Positive Airway Pressure + NAC for COPD

(TEAM Trial)

Overseen By John Fahy, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, San Francisco

Must be taking: Inhaled corticosteroids, Biologic therapy

Disqualifiers: Pregnancy, URI, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 4 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to determine if positive pressure during inspiration will improve penetration of aerosolized N-Acetylcysteine (NAC) into airway mucus plugs in the lungs of patients with asthma or Chronic Obstructive Pulmonary Disease (COPD). The main questions it aims to answer are: * Does delivery of aerosolized NAC with positive inspiratory pressure have a greater effect on mucus plug burden in the lungs than delivery of NAC without positive pressure. * Does delivery of aerosolized NAC with positive inspiratory pressure have a greater effect on lung function than delivery of NAC without positive pressure. Participants will be assigned (in a single blind design) to the NAC via jet nebulizer group or the NAC via AeroEclipse-VersaPAP nebulizer group. Participants will each complete 5 treatment visits over the course of 30 days. Each treatment visit will consist of two treatments of a 10% NAC (3 mL) and 2.5 mg albuterol (0.5mL) inhalation solution separated by 4 hours, via the nebulization method specific to their group.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves treatments for asthma or COPD, it's possible that you may need to continue your existing inhaled corticosteroids or biologic therapy if you are in the asthma group.

What data supports the effectiveness of the treatment Positive Airway Pressure + NAC for COPD?

Research shows that salbutamol, a component of the treatment, can improve lung function in patients with pulmonary emphysema, a condition related to COPD, by increasing vital capacity (the maximum amount of air a person can expel from the lungs after a maximum inhalation). This suggests it may help improve breathing in COPD patients as well. ^{1 2 3 4 5}

Is the combination of Positive Airway Pressure and NAC safe for humans?

The studies reviewed indicate that salbutamol (also known as albuterol or Ventolin) is generally safe and well-tolerated in humans when used for asthma and COPD. However, specific safety data for the combination of Positive Airway Pressure and N-acetylcysteine (NAC) for COPD is not directly available from these studies. ^{6 7 8 9 10}

How does the drug Albuterol and NAC differ from other COPD treatments?

The combination of Albuterol (a bronchodilator) and NAC (N-acetylcysteine, which helps thin mucus) is unique because it not only helps open the airways but also improves mucus clearance, potentially offering dual benefits for COPD patients. This differs from other treatments that primarily focus on either bronchodilation or anti-inflammatory effects. ^{2 5 8 11 12}

Research Team

John Fahy, MD, MS

Principal Investigator

Professor of Medicine

Eligibility Criteria

Adults aged 18-85 with asthma or COPD, who are current/former smokers (COPD group) and have a history of using inhaled corticosteroids or biologic therapy for asthma. Participants must be able to perform spirometry tests and have a CT mucus score ≥3. Pregnant individuals or those with recent upper respiratory infections are excluded.

Inclusion Criteria

My asthma severity varies, but I can tolerate treatments without major lung function loss.

COPD Group: Written informed consent obtained from subject and ability for subject to comply with the requirements of the study

I have COPD and either have mucus plugging with no FEV1 limit or unknown plugging with FEV1<50%.

Exclusion Criteria

Currently pregnant

A history of medical disease, which in the opinion of the investigator may put the subject at extra risk from study-related procedures or because the disease may influence the results of the study

I have had an upper respiratory infection in the last 10 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive aerosolized NAC with or without positive inspiratory pressure over 5 treatment visits

4 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Albuterol
• Hillrom-Volara System
• NAC

Trial Overview The trial is testing if inhaling N-Acetylcysteine (NAC) combined with albuterol through positive pressure improves mucus clearance and lung function in patients compared to standard NAC inhalation without pressure. It's single-blind, meaning participants won't know which treatment they're getting.

Participant Groups

Group I: NAC via AeroEclipse-VersaPAP Experimental Treatment 2 Interventions

NAC (trade name: Mucomyst) is manufactured by American Regent. The active drug studied here is 10% NAC coadministered with albuterol and delivered via the AeroEclipse-VersaPAP system. Participants will each complete 5 treatment visits over the course of 30 days. Each treatment visit will consist of two treatments separated by 4 hours.

