Diesel Exhaust + Corticosteroids for Glucocorticoid Resistance

(DIGR Trial)

Overseen By Parteek (PJ) Johal, BCS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of British Columbia

Must not be taking: Antihistamines, NSAIDs, Corticosteroids, others

Disqualifiers: Smoking, Pregnancy, Cardiac condition, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 4 visits

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how diesel exhaust affects people with asthma, particularly when using the common asthma medication budesonide (a corticosteroid). Researchers aim to determine if pollution hinders the medication's ability to reduce lung inflammation, worsening asthma symptoms. Participants will breathe either filtered air or diesel exhaust after taking a placebo or budesonide, and researchers will observe lung reactions. This trial suits adults with asthma who are not currently using certain medications like corticosteroids or antihistamines and do not smoke or vape. As a Phase 4 trial, this research helps clarify how an already FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

Yes, you will need to stop taking regular anti-histamines, NSAIDs, corticosteroids, or other controller medications to participate in this trial.

What is the safety track record for budesonide?

Research has shown that budesonide, when used as an inhaler, is generally safe. Some studies report mild side effects, such as skin or eye irritation, but these are usually not serious for most users.

Conversely, studies indicate that diesel exhaust can worsen lung inflammation, particularly in individuals with asthma. This suggests that while budesonide is typically safe, exposure to diesel exhaust might increase lung irritation or worsen symptoms, even when using the medication.

Overall, the common use and approval of budesonide for other conditions support its safety. However, caution is advised if there is exposure to diesel exhaust. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the budesonide treatment in this trial because it tackles glucocorticoid resistance in a novel way, especially in environments with diesel exhaust exposure. Unlike standard treatments that may not address the inflammatory effects of pollutants effectively, budesonide is a corticosteroid that could potentially counteract inflammation caused by air pollution. Its use in this setting could lead to improved outcomes for individuals exposed to diesel exhaust, which is a common urban pollutant. This approach could redefine how we manage respiratory conditions in polluted environments, offering a targeted solution where standard treatments might fall short.

What evidence suggests that this trial's treatments could be effective for glucocorticoid resistance?

Research has shown that budesonide can help reduce lung inflammation. Many people with asthma use inhaled medications like budesonide to manage their symptoms. However, exposure to air pollution, such as diesel exhaust, might reduce the effectiveness of these medications. This trial will compare different scenarios: some participants will receive budesonide and be exposed to diesel exhaust, while others will receive budesonide and be exposed to filtered air. Additional groups will receive a placebo with either diesel exhaust or filtered air. Early findings suggest that while budesonide can help, its effectiveness may decrease when people are exposed to high levels of pollution. ^{2 6 7 8 9}

Who Is on the Research Team?

Chris Carlsten, MD

Principal Investigator

University of British Columbia

Christopher F Rider, PhD

Principal Investigator

University of British Columbia

Robert Newton, PhD

Principal Investigator

University of Calgary

Are You a Good Fit for This Trial?

This trial is for adults aged 19-49 with physician-diagnosed asthma, confirmed through various tests and questionnaires. Participants must not have a relevant heart condition, be pregnant or breastfeeding, use certain medications regularly, have a high body mass index (>35), smoke or vape, or be on corticosteroids in the past 6 months.

Inclusion Criteria

My asthma has been confirmed by tests and doctor's evaluation.

I am between 19 and 49 years old.

Exclusion Criteria

Your methacholine PC20 level is higher than 16.

Pregnancy or breastfeeding

Currently participating in another study that may interfere with this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants inhale either a placebo or budesonide and are exposed to filtered air or diesel exhaust in a controlled environment

4 visits

4 visits (in-person)

Sample Collection and Analysis

Blood samples, bronchoalveolar lavage, bronchial washes, bronchial brushes, and tissue biopsies are collected for analysis of gene expression and epigenetic endpoints

6 hours post-exposure

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Budesonide

Trial Overview The study examines how diesel exhaust affects lung inflammation and if it reduces the effectiveness of an inhaled corticosteroid (Budesonide) in asthmatics. Volunteers will inhale either placebo or Budesonide before spending two hours breathing filtered air or diluted diesel exhaust to assess changes.

How Is the Trial Designed?

Group I: Budesonide and Diesel Exhaust Experimental Treatment 2 Interventions

Volunteers will inhale 1.6mg of budesonide before sitting in a booth and being exposed to 300µg/m³ concentration of diesel exhaust for 2 hours.

Group II: Placebo and Diesel Exhaust Active Control 2 Interventions

Volunteers will use an inhaler that does not contain any medication, before sitting in a booth and being exposed to 300µg/m³ concentration of diesel exhaust for 2 hours.

Group III: Budesonide and Filtered Air Active Control 2 Interventions

Volunteers will inhale 1.6mg of budesonide before sitting in a booth and being exposed to HEPA filtered air for 2 hours.

Group IV: Placebo and Filtered Air Placebo Group 2 Interventions

Volunteers will use an inhaler that does not contain any medication, before sitting in a booth and being exposed to high-efficiency particulate air (HEPA) filtered air for 2 hours.

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

Approved in European Union as Pulmicort for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Allergic rhinitis
• Crohn's disease
• Ulcerative colitis
• Microscopic colitis
• Eosinophilic esophagitis
• Primary immunoglobulin A nephropathy

Approved in United States as Entocort EC for:

• Crohn's disease
• Ulcerative colitis
• Primary immunoglobulin A nephropathy
• Eosinophilic esophagitis

Approved in Canada as Pulmicort for:

• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Allergic rhinitis

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

AllerGen NCE Inc.

