Clinical trial NCT03988816: Effect of Roflumilast on Quality of Life, Lung Function and Mucus Properties in Patients With Bronchiectasis
Official title: Effect of Roflumilast on Quality of Life, Lung Function and Mucus Properties in Patients With Non-cystic Fibrosis Bronchiectasis: a Cross-over, Unicentric, Double-blind and Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Bronchiectasis Adult
Keywords: bronchiectasis
lung function
quality of life
mucus properties
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
First posted: 2019-06-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Although relatively common, bronchiectasis is considered an orphan disease as there is little evidence for adequate treatment, most of the therapeutic options are extrapolated from studies with patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). Inhaled bronchodilators and corticosteroids should be used as a therapeutic test and maintained if there is improvement of symptoms or lung function. There is no evidence to justify the use of mucolytic agents for these patients. The treatment with greater evidence is the use of macrolides, especially azithromycin. A meta-analysis published in 2014 showed that there was a reduction in the number of exacerbations, an improvement in the quality of life and a reduction in the decrease in FEV1. However, studies have shown conflicting results regarding quality of life and pulmonary function.

Roflumilast is a phosphodiesterase-4 inhibitor with an anti-inflammatory effect in vitro and in vivo due to the inhibition of cyclic adenosine monopostat breakdown (cAMP) to its inactive phosphodiesterase form. As this enzyme is expressed in high concentrations in leukocytes and other inflammatory cells responsible for the pathogenesis of pulmonary diseases such as COPD, it has been studied and used for this disease. COPD is characterized by a chronic inflammatory process of the airways, predominantly neutrophils and high levels of proinflammatory cytokines related to this cell, such as interleukin-8, neutrophil elastase, tumor necrosis factor (TNF) alpha and E-selectin. The REACT study showed that roflumilast prevents moderate and severe infectious exacerbations in addition to improved lung function in patients with COPD who continue to exacerbate despite the use of combined bronchodilator and inhaled corticosteroid therapy.

Since bronchiectasis and COPD are chronic inflammatory diseases, they present similar inflammatory processes, with neutrophil as the main inflammatory cell, it is expected that the use of roflumilast also has an anti-inflammatory effect in bronchiectasis. In addition, since bronchiectasis is a disease with poor evidence for pharmacological treatment, it is necessary to search for new therapeutic possibilities.


Eligibility criteria: Inclusion Criteria:

* Age \> 18 years;
* Diagnosis of bronchiectasis by chest tomography;
* FEV1 \<60% of predicted;
* History of chronic bronchitis (chronic cough and sputum for at least 3 months in the last 2 years);
* 2 or more infectious exacerbations in the last year (defined as worsening of cough and / or dyspnoea and / or decreased general condition, increased quantity and purulence of sputum that required systemic antibiotic use (oral or intravenous).

Exclusion Criteria:

* Hemoptysis in the last 6 months (significance at the discretion of the investigator);
* Current or prior smoking if \> 10 pack-years;
* FEV1 \< 30% of predicted;
* Known allergy to roflumilast;
* Pulmonary exacerbation present or occurring in the last 4 weeks;
* Child B or C cirrhosis;
* Active cancer (except basal cell carcinoma);
* Severe heart failure;
* Depression associated with suicidal ideation;
* Pregnancy.

Primary outcomes:
measure: Quality of life questionnaire
timeFrame: 12 weeks
Secondary outcomes:
measure: Other tools for quality of life
timeFrame: 12 weeks
measure: Dyspnea
timeFrame: 12 weeks
measure: Lung function
timeFrame: 12 weeks
measure: Adverse events
timeFrame: 12 weeks
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Heart Institute (InCor) - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
state: SP
Study officials:
affiliation: Medical Assistant
name: Rodrigo A Athanazio, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fjaellegaard K, Sin MD, Browatzki A, Ulrik CS. Antibiotic therapy for stable non-CF bronchiectasis in adults - A systematic review. Chron Respir Dis. 2017 May;14(2):174-186. doi: 10.1177/1479972316661923. Epub 2016 Aug 9.
citation: Quint JK, Millett ER, Joshi M, Navaratnam V, Thomas SL, Hurst JR, Smeeth L, Brown JS. Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study. Eur Respir J. 2016 Jan;47(1):186-93. doi: 10.1183/13993003.01033-2015. Epub 2015 Nov 5.
citation: McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2013 Sep 15;188(6):647-56. doi: 10.1164/rccm.201303-0411CI.
citation: Beghe B, Rabe KF, Fabbri LM. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am J Respir Crit Care Med. 2013 Aug 1;188(3):271-8. doi: 10.1164/rccm.201301-0021PP.
citation: Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007 Dec;62(12):1081-7. doi: 10.1136/thx.2006.075937. Epub 2007 Jun 15.