Group II: NAC via jet nebulizer Active Control 1 Intervention

NAC (trade name: Mucomyst) is manufactured by American Regent. The active drug studied here is 10% NAC coadministered with albuterol and delivered via standard jet nebulizer. Participants will each complete 5 treatment visits over the course of 30 days. Each treatment visit will consist of two treatments separated by 4 hours.

Albuterol is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Albuterol for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Exercise-induced bronchospasm

Approved in European Union as Salbutamol for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Exercise-induced bronchospasm

Approved in Canada as Salbutamol for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Exercise-induced bronchospasm

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 20 patients with pulmonary emphysema, inhaling 400 micrograms of salbutamol led to a significant increase in vital capacity (VC) and a reduction in residual volume, indicating improved lung function.

14 out of 20 patients reported symptomatic improvement after using salbutamol, suggesting it is an effective treatment option for enhancing respiratory function in emphysema, with VC being a better measure of response than the FEV1/VC ratio.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of salbutamol aerosol on lung function in patients with pulmonary emphysema. Bellamy, D., Hutchison, DC.[2019]

In a 3-year study involving 6112 patients with moderate to severe COPD, inhaled salmeterol plus fluticasone propionate (SFC) significantly improved lung function (FEV1) and reduced exacerbation rates across all GOLD stages, with the most notable improvement in patients with moderate COPD (GOLD stage II).

SFC treatment was associated with a 33% reduction in mortality risk for patients with GOLD stage II COPD, indicating its potential as an effective treatment option, while the incidence of adverse events, including pneumonia, was similar across treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Jenkins, CR., Jones, PW., Calverley, PM., et al.[2022]

In a 12-month study involving 1016 COPD patients, treatment with the fixed-dose combination of salmeterol and fluticasone propionate (SFC) significantly improved lung function (FEV1) and dyspnea scores, regardless of the presence of comorbidities.

Patients without comorbidities experienced greater improvements in lung function compared to those with comorbidities, but both groups showed statistically significant benefits, indicating the efficacy of SFC in managing COPD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Clinical Effectiveness of the Salmeterol/Fluticasone Fixed-Dose Combination Delivered via the Elpenhaler&#174; Device in Greek Patients with Chronic Obstructive Pulmonary Disease and Comorbidities: The AEOLOS Study. Steiropoulos, P., Tryfon, S., Kyriakopoulos, C., et al.[2021]

In a study involving 58 patients with chronic airflow obstruction, controlled release salbutamol (SCR) showed a small but significant improvement in lung function measured by FEV1, with a net change of 95 ml compared to placebo after 6 weeks.

Despite some favorable trends in other measurements, the overall benefits of SCR in improving lung function were minimal, suggesting limited clinical significance for patients with stable non-reversible chronic airflow obstruction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of controlled-release salbutamol in predominantly non-reversible chronic airflow obstruction. Mohammed, AF., Anderson, K., Matusiewicz, SP., et al.[2019]

In a study involving 365 patients with COPD over 8 weeks, fluticasone propionate/salmeterol was found to be more effective than ipratropium bromide/albuterol in improving lung function and reducing symptoms, including morning pre-dose FEV(1) and nighttime awakenings.

Both treatments had similar safety profiles, but fluticasone propionate/salmeterol was associated with a higher incidence of oral candidiasis, indicating a potential side effect to monitor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A short-term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD. Donohue, JF., Kalberg, C., Emmett, A., et al.[2019]

In a study involving 423 patients with mild to moderate asthma, both CFC and HFA formulations of salbutamol were found to be equally effective in improving lung function and managing asthma symptoms over a 4-week period.

Both inhaler formulations were well tolerated by patients, indicating that the HFA 134a pMDI is a safe alternative to the CFC pressurized metered dose inhaler for delivering salbutamol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Equivalence of as-required salbutamol propelled by propellants 11 and 12 or HFA 134a in mild to moderate asthmatics. German Study Group. Baumgarten, CR., Dorow, P., Weber, HH., et al.[2018]

In a study involving 24 asthmatic patients, both HFA 134a salbutamol sulfate and CFC 11/12 salbutamol showed equivalent improvements in lung function (FEV1 and FVC) after inhalation, indicating similar efficacy.