Industry Sponsor

Trials

9

Recruited

380+

Published Research Related to This Trial

Budesonide, an inhalation glucocorticosteroid, significantly improved asthma symptoms in 20 patients, showing a response by the end of the first week of treatment, with a notable reduction in acute asthma episodes and decreased reliance on short-acting beta 2-agonists.

After 12 months of treatment, budesonide improved lung function, as indicated by a 31% reduction in peak expiratory velocity variability, but did not fully normalize the bronchial mucosa, suggesting that longer treatment may be necessary for complete recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinicomorphological assessment of budesonide efficiency in patients with bronchial asthma]. Budkova, AA., Volkova, LI., Budkov, SR., et al.[2006]

A review of 34 controlled clinical studies involving 4466 adults and adolescents, and 1532 children with asthma shows that once-daily budesonide is as effective as twice-daily regimens for treating mild-to-moderate asthma.

Budesonide is well tolerated and simplifies treatment regimens, potentially improving patient compliance, making it a suitable option for both initial and maintenance therapy in asthma management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily inhaled budesonide for the treatment of asthma: clinical evidence and pharmacokinetic explanation. Selroos, O., Edsbäcker, S., Hultquist, C.[2019]

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]

In a study involving 159 adults with moderate-to-severe asthma, budesonide delivered via an inhaler significantly reduced the need for oral glucocorticosteroids (GCSs) by 79-83% compared to only 27% in the placebo group, indicating its efficacy in managing asthma while minimizing systemic steroid use.

Approximately two-thirds of participants using budesonide were able to completely stop oral corticosteroids, and they also experienced improvements in lung function and asthma symptoms, suggesting that budesonide not only spares oral GCSs but also maintains or enhances asthma control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral glucocorticosteroid-sparing effect of budesonide administered by Turbuhaler: a double-blind, placebo-controlled study in adults with moderate-to-severe chronic asthma. Pulmicort Turbuhaler Study Group. Nelson, HS., Bernstein, IL., Fink, J., et al.[2019]

Budesonide inhalation suspension significantly improves both nighttime and daytime asthma symptoms in children under 4 years and those 4 years and older, based on a retrospective analysis of two randomized studies involving children aged 6 months to 8 years.

The treatment is generally safe, with no significant differences in adverse events between age groups, although a notable effect on hypothalamic-pituitary-adrenal-axis function was observed in younger children at the lowest dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily budesonide inhalation suspension in infants and children or = 4 years of age with persistent asthma. Scott, MB., Ellis, MH., Cruz-Rivera, M., et al.[2019]

In a study of 71 patients, budesonide-MMX demonstrated a significantly better safety profile compared to methylprednisolone, with only 1.9% experiencing glucocorticoid-related adverse events compared to 47.4% in the methylprednisolone group.

The efficacy of budesonide-MMX was influenced by the CYP3A5 genotype, suggesting that genetic factors may play a role in how well patients respond to this treatment, although further research is needed to explore this relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible genetical predictors of efficacy and safety of budesonide-MMX in patients with mild-to-moderate ulcerative colitis, and safety comparison with methylprednisolone. Resál, T., Mangó, K., Bacsur, P., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03615742?tab=table

Diesel Exhaust Induces Glucocorticoid Resistance The investigators are studying the effects of exposure to diesel exhaust on lung inflammation in the presence and absence of an inhaled corticosteroid. Although ...

2. clinicaltrial.be clinicaltrial.be/en/details/67797?per_page=100&only_recruiting=1&only_eligible=0&only_active=0

Diesel Exhaust Induces Glucocorticoid Resistance Correlational data indicate that exposure to air pollution increases inhaled corticosteroids (ICS) use in asthmatics, suggesting that steroidal ...

3. ctv.veeva.com ctv.veeva.com/study/diesel-exhaust-induces-glucocorticoid-resistance

Diesel Exhaust Induces Glucocorticoid Resistance (DIGR) The investigators are studying the effects of exposure to diesel exhaust on lung inflammation in the presence and absence of an inhaled ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8471691/

Oxidative Stress Promotes Corticosteroid Insensitivity in ... In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses.

5. clinconnect.io clinconnect.io/trials/NCT03615742

Diesel Exhaust Induces Glucocorticoid Resistance - ClinConnect The investigators are studying the effects of exposure to diesel exhaust on lung inflammation in the presence and absence of an inhaled corticosteroid.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9207822/

Intranasal budesonide for rhinitis during a high airborne ... One study was able to observe that concomitant exposure to environmental pollutants, such as diesel exhaust particles, and house dust mites may ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3260803/

Diesel Exhaust Particulates Exacerbate Asthma-Like ... These results demonstrate that DEP exacerbates airway inflammation induced by allergen through increased pulmonary expression of the CXC chemokines.

8. publications.ersnet.org publications.ersnet.org/content/erj/17/5/909

Diesel exhaust enhances airway responsiveness in asthmatic ... This study indicated that short-term exposure to diesel exhaust, equal to high ambient levels of particulate matter, is associated with adverse effects in ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04342039

NCT04342039 | Epigenetic Health Benefits of Budesonide Exposure to allergens such as dust mites and pollen, as well as air pollutants such as diesel exhaust particulates, can alter the ability of critical genes ...