Chronic obstructive pulmonary disease (COPD) is a common chronic disease of incompletely reversible pulmonary ventilatory disorder that can progress to pulmonary heart disease and respiratory failure. It is characterized by persistent airflow limitation and progressive development, which is associated with abnormal inflammatory reactions caused by airway and lung tissue stimulated by harmful gases or particles such as cigarette smