Elsevier

The Lancet

Volume 385, Issue 9971, 7–13 March 2015, Pages 857-866
The Lancet

Articles
Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial

https://doi.org/10.1016/S0140-6736(14)62410-7Get rights and content

Summary

Background

Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment.

Methods

For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3–4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029.

Findings

Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753–1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740–0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group.

Interpretation

Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with tiotropium.

Funding

Takeda.

Introduction

Severe chronic obstructive pulmonary disease is associated with periodic exacerbations of respiratory symptoms that need aggressive treatment and often necessitate hospital admission.1, 2 These exacerbations worsen patient health status, accelerate decline in lung function, and increase mortality.1, 2 The two alternative recommended pharmacological treatments to prevent exacerbations are either an inhaled longacting muscarinic antagonist alone, a fixed combination of an inhaled corticosteroid and longacting β2 agonist, or these two treatments combined.1 These therapies significantly reduce, but do not eliminate, chronic obstructive pulmonary disease exacerbations, especially those necessitating hospital admission, which is problematic for patients at risk of frequent or severe events.3, 4, 5 To increase the doses of longacting bronchodilators6 and inhaled corticosteroids is not a practical option because of the flat dose–response curve and raised risk of side-effects, especially pneumonia with inhaled corticosteroids.7, 8

Alternative approaches to prevent chronic obstructive pulmonary disease exacerbations have been investigated, including long-term macrolide therapy, which is effective but associated with the risks of side-effects and antibiotic resistance;9 statins, which are ineffective;10 and theophylline11 and acetylcysteine,12, 13 which produce inconsistent results. None of these studies have investigated whether or not treatment reduced exacerbations in severe chronic obstructive pulmonary disease not adequately controlled with the best available inhalation therapy with inhaled corticosteroid–longacting β2 agonist combinations or triple longacting muscarinic antagonist–inhaled corticosteroid–longacting β2 agonist therapy.

Research in context

Evidence before this study

We searched Medline for articles published in any language up until Jan 8, 2015, with the search terms “roflumilast” and “chronic obstructive pulmonary disease” but not “asthma” or “randomised trial”. Our final search was done on Jan 8, 2015. We identified 19 articles reporting randomised controlled trials. However, only five trials compared 1-year treatment with roflumilast versus placebo in more than 1000 patients with moderate-to-very-severe chronic obstructive pulmonary disease and included the assessment of lung function, symptoms, quality of life, and exacerbations. These five trials were reported in three original reports. Two replicate positive randomised clinical trials and the pooled analysis of two negative clinical trials showed a significant effect of roflumilast on moderate-to-severe exacerbations and lung function, especially in patients with severe-to-very-severe chronic obstructive pulmonary disease, symptoms of chronic bronchitis, and a risk of exacerbations. However, none of these trials included patients at high risk of exacerbations (>2 per year) while receiving the standard of care, ie inhaled corticosteroid–longacting β2 agonist combinations.

Added value of this study

Our findings show that roflumilast reduces moderate-to-severe exacerbations, especially those that lead to hospital admissions, and improves lung function in patients with severe chronic obstructive pulmonary disease with chronic bronchitis at risk of frequent exacerbations, even those receiving an inhaled corticosteroid–longacting β2 agonist combination or triple therapy with an inhaled corticosteroid–longacting β2 agonist combination plus tiotropium. To identify publications reporting the effects of any other drug in patients with severe to very severe chronic obstructive pulmonary disease, chronic bronchitis, and a high risk of exacerbations while being treated with an inhaled corticosteroid–longacting β2 agonist combination, we also searched Medline using the search terms “cilomilast”, “phosphodiesterase IV inhibitors”, “beclomethasone”, “fluticasone”, “budesonide”, “salmeterol”, “formoterol”, “theophylline”, “aminophylline”, “antibiotics”, “macrolides”, “infliximab”, “benralizumab”, “chronic bronchitis”, “emphysema”, and “randomised trial”. We did not find any studies that had been done in patients with these characteristics.

