Roflumilast in Non-CF Bronchiectasis Study (2019)

NCT04322929 | Completed Phase 2

• 1 other identifier: ROF2019_v2
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-arm, open label, Phase II study of 12-week use of Roflumilast in stable-state non-cystic fibrosis bronchiectasis subjects. Bronchiectasis refers to a suppurative lung condition characterized by pathological dilatation of bronchi. The predominant aetiology of bronchiectasis in the Western population is related to cystic fibrosis (CF), which is genetically determined. Bronchiectasis due to other causes are generally grouped under the term "non-CF bronchiectasis", which accounts for practically all cases that are seen commonly in Hong Kong and many other Chinese populations. The main pathogenesis of non-CF bronchiectasis involves airway inflammation, abnormal mucus clearance and bacterial colonization, resulting in progressive airway destruction and distortion. This destructive process perpetuates in a vicious circle even when the initial insult has subsided, which is commonly due to an infective process like tuberculosis in Hong Kong. Patients with extensive bronchiectasis present with chronic cough, copious purulent sputum, haemoptysis, progressive lung function loss, and episodes of infective exacerbations. The current treatment strategies mainly focus on targeting the key elements in the pathogenesis of non-CF bronchiectasis. Apart from regular chest physiotherapy and postural drainage to help clearing mucus from bronchiectatic airways, inhalational and parenteral antibiotics have also been used to reduce the bacterial load in destroyed airways, thus controlling and preventing infective exacerbations. In recent years, accumulated evidence has suggested a central role of airway inflammation and immune dysregulation in the evolution of non-CF bronchiectasis. Chronic obstructive pulmonary disease (COPD) is a progressive destructive process on exposure to noxious environmental agents (e.g. tobacco smoke) that affects both the airways (chronic bronchitis) and lung parenchyma (emphysema), leading to loss of lung function and exercise capacity. Both COPD and bronchiectasis share similarities in clinical presentation and pathogenetic mechanisms. Neutrophilic inflammation and bacterial colonization are also the cornerstone in the airways of patients with COPD. Roflumilast, a phosphodiesterase 4 (PDE4) inhibitor, has demonstrated anti-inflammatory activity in COPD resulting in reduction in exacerbation frequency. This is the first-in-class and the only one clinically available PDE4 inhibitor that is approved worldwide (including Hong Kong) for treatment of severe COPD with frequent exacerbations. At the time of writing, the exact role and clinical evidence for roflumilast in dampening airway inflammation in non-CF bronchiectasis is still lacking. Given the common pathogenetic mechanism via neutrophilic inflammation between non-CF bronchiectasis and COPD, as well as the robust clinical activity of roflumilast in COPD, this study is designed to provide initial scientific evidence on the activity of roflumilast on neutrophilic airway inflammation in patients with stable-state non-CF bronchiectasis. This study aims to investigate the effect of 12-week treatment with roflumilast on neutrophilic airway inflammation in stable-state non-CF bronchiectasis.

Conditions

Non-cystic Fibrosis Bronchiectasis

Keywords

24-hour sputum volume; Roflumilast

Outcome Measures

Primary Outcomes (1)

• 24-hour sputum volume

  Daily sputum volume is determined as the average of a three consecutive day collection (9:00 a.m. to 9:00 a.m.) at home, using clear pre-labeled sterile plastic (60 ml) pots stored at 4°C. Subjects are instructed and trained to completely empty the contents of their mouth before expectorating into the sputum pots to ensure minimal contamination by saliva and food debris. The volume of a 24-hour sputum specimen is determined as the volume of water (to the nearest 0.1 ml) in an adjacent identical pot containing water at the same level as the sputum in the sputum-containing pot.

  Reduction in 24-h sputum volume in 12 weeks

Secondary Outcomes (5)

• Sputum leukocyte density

  Reduction in sputum leukocyte density in 12 weeks

• Sputum pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, and IL-17) and LTB4

  Reduction in sputum pro-inflammatory cytokines in 12 weeks

• Sputum neutrophil elastase

  Reduction in sputum neutrophil elastase in 12 weeks

• Sputum bacterial colonization and load

  No change in sputum bacterial colonization and load in 12 weeks

• Health-related quality of life (HRQoL)

  Improvement in HRQoL in 12 weeks

Study Arms (1)

Oral roflumilast

EXPERIMENTAL

Oral roflumilast 250 microgram daily will be started at the baseline visit for 4 weeks. For those who can tolerate the initial 4-week treatment, roflumilast will be increased to 500 microgram daily, allowing subsequent dose reduction back to 250 microgram daily in case of CTCAE grade 3 or 4 toxicities.

Drug: Roflumilast Oral Tablet

Interventions

Roflumilast Oral Tablet DRUG

Roflumilast, a phosphodiesterase 4 (PDE4) inhibitor is approved worldwide (including Hong Kong) for treatment of severe chronic obstructive pulmonary disease (COPD) with frequent exacerbations. Roflumilast has been shown to have anti-inflammatory effect in patients with COPD, with significant reduction of sputum absolute neutrophil count, IL-8 and neutrophil elastase compared with placebo treatment. Roflumilast can also improve the lung function parameters in patients with COPD and reduce the rate of moderate-to-severe exacerbations.

Also known as: Daxas

Oral roflumilast

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 18 years or above, male or female.
• Never-smokers or those who have smoked less than 100 cigarettes in their lifetime.
• Confirmed diagnosis of non-CF bronchiectasis based on high-resolution computed tomography (HRCT) scan.
• Significant sputum production (≥ 10 ml per day).
• In stable-state bronchiectasis with no change in regular medications (e.g. inhaled steroid, macrolide) or exacerbations in the past 3 months.
• Written informed consent obtained.

You may not qualify if:

• Eversmokers (≥ 100 cigarettes in their lifetime).
• Known chronic obstructive pulmonary disease or asthma.
• Moderate to severe liver impairment (Child-Pugh B or C).
• Known psychiatric illness with increased suicidal risks.
• Body-mass index below 18 kg/m2.
• Concomitant use of strong cytochrome P450 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin).
• Patients who are hypersensitive to roflumilast or its constituents.
• Pregnant or lactating women.

Sponsors & Collaborators

• The University of Hong Kong: lead

Study Sites (1)

Queen Mary Hospital

Hong Kong, Hong Kong

Location

MeSH Terms

Interventions

Roflumilast

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Associate Professor

Study Record Dates

• First Submitted: March 24, 2020
• First Posted: March 26, 2020
• Study Start: November 12, 2020
• Primary Completion: June 30, 2024
• Study Completion: November 30, 2024
• Last Updated: December 9, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

HK (1)