Roflumilast in Non-CF Bronchiectasis Study (2019)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04322929|
Recruitment Status : Recruiting
First Posted : March 26, 2020
Last Update Posted : November 2, 2022
|First Submitted Date ICMJE||March 24, 2020|
|First Posted Date ICMJE||March 26, 2020|
|Last Update Posted Date||November 2, 2022|
|Actual Study Start Date ICMJE||November 12, 2020|
|Estimated Primary Completion Date||June 30, 2024 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||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.
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Roflumilast in Non-CF Bronchiectasis Study (2019)|
|Official Title ICMJE||Anti-inflammatory Effects of Roflumilast Treatment for 12 Weeks in Stable-state Non-cystic Fibrosis Bronchiectasis|
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.
In a 4-week crossover study in 38 patients with COPD, roflumilast 500μg daily significantly reduced sputum absolute neutrophil count, IL-8 and neutrophil elastase compared with placebo treatment. Interestingly, the mechanism of anti-neutrophilic inflammation with roflumilast treatment in patients with COPD was recently found to be mediated through decreasing prolyl endopeptidase activity and acetyl-proline-glycine-proline (AcPGP), thus providing a clear biological plausibility for clinical activity of roflumilast. The clinical benefits of roflumilast treatment in COPD were subsequently demonstrated in 2 identical RCTs involving 3,096 patients with COPD having severe airflow limitation and history of exacerbations. Treatment with roflumilast 500μg daily resulted in better prebronchodilator FEV1 (by 48 ml in 52 weeks) and lower rate of exacerbations (reduction by 17%) compared with placebo treatment. The benefit of roflumilast on lung function has also been confirmed in another 2 identical RCTs among those patients with moderate to severe COPD already treated with long-acting bronchodilators (salmeterol or tiotropium). The mean pre-bronchodilator FEV1 was significantly improved with roflumilast compared to placebo treatment for 24 weeks by 49ml and 80ml respectively in patients with COPD already treated with salmeterol and tiotropium respectively. More recently, among patients with more severe COPD requiring combination ICS/long-acting β2 agonist, roflumilast treatment for 52 weeks significantly reduced the rate of moderate-to-severe exacerbations by 13.2% compared to placebo group. The safety and adverse effects of roflumilast have been well-tolerated, resulting in worldwide (including Hong Kong) approval for clinical use in COPD. The common adverse effects of roflumilast treatment include weight reduction (>10% loss in 7% subjects), decreased appetite (2%), insomnia (2%), headache (4%), diarrhea (10%) and nausea (5%).
Our group has previously embarked on various clinical studies in non-CF bronchiectasis: a 4-week treatment of inhaled fluticasone (ICS) compared with placebo (1), a subsequent 52-week randomized controlled trial of inhaled fluticasone in 86 patients (4), and a separate study on sputum elastase in 30 patients (2). These support the feasibility of conducting similar clinical trials, like the current proposal, on non-CF bronchiectasis in our unit. To prepare for the current study proposal, we have conducted a pilot and feasibility study of 4-week treatment of roflumilast in stable-state non-CF bronchiectasis with the exact inclusion/exclusion criteria as the current proposal (HKU/HA HKW IRB approval no. UW 17-444) since March 2018. Up to January 2019, we have successfully recruited 15 eligible study subjects. The initial study protocol mandated the starting dose of roflumilast at 500 microgram daily. The first two study subjects experienced intolerable gastrointestinal side effects within 1-2 weeks of treatment, leading to premature treatment cessation. An amended study protocol (HKU/HA HKW IRB approval dated 24 July 2018) was approved that allowed a lower initiating dose of 250 microgram daily, which is in line with the current recommended prescription in COPD patients. Nine out of the subsequent 13 subjects (including the most recent 8 subjects consecutively) were able to complete roflumilast 250 microgram daily treatment for a total of 4 weeks, with less than grade 1 toxicities. The characteristics of the nine per-protocol study subjects include: M:F=4:5, age of 69.9 ± 9.1 years (mean ± SD) and baseline 24-h sputum volume of 30.00 ± 26.93 ml (for all 15 subjects: 27.47 ± 22.59 ml). The preliminary results showed insignificant change in sputum volume and a trend of reduced sputum IL-1β (pre- vs post-treatment: 10.84 vs 2.63 ng/ml, p=0.102). This indicates a possible anti-inflammatory effect of roflumilast in non-CF bronchiectasis with just 4 weeks of treatment, though this pilot was meant for feasibility study and not powered to detect significant change. The true benefit will likely require a longer duration of treatment (thus proposing 12 weeks in this study) with sufficient sample size.
This study aims to investigate the effect of 12-week treatment with roflumilast on neutrophilic airway inflammation in stable-state non-CF bronchiectasis. The primary outcome measure is 24-h sputum volume. The extent of airway inflammation in non-CF bronchiectasis is indicated by sputum leukocyte density, pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, LTB4 and IL-17) and neutrophil elastase. Health-related quality of life (HRQoL) is a key secondary outcome. We hypothesize that 12-week treatment of roflumilast in stable-state non-CF bronchiectasis can result in: (1) reduction in 24-h sputum volume (primary hypothesis); (2) reduction in sputum leukocyte density; (3) reduction in sputum pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, and IL-17) and LTB4; (4) reduction in sputum neutrophil elastase; (5) no change in sputum bacterial colonization and load; (6) improvement in HRQoL.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Non-cystic Fibrosis Bronchiectasis|
|Intervention ICMJE||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
|Study Arms ICMJE||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.
Intervention: Drug: Roflumilast Oral Tablet
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||November 30, 2024|
|Estimated Primary Completion Date||June 30, 2024 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||Hong Kong|
|Removed Location Countries|
|NCT Number ICMJE||NCT04322929|
|Other Study ID Numbers ICMJE||ROF2019_v2|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||Not Provided|
|Current Responsible Party||James Chung-Man HO, The University of Hong Kong|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||The University of Hong Kong|
|Original Study Sponsor ICMJE||Same as current|
|Collaborators ICMJE||Not Provided|
|Investigators ICMJE||Not Provided|
|PRS Account||The University of Hong Kong|
|Verification Date||October 2022|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP