Budesonide + Azithromycin for Laryngeal Injury after Intubation

Overseen By Anne S Lowery, BA

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vanderbilt University Medical Center

Must not be taking: QTc prolonging drugs

Disqualifiers: Neck trauma, Head/neck malignancies, COPD, others

Compensation: Varies

Number of Visits: 5

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore the frequency of throat injuries after using a breathing machine and how certain medicines might help. Researchers are examining the effects of azithromycin, an antibiotic, and budesonide, an anti-inflammatory, on breathing problems caused by these injuries. Participants will receive either the treatment or a placebo for comparison. Those who spent more than a day but less than a week on a ventilator in the ICU and do not have pre-existing conditions like asthma or COPD might be suitable candidates. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical research.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on medications that prolong the QTc interval or are associated with Torsades de pointes (except amiodarone), you may not be eligible to participate.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking medications that prolong the QTc interval (a heart rhythm measurement), you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that azithromycin and budesonide are usually well-tolerated, but some concerns exist. Azithromycin can sometimes cause serious side effects, such as heart rhythm problems and liver issues. Budesonide, often used for asthma, is generally safe but may cause side effects like throat irritation or coughing. However, no specific safety information exists for using these two drugs together to treat laryngeal injury. As this trial is in its early stages, researchers are closely studying the safety of this combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Budesonide and Azithromycin for laryngeal injury after intubation because it offers a novel approach to healing. Unlike the usual treatments that often focus on symptomatic relief, this combination aims to reduce inflammation and bacterial infection simultaneously, potentially speeding up recovery. Budesonide is a corticosteroid that targets inflammation directly at the site, while Azithromycin adds an antibacterial effect, which could help prevent secondary infections. This dual-action treatment could lead to faster and more effective healing compared to the standard care options available.

What evidence suggests that this trial's treatments could be effective for laryngeal injury after intubation?

This trial will test the combination of budesonide and azithromycin to determine if they can improve breathing after using a breathing tube. Research has shown that budesonide reduces swelling and eases symptoms in people with asthma, while azithromycin also reduces swelling. Early results suggest that this combination might ease breathing and improve breathing test results. Participants in this trial will receive either the combination of budesonide and azithromycin or a placebo control. ^{1 2 3 4 6}

Who Is on the Research Team?

Alexander Gelbard, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

This trial is for English-speaking adults who've been intubated in the ICU for 24 hours to 7 days. It's not for those under 18, pregnant/breastfeeding individuals, patients unable to consent, with certain heart conditions or severe hearing loss, neck trauma, head/neck cancers, expected early discharge post-extubation, dependent on others pre-admission, with pre-existing airway or respiratory conditions like COPD or asthma, previous long-term intubation history, allergies to study drugs or a high resting heart rate.

Inclusion Criteria

I was on a breathing machine in the ICU for 1 to 7 days.

English-speaking

Exclusion Criteria

I am unable to give consent by myself.

My heart's electrical cycle is normal and I don't take QT-prolonging drugs, except amiodarone.

I have cancer in my head or neck.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Within 72 hours of extubation

1 visit (in-person)

Initial Examination

Routine medical examination of the larynx with flexible nasolaryngoscopy

1 week

1 visit (in-person)

Treatment

Randomized to receive azithromycin and budesonide or placebo for 14 days

2 weeks

1 visit (in-person), 1 visit (virtual)

Follow-up Examination

Repeat examination scheduled to assess the effects of treatment

12 weeks

1 visit (in-person)

Follow-up

Participants are monitored for chronic laryngeal injury and other outcomes

8-12 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin
• Budesonide
• Placebo control of budesonide and azithromycin

Trial Overview The trial aims to measure how common acute and chronic laryngeal injuries are after intubation and identify risk factors. It includes a randomized control test where some patients will receive Budesonide and Azithromycin while others get placebo controls. The goal is to see if these medications can improve breathing in patients with Acute Laryngeal Injury from intubation.

How Is the Trial Designed?

Group I: Medical Therapy Experimental Treatment 1 Intervention

medical therapy group consisting of azithromycin 250 mg and budesonide 0.5 mg for 14 days

Group II: Placebo Control Placebo Group 1 Intervention

Placebo control medication for 14 days

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

Approved in European Union as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in United States as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in Canada as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Published Research Related to This Trial

In a study of 30,512 individuals with rheumatoid arthritis (RA) treated with methotrexate (MTX), there was no increased risk of interstitial lung disease (ILD) or respiratory failure associated with MTX treatment over a 5-year follow-up period.

While individuals with RA had a higher risk of ILD compared to the general population, MTX treatment did not further elevate this risk, suggesting that MTX is safe regarding lung disease in RA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate and risk of interstitial lung disease and respiratory failure in rheumatoid arthritis: a nationwide population-based study. Ibfelt, EH., Jacobsen, RK., Kopp, TI., et al.[2021]

In a study of 25 patients with intrinsic asthma, treatment with budesonid for an average of 36 days led to a significant reduction in systemic corticosteroid dosage by nearly two-thirds, while improving asthma symptoms.

Budesonid treatment resulted in a 43% increase in plasma cortisol levels in 52% of patients, along with a 26% improvement in peak flow measurements, demonstrating its efficacy and safety with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of treatment with budesonide (Pulmicort) in corticosteroid-dependent intrinsic asthma]. Petri, E.[2013]

A nationwide survey involving 1113 doctors and 100,980 patients revealed that budesonide is commonly prescribed for croup, asthma, and COPD due to its established safety and efficacy, with safety being the most important factor for 78.7% to 91.0% of doctors.

Doctors often rely on their personal experience with budesonide over scientific recommendations, with 63.7% of croup patients receiving it as monotherapy, compared to only 13.5% of COPD patients, indicating varied prescribing patterns based on the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors affecting the choice of budesonide in the therapy of croup, asthma and chronic obstructive pulmonary disease. Olszanecka-Glinianowicz, M., Chudek, J., Urcus, A., et al.[2022]

Inhaled budesonide is a highly effective corticosteroid for treating asthma and COPD, with a favorable safety profile due to its unique properties that enhance airway selectivity and minimize systemic exposure.

The combination of budesonide with formoterol not only serves as a maintenance therapy but can also be used as a reliever medication with anti-inflammatory effects, marking a novel approach in asthma management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease. Tashkin, DP., Lipworth, B., Brattsand, R.[2020]

Budesonide, an inhaled corticosteroid for asthma, shows significant differences in lung deposition based on the inhaler device used, with only 15% reaching the lungs via a pressurized metered dose inhaler (pMDI) compared to 32% with a dry powder inhaler (DPI).

In patients with asthma, the pharmacokinetics of budesonide are dose-dependent, with a quick peak plasma concentration (Cmax) reached within 0.28 to 0.40 hours after inhalation, indicating effective absorption and a relatively short elimination half-life of about 3 hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of inhaled budesonide. Donnelly, R., Seale, JP.[2020]

In a 74-week study involving 575 rheumatoid arthritis patients treated with infliximab, adverse events (AEs) were most common in the first 26 weeks, with infusion reactions and infections being the leading causes for treatment discontinuation.

Older age was identified as a predictor for serious adverse events and infections, highlighting the need for careful monitoring of older patients receiving infliximab for rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

74-week follow-up of safety of infliximab in patients with refractory rheumatoid arthritis. Delabaye, I., De Keyser, F.[2021]

Long-term treatment with macrolides like azithromycin and erythromycin significantly reduces the number of acute exacerbations of COPD, with a minimum effective duration of 6 months based on a meta-analysis of 12 studies involving 2,151 cases.

While macrolide therapy improves some quality of life measures, it also increases the risk of adverse events and does not significantly reduce hospitalizations, indicating a need for careful consideration of risks versus benefits in long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term macrolide treatment for the prevention of acute exacerbations in COPD: a systematic review and meta-analysis. Cui, Y., Luo, L., Li, C., et al.[2022]

In a study of 128 patients with refractory chronic rhinosinusitis who had previously undergone endoscopic sinus surgery, low-dose azithromycin did not significantly improve overall disease clearance compared to placebo, but it did lead to better symptom improvements in those who did clear their disease.

For patients without aspirin-exacerbated respiratory disease (AERD), azithromycin showed a significant increase in disease clearance rates (71% vs 35% compared to placebo), suggesting it can be an effective treatment option for this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin in high-risk, refractory chronic rhinosinusitus after endoscopic sinus surgery and corticosteroid irrigations: a double-blind, randomized, placebo-controlled trial. Maniakas, A., Asmar, MH., Renteria, AE., et al.[2021]

In a study of 12 patients with chronic rhinosinusitis and asthma, nasal irrigation with budesonide significantly improved symptoms, as shown by a reduction in the SNOT-22 score from 30.8 to 14.2 after 6 months (P=0.030).