Implications of all the available evidence

Roflumilast is the only available oral anti-inflammatory drug that provides additional, clinically relevant benefits without unacceptable side-effects. Our findings should help to inform treatment choices for patients with severe to very severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of severe exacerbations even when they are already taking maximum doses of existing inhalation treatments.

Roflumilast is an oral phosphodiesterase-4 inhibitor with anti-inflammatory actions both in vitro and in vivo.14 It consistently improves lung function and reduces the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease, symptoms of chronic bronchitis, and a history of frequent exacerbations.15, 16, 17 The effect on exacerbations is maintained in patients treated with longacting β2 agonists, and is more pronounced in patients with frequent exacerbations.18 However, whether or not roflumilast can effectively reduce exacerbations when patients with chronic obstructive pulmonary disease use inhaled corticosteroid–longacting β2 agonist combinations as their maintenance therapy, which is the regimen recommended at present by evidence-based guidelines,1, 2 is not known.

We postulated that roflumilast would be effective in patients with severe chronic obstructive pulmonary disease who are at risk for exacerbations and whose disease is not adequately controlled with inhaled corticosteroid–longacting β2 agonist combinations or triple longacting muscarinic antagonist–inhaled corticosteroid–longacting β2 agonist therapy. Additionally, we wanted to understand the adverse event profile in this subset of patients to help establish the risk:benefit balance of treatment. To achieve these aims, we undertook the REACT (Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy) study.19

Section snippets

Patients

REACT was a 1-year, double-blind, placebo-controlled, parallel-group, multicentre study. Patients were recruited from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries worldwide (appendix pp 3–5). Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation (confirmed by a post-bronchodilator forced expiratory

Results

Patient recruitment began on April 3, 2011, and the study ended on May 27, 2014. Of 2708 patients recruited, 1945 were randomly assigned and 1935 actually received treatment (969 in the roflumilast group and 966 in the placebo group; figure 1). Table 1 shows the demographic and baseline characteristics of the randomly assigned patients who received at least one dose of study medication. The mean pre-bronchodilator FEV1 was 1·0 L (SD 0·32) and the mean post-bronchodilator FEV1 was 1·1 L (SD

Discussion

Our findings show that roflumilast prevented moderate and severe exacerbations and improved lung function in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who continued to have exacerbations despite inhaled combination therapy. The number of hospital admissions of patients with severe chronic obstructive pulmonary disease was significantly reduced in patients receiving roflumilast, without a change in symptoms. Additionally, the anticipated side-effects of

References (33)

  • J Vestbo et al.

    Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary

    Am J Respir Crit Care Med

    (2013)
  • J O'Reilly et al.

    Management of stable chronic obstructive pulmonary disease in primary and secondary care: summary of updated NICE guidance

    BMJ

    (2010)
  • PM Calverley et al.

    Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease

    N Engl J Med

    (2007)
  • JA Wedzicha et al.

    The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide

    Am J Respir Crit Care Med

    (2008)
  • SD Aaron et al.

    Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial

    Ann Intern Med

    (2007)
  • D Spina

    Current and novel bronchodilators in respiratory disease

    Curr Opin Pulm Med

    (2014)
  • Cited by (302)

    • Nouveautés dans la prise en charge de la BPCO

      2023, Revue des Maladies Respiratoires Actualites
    • Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission

      2022, The Lancet
      Citation Excerpt :

      Even though COPD is the third leading cause of death worldwide, there are currently only 780 ongoing therapeutic clinical trials related to the disease, compared with more than 41 000 trials of cancer treatments. This lack of research partly explains the fact that only one new drug class has been approved for COPD in the past three decades.232 A global analysis233 in 2019 also showed that only 31% of molecular targeted therapies under investigation in COPD were classified as first in class, compared with an average of more than 40% across all other indications.

    View all citing articles on Scopus
    *

    Joint first authors

    Joint last authors

    View full text