Autoimmune Pulmonary Alveolar ProteinosisPhase 1PioPAPNCT03231033
Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis Autoimmune Pulmonary Alveolar Proteinosis
A Phase 1 study testing Pioglitazone in people with Autoimmune Pulmonary Alveolar Proteinosis, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Autoimmune Pulmonary Alveolar Proteinosis
- What is being tested?
- Pioglitazone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Aug 2017to 2 Apr 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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
Who cannot join
- 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
Show all 17Show fewer
- 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
- Women who are pregnant or plan to become pregnant
- Concomitant or recent use of specific medicines
Trial locations and contacts
1 site in 1 country.
United States1 site
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
About this study
Official title: First in Human Study of Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis
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.
Read the 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 and/or 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 I/II 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.
- Being tested
- Pioglitazone
- 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.
PioglitazoneDrug
Also called Actos
Participants will receive three doses of Pioglitazone, 15 mg/day for 12 weeks, 30 mg/day for 12 weeks, and 45 mg/day for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| Pioglitazone | Experimental | Oral administration of Actos at 15 mg/day for 12 weeks, 30 mg/day for 12 weeks, and 45 mg/day for 12 weeks Receives: Drug: Pioglitazone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Occurrence of any treatment-emergent adverse events and serious adverse events
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measured: 1 year
Secondary outcomes (9)
Alveolar-arterial oxygen concentration gradient (A-aDO2)
Change from Baseline (Day 0) in the A-aDO2 gradient as measured at the End of Treatment
Measured: 1 year
PaO2
Change from Baseline (Day 0) in the PaO2 as measured at the End of Treatment
Measured: 1 year
Minimum SpO2 during a standardized treadmill exercise test
Change from Baseline (Day 0) in the minimum SpO2 during a treadmill exercise test as measured at the End of Treatment
Measured: 1 year
Time during a standardized treadmill exercise test required for SpO2 to fall below 88% (or discontinuance of testing due to dyspnea)
Change from Baseline (Day 0) in the time for the SpO2 to fall below 88% during the treadmill exercise test as measured at the End of Treatment
Measured: 1 year
DLCO (Diffusion capacity of the lung for carbon monoxide)
Change from Baseline (Day 0) in the DLCO as measured at the End of Treatment
Measured: 1 year
Parenchymal lung density determined by quantitative computed tomography (CT) densitometry
Change from Baseline (Day 0) in the parenchymal densitometry as measured at the End of Treatment
Measured: 1 year
Quality of Life measured by SF-36
Change from Baseline (Day 0) in the quality of life as measured at the End of Treatment
Measured: 1 year
Quality of Life measured by St. George's Respiratory Questionnaire
Change from Baseline (Day 0) in the quality of life as measured at the End of Treatment
Measured: 1 year
Shortness of breath measured by San Diego Dyspnea Score
Change from Baseline (Day 0) in the quality of life as measured at the End of Treatment
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2017
- Study start17 Aug 2017
- Primary completion2 Apr 2019
- Study completion2 Apr 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Autoimmune Pulmonary Alveolar ProteinosisStudies of the same condition, open and under way.
- More trials run by Children's Hospital Medical Center, CincinnatiThe 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 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Bruce Trapnell, MD, Study director, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03231033
- Sponsor's protocol ID
- TPSC-114
- Acronym
- PioPAP
- Status last verified
- Jan 2019
- First submitted
- 19 Jun 2017
- Last updated
- 18 Jan 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- First in Human Study of Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis
- ClinicalTrials.gov ID
- NCT03231033
- Acronym / sponsor ID
- PioPAP / TPSC-114
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Study start
- 17 Aug 2017 (actual)
- Primary completion
- 2 Apr 2019 (actual)
- Study completion
- 2 Apr 2019 (actual)
- First posted
- 27 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 and/or 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 I/II 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 design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pioglitazone | Experimental | Drug: PioglitazoneOral administration of Actos at 15 mg/day for 12 weeks, 30 mg/day for 12 weeks, and 45 mg/day for 12 weeks |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (17 listed)
- Diagnosis of any other PAP-causing disease
- aPAP complicated by:
- History of any clinically significant:
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 |
|---|---|---|
| PioglitazoneAlso: ActosParticipants will receive three doses of Pioglitazone, 15 mg/day for 12 weeks, 30 mg/day for 12 weeks, and 45 mg/day for 12 weeks | Drug | Pioglitazone |
Primary outcome
Occurrence of any treatment-emergent adverse events and serious adverse events
Time frame: 1 year
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
9 secondary outcomes
Alveolar-arterial oxygen concentration gradient (A-aDO2)
Time frame: 1 year
PaO2
Time frame: 1 year
Minimum SpO2 during a standardized treadmill exercise test
Time frame: 1 year
Time during a standardized treadmill exercise test required for SpO2 to fall below 88% (or discontinuance of testing due to dyspnea)
Time frame: 1 year
DLCO (Diffusion capacity of the lung for carbon monoxide)
Time frame: 1 year
Parenchymal lung density determined by quantitative computed tomography (CT) densitometry
Time frame: 1 year
Quality of Life measured by SF-36
Time frame: 1 year
Quality of Life measured by St. George's Respiratory Questionnaire
Time frame: 1 year
Shortness of breath measured by San Diego Dyspnea Score
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2020.
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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.
Bruce Trapnell, MD study director
Children's Hospital Medical Center, Cincinnati
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Pioglitazone in people with Autoimmune Pulmonary Alveolar Proteinosis, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
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 11 inclusion and 17 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 18 Jan 2020. 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 United States. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Occurrence of any treatment-emergent adverse events and serious adverse events (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 18 Jan 2020.