The use of budesonide nasal irrigation also led to a substantial decrease in the need for oral steroids, dropping from an average of 397.8 mg to 72.7 mg over the same period (P<0.001), indicating its effectiveness in managing the condition postoperatively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Budesonide Nasal Irrigation After Endoscopic Sinus Surgery in Chronic Rhinosinusitis With Asthma. Kang, TW., Chung, JH., Cho, SH., et al.[2020]

In a long-term study of 45 patients with rheumatoid arthritis treated with methotrexate (MTX) for over 3 years, 96% experienced adverse effects, leading to a 44% discontinuation rate over 176 weeks.

Despite the high frequency of adverse experiences, the study found no cases of hepatic or pulmonary fibrosis, and identified potential predictors of adverse effects, such as baseline white blood cell counts and creatinine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. Furst, DE., Erikson, N., Clute, L., et al.[2013]

In a study involving over 956,000 users of hydroxychloroquine, no short-term increased risk of severe adverse events was found when compared to sulfasalazine in patients with rheumatoid arthritis, suggesting it is safe for short-term use.

However, long-term use of hydroxychloroquine is associated with increased cardiovascular mortality, and the addition of azithromycin significantly raises the risk of heart failure and cardiovascular mortality even in the short term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study. Lane, JCE., Weaver, J., Kostka, K., et al.[2022]

A systematic review of 35 studies found no clear evidence linking methotrexate (MTX) treatment in rheumatoid arthritis (RA) patients to an increased risk of varicella zoster virus (VZV) infections or herpes zoster (HZ), suggesting that MTX is safe in this regard.

The data on the association between MTX and HZ is conflicting, with some studies showing no increased infection rates compared to other RA therapies, leading to a recommendation against routine pre-MTX VZV screening to avoid delaying RA treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review. Zhang, N., Wilkinson, S., Riaz, M., et al.[2018]

Azithromycin, an antibiotic with immunomodulatory effects, can significantly reduce the frequency of pulmonary exacerbations in patients with bronchiectasis and COPD, making it a suitable maintenance therapy for those with frequent exacerbations or declining lung function.

While azithromycin is generally well-tolerated, it should be used cautiously in patients with cardiovascular risks, and regular monitoring for potential side effects, including hearing loss and cardiac issues, is recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-term macrolide treatment in adult chronic bronchial diseases: benefits and limits]. Jouneau, S., Desrues, B.[2016]

In a study of 86 patients with acute exacerbation of COPD, inhaling ipratropium bromide and budesonide through a ventilator mask significantly reduced inflammatory markers (TNF-α, IL-6, CRP) compared to standard saline treatment.

The treatment with ipratropium bromide and budesonide also improved lung function and blood gas levels, leading to better clinical outcomes and shorter ventilation and treatment times compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of COPD in acute exacerbation period on circulating levels of inflammation and prognosis. Jiang, DH., Wang, X., Liu, LS., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6661707/

Early medical therapy for acute laryngeal injury (ALgI) ... In this study, we will examine the ability of a postextubation medical regime (azithromycin and inhaled budesonide) to improve breathing 12 weeks after ALgI.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03250975

Incidence of Acute Laryngeal Injury Following ... The second phase of this study will investigate the effects of azithromycin and budesonide to improve objective and subjective breathing measures in patients ...

3. withpower.com withpower.com/trial/phase-2-wounds-and-injuries-7-2017-b3770

Budesonide + Azithromycin for Laryngeal Injury after ... Budesonide has shown effectiveness in reducing inflammation and improving symptoms in asthma patients, while azithromycin has been effective in reducing ...

4. bmjopen.bmj.com bmjopen.bmj.com/content/bmjopen/9/7/e027963.full.pdf

Early medical therapy for acute laryngeal injury (ALgI) ... They will then take the azithromycin 250 mg and budesonide 0.5 mg 14 days. A. KSP will get in contact with the participants weekly to ensure ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31352415/

Early medical therapy for acute laryngeal injury (ALgI ... In this study, we will examine the ability of a postextubation medical regime (azithromycin and inhaled budesonide) to improve breathing 12 weeks after ALgI.

6. researchgate.net researchgate.net/publication/385975098_Evaluation_and_Treatment_of_Acute_Laryngeal_Injury_at_Time_of_Tracheostomy_for_Prolonged_Intubation

Evaluation and Treatment of Acute Laryngeal Injury at Time ... Abstract. Objectives: The primary objective was to assess incidence and severity of acute laryngeal injury (ALgI) following intubation.