Efficacy and safety of once-daily single-inhaler triple therapy for mild-to-moderate chronic obstructive pulmonary disease: a study protocol for a randomised and interventional study.

INTRODUCTION: Bronchodilators, including long-acting muscarinic antagonists (LAMA) and long-acting beta 2 agonists (LABA), are the main treatments for chronic obstructive pulmonary disease (COPD). The efficacy of triple therapy (inhaled corticosteroids/LAMA/LABA) has also been reported. However, the effect of triple therapy on patients with mild-to-moderate COPD has not yet been clarified. This study aims to investigate the safety and efficacy of triple therapy, compared with LAMA/LABA combination therapy, for lung function and health-related quality of life in patients with mild-to-moderate COPD and identify baseline characteristics and biomarkers to predict responders and non-responders to triple therapy. METHODS AND ANALYSIS: This is a multicentre, prospective, open-label, randomised, parallel-group study. Mild-to-moderate patients with COPD will be randomised to receive fluticasone furoate/umeclidinium/vilanterol or umeclidinium/vilanterol for 24 weeks. A total of 668 patients will be enrolled from March 2022 to September 2023 from 38 sites in Japan. The primary endpoint is the change in the trough forced expiration volume in 1 s after 12 weeks of treatment. Secondary endpoints are responder rates based on the COPD assessment test score and the St. George's Respiratory Questionnaire total score after 24 weeks of treatment. The safety endpoint is the occurrence of any adverse events. We will also investigate safety in terms of changes in microbial colonisation in sputum and antimycobacterium avium complex antibodies. ETHICS AND DISSEMINATION: The study protocol and informed consent documents were approved by the Saga University Clinical Research Review Board (approval number: CRB7180010). Written informed consent will be obtained from all patients. Recruitment of the patients began in March 2022. The results will be disseminated through scientific peer-reviewed publications and domestic and international medical conferences. TRIAL REGISTRATION NUMBERS: UMIN000046812 and jRCTs031190008.

LABA/LAMA as First-Line Therapy for COPD: A Summary of the Evidence and Guideline Recommendations.

Inhaled bronchodilators (alone or in combination) are the cornerstone of treatment for symptomatic patients with COPD, either as initial/first-line treatment or for second-line/treatment escalation in patients who experience persistent symptoms or exacerbations on monotherapy. The Global Initiative for Chronic Obstructive Lung Disease 2022 report recommends initial pharmacological treatment with a long-acting muscarinic antagonist (LAMA) or a long-acting ß2-agonist (LABA) as monotherapy for most patients, or dual bronchodilator therapy (LABA/LAMA) in patients with more severe symptoms, regardless of exacerbation history. The recommendations for LABA/LAMA are broader in the American Thoracic Society treatment guidelines, which strongly recommend LABA/LAMA combination therapy over LAMA or LABA monotherapy in patients with COPD and dyspnea or exercise intolerance. However, despite consistent guideline recommendations, real-world prescribing data indicate that LAMA and/or LABA without an inhaled corticosteroid are not the most widely prescribed therapies in COPD. This article reviews global and regional/national guideline recommendations for the use of LABA/LAMA in COPD, examines the evidence for the effectiveness and safety of LABA/LAMA versus other therapies and offers a practical guide for clinicians to help ensure appropriate use of LABA/LAMA therapy.

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis.

BACKGROUND: In symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978). METHODS: We searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest. RESULTS: We identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV1 (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies. CONCLUSIONS: In the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV1 in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.

Triple versus LAMA/LABA combination therapy for patients with COPD: a systematic review and meta-analysis.

BACKGROUND: Recently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial. METHODS: We searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest. RESULTS: We identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64-0.83) and improved the QOL score and trough FEV1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18-0.48) and mortality (odds ratio 0.66, 95% CI 0.50-0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16-2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV1 than LAMA/LABA. Concerning the trough FEV1, QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference. CONCLUSION: Triple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations. CLINICAL TRIAL REGISTRATION: PROSPERO; CRD42020191978.

Treatment with LABA versus LAMA for stable COPD: a systematic review and meta-analysis.

BACKGROUND: Inhaled bronchodilators including long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) play a central role in the treatment of stable chronic obstructive pulmonary disease (COPD). However, it is still unclear whether LABA or LAMA should be used for the initial treatment. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LABA versus LAMA in patients with stable COPD. METHODS: We searched relevant randomized control trials (RCTs) with a period of treatment of at least 12 weeks and analyzed the exacerbations, quality of life, dyspnea score, lung function and adverse events as the outcomes of interest. RESULTS: We carefully excluded unblinded data and identified a total of 19 RCTs (N = 28,211). LAMA significantly decreased the exacerbations compared to LABA (OR 0.85, 95% CI 0.74 to 0.98; P = 0.02). In St George's Respiratory Questionnaire and transitional dyspnoea index score, there were no differences between LABA and LAMA treatment. Compared to LABA, there was a small but significant increase in the trough FEV1 after LAMA treatment (Mean difference 0.02, 95% CI 0.01 to 0.03, P = 0.0006). In the safety components, there was no difference in the serious adverse events between LABA and LAMA. However, LAMA showed a significantly lower incidence of total adverse events compared to LABA (OR 0.92, 95% CI 0.86 to 0.98; P = 0.02). CONCLUSION: Treatment with LAMA in stable COPD provided a significantly lower incidence of exacerbation and non-serious adverse events, and a higher trough FEV1 compared to LABA. TRIAL REGISTRATION: (PROSPERO: CRD42019144764).

[Comparison of ciprofloxacin with biapenem in patients with moderate or severe pneumonia].

We conducted the comparative study to clarify the clinical efficacy and features of ciprofloxacin (CPFX) and biapenem (BIPM) in the treatment of moderate or severe pneumonia. Among 209 patients enrolled, 173 patients (CPFX; 87, BIPM; 86) complying with the protocol were evaluated for safety and 171 (CPFX; 85, BIPM; 86) for efficacy. No significant difference was noted between groups in patient profiles. Both groups were similar in efficacy, as evaluated by the following variables: fever, WBC, CRP, and chest X ray score. The incidence of adverse drug reactions was 16.1% (14/87 patients) in the CPFX group and 16.3% (14/86 patients) in the BIPM group. Phlebitis occasionally occurred in the CPFX group and drug eruption and liver function disorder occasionally in the BIPM group. In conclusion, both CPFX and BIPM were useful in treating moderate or severe pneumonia and no difference was seen between groups in efficacy. Some differences were noted in adverse reactions, however.