The safety profiles of both medications were comparable, with no significant differences in heart rate, blood pressure, or adverse events, suggesting that HFA 134a salbutamol sulfate is a safe alternative to CFC 11/12 salbutamol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cumulative dose-response study of non-CFC propellant HFA 134a salbutamol sulfate metered-dose inhaler in patients with asthma. Kleerup, EC., Tashkin, DP., Cline, AC., et al.[2019]

Fluticasone propionate/salmeterol (Advair) is an effective treatment for chronic obstructive pulmonary disease (COPD), improving lung function, reducing symptoms, and enhancing quality of life for some patients.

This combination inhaler not only acts as a potent bronchodilator but also helps decrease the frequency of exacerbations in patients with more severe COPD, although careful patient selection is important for optimal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluticasone propionate/salmeterol for the treatment of chronic-obstructive pulmonary disease. Dransfield, MT., Bailey, WC.[2019]

Inhalation of salbutamol (100 microg) significantly protects against bronchoconstriction induced by methacholine in patients with moderate asthma, regardless of the inhalation device used (pMDI, pMDI + spacer, or Autohaler).

While there was a slight trend suggesting that using a pMDI with a spacer may enhance the protective effect of salbutamol, the differences among the inhalation techniques were not statistically significant, confirming the drug's efficacy across various methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The protective effect of salbutamol inhaled using different devices on methacholine bronchoconstriction. Giannini, D., Di Franco, A., Bacci, E., et al.[2019]

In a study of 209 adults with COPD, nebulized levalbuterol (both 0.63 mg and 1.25 mg) showed significant improvements in lung function (FEV1) compared to placebo, indicating its efficacy as a bronchodilator.

Levalbuterol was generally well tolerated, with a lower rate of rescue medication use compared to racemic albuterol, and fewer withdrawals due to COPD exacerbations, suggesting it may offer better clinical control for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the efficacy and safety of levalbuterol in subjects with COPD. Donohue, JF., Parsey, MV., Andrews, C., et al.[2019]

Eliminating exposure to irritants like tobacco smoke is the most effective measure for improving outcomes in COPD, as regular medication is not necessary for patients without recurrent symptoms.

Long-acting beta-2 agonists, such as salmeterol and formoterol, significantly reduce breathlessness and acute exacerbations in moderate to severe COPD, preventing about two hospital admissions per 100 patients treated for 7 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic obstructive pulmonary disease: Useful medications for patients with recurrent symptoms. [2019]

In a study involving 10 patients with chronic obstructive airway disease (COAD), inhaled salbutamol, ipratropium bromide, and beclomethasone dipropionate did not significantly improve mucociliary clearance compared to a placebo.

Although two patients showed some improvement with salbutamol, overall, the results indicated that a single dose of these inhaled medications does not appreciably enhance mucociliary function in COAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of single inhalation of a salbutamol, ipratropium bromide and beclomethasone on mucociliary clearance in patients with chronic obstructive airway disease. Guleria, R., Singh, TR., Sinha, S., et al.[2016]

References

1. England pubmed.ncbi.nlm.nih.gov

The effects of salbutamol aerosol on lung function in patients with pulmonary emphysema. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Evaluation of the Clinical Effectiveness of the Salmeterol/Fluticasone Fixed-Dose Combination Delivered via the Elpenhaler&#174; Device in Greek Patients with Chronic Obstructive Pulmonary Disease and Comorbidities: The AEOLOS Study. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Effect of controlled-release salbutamol in predominantly non-reversible chronic airflow obstruction. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

A short-term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Equivalence of as-required salbutamol propelled by propellants 11 and 12 or HFA 134a in mild to moderate asthmatics. German Study Group. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Cumulative dose-response study of non-CFC propellant HFA 134a salbutamol sulfate metered-dose inhaler in patients with asthma. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Fluticasone propionate/salmeterol for the treatment of chronic-obstructive pulmonary disease. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

The protective effect of salbutamol inhaled using different devices on methacholine bronchoconstriction. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Evaluation of the efficacy and safety of levalbuterol in subjects with COPD. [2019]

11. France pubmed.ncbi.nlm.nih.gov

Chronic obstructive pulmonary disease: Useful medications for patients with recurrent symptoms. [2019]

12. India pubmed.ncbi.nlm.nih.gov

Effect of single inhalation of a salbutamol, ipratropium bromide and beclomethasone on mucociliary clearance in patients with chronic obstructive airway disease. [2016]