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Roflumilast in Non-CF Bronchiectasis Study (2019)

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ClinicalTrials.gov Identifier: NCT04322929
Recruitment Status : Not yet recruiting
First Posted : March 26, 2020
Last Update Posted : March 26, 2020
Sponsor:
Information provided by (Responsible Party):
James Chung-Man HO, The University of Hong Kong

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.


Condition or disease Intervention/treatment Phase
Non-cystic Fibrosis Bronchiectasis Drug: Roflumilast Oral Tablet Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Anti-inflammatory Effects of Roflumilast Treatment for 12 Weeks in Stable-state Non-cystic Fibrosis Bronchiectasis
Estimated Study Start Date : April 30, 2020
Estimated Primary Completion Date : February 28, 2022
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Roflumilast

Arm Intervention/treatment
Experimental: Oral roflumilast
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
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.
Other Name: Daxas




Primary Outcome Measures :
  1. 24-hour sputum volume [ Time Frame: Reduction in 24-h sputum volume in 12 weeks ]
    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.


Secondary Outcome Measures :
  1. Sputum leukocyte density [ Time Frame: Reduction in sputum leukocyte density in 12 weeks ]
    A fresh sputum sample is collected in a sterile clear plastic pot after thorough mouth emptying on the day of planned clinic visit. Sputum leukocyte density is measured within 2 hours of collection by a designated technician, based on five aliquots chosen randomly from the center of a fresh specimen, which are then serially diluted with phosphate-buffered saline (PBS) and read with a light microscope and a hemocytometer as we previously described.

  2. Sputum pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, and IL-17) and LTB4 [ Time Frame: Reduction in sputum pro-inflammatory cytokines in 12 weeks ]
    Fresh sputum sample is stored at −70° C within 15 min of collection until ultracentrifugation (100,000 g for 30 min at 4° C) to obtain the sol phase used for enzyme-linked immunoabsorbent assay of cytokines (IL-1β, IL-8, TNF-alpha, IL-17) and LTB4 levels using commercially available kits.

  3. Sputum neutrophil elastase [ Time Frame: Reduction in sputum neutrophil elastase in 12 weeks ]
    Sputum neutrophil elastatse is measured using a commercially available kinetic, chromogenic microtitre plate assay with succinyl-Ala-Ala-Pro-Val-p-nitroanalide (Bachem) as a substrate, as we previously described. A standard curve, constructed from known concentrations of purified elastase, is included in each assay.

  4. Sputum bacterial colonization and load [ Time Frame: No change in sputum bacterial colonization and load in 12 weeks ]
    Sputum for bacterial culture is saved and sputum bacterial load is measured at designated visits as described previously with modifications.

  5. Health-related quality of life (HRQoL) [ Time Frame: Improvement in HRQoL in 12 weeks ]
    Patients' HRQoL will be measured by St. George's Respiratory Questionnaire Hong Kong Chinese version (SGRQ-HK). SGRQ-HK is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airway disease. It consists of 2 parts with 50 items. It addresses frequency and severity patients' symptoms, as well as activities that cause or are limited by breathlessness. The scores range from 0 to 100, with higher scores indicating more limitations. The minimally important difference is a mean change of 4 units for slightly efficacious treatment, 8 units for moderately efficacious change and 12 units for very efficacious treatment. SGRQ-HK has been validated in patients with bronchiectasis and is considered a valid and sensitive instrument for determining quality of life in bronchiectasis patients.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04322929


Contacts
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Contact: James CM Ho, MD 852-2255 4999 jhocm@hku.hk

Locations
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Hong Kong
Queen Mary Hospital
Hong Kong, Hong Kong
Sponsors and Collaborators
The University of Hong Kong

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Responsible Party: James Chung-Man HO, Clinical Associate Professor, The University of Hong Kong
ClinicalTrials.gov Identifier: NCT04322929    
Other Study ID Numbers: ROF2019_v2
First Posted: March 26, 2020    Key Record Dates
Last Update Posted: March 26, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by James Chung-Man HO, The University of Hong Kong:
24-hour sputum volume
Roflumilast
Additional relevant MeSH terms:
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Bronchiectasis
Fibrosis
Pathologic Processes
Bronchial Diseases
Respiratory Tract Diseases
Anti-Inflammatory Agents