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

Trial Summary

What is the purpose of this trial?

The investigators are studying the effects of exposure to diesel exhaust on lung inflammation in the presence and absence of an inhaled corticosteroid. Although data is mixed, studies show that asthmatics have increased lung inflammation and worse symptoms during periods of higher air pollution despite taking their anti-inflammatory corticosteroid medication. One possible reason is that air pollution exposure may decrease the ability of corticosteroids to combat inflammation. To test this volunteers will inhale either a placebo or a corticosteroid, before sitting in an exposure booth for 2 hours breathing either filtered air or diluted diesel exhaust. Samples will be collected before and after exposure to analyze the effects of budesonide and diesel exhaust exposure.

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 data supports the effectiveness of the drug Budesonide for glucocorticoid resistance?

Research shows that Budesonide, when inhaled, can effectively reduce the need for oral steroids in asthma patients, improving breathing and reducing symptoms like coughing and breathlessness. It also has a favorable safety profile, making it a good option for managing conditions that require corticosteroids. ^{1 2 3 4 5}

What makes the drug Budesonide unique for treating glucocorticoid resistance?

Budesonide is unique because it is an inhaled corticosteroid that can reduce the need for oral glucocorticosteroids in asthma patients, offering a targeted anti-inflammatory effect with fewer systemic side effects. It is administered via inhalers or nebulizers, making it suitable for both adults and children with asthma. ^{1 2 3 4 6}

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

Eligibility Criteria

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

Pregnancy or breastfeeding

Your methacholine PC20 level is higher than 16.

I have a heart condition or irregular heartbeat.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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, 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 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]

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]

References

1. United States 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. [2019]

2. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Clinicomorphological assessment of budesonide efficiency in patients with bronchial asthma]. [2006]

3. England pubmed.ncbi.nlm.nih.gov

Once-daily inhaled budesonide for the treatment of asthma: clinical evidence and pharmacokinetic explanation. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. England 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. [2023]

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

Once-daily budesonide inhalation suspension in infants and children or = 4 years of age with persistent asthma. [2019]