion and exclusion criteria The study design will involve recruitment screening and enrollment of participants into a phase I open-label dose-escalating single site study Oral pioglitazone will be administered to autoimmune PAP patients with a personalized dose escalation plan beginning at 15 mg per day advancing to 30 mg per day and then 45 mg per day if tolerated in 12 week increments Adverse events AEs serious AEs SAEs and pharmacodynamics PD parameters will be evaluated The experimental approach will evaluate 1 safety of oral pioglitazone by documenting occurrence of treatment-emergent AEs and SAEs 2 physiological effects of oral pioglitazone by measuring changes in the physiological clinical and quality of life parameters and 3 biochemical effects of pioglitazone on the transcriptome phenotype and function of mononuclear phagocytes alveolar macrophages and monocytes from autoimmune PAP patients Anticipated results will determine the safety efficacy and biochemical effects of oral pioglitazone in patients with autoimmune PAP These results will impact the field by 1 monitoring safety of oral pioglitazone in autoimmune PAP patients 2 translating existing preclinical data in humans and 3 demonstrating the results of pioglitazone in a personalized treatment plan with dose escalation in a pilot trial to evaluate the efficacy of oral pioglitazone for aPAP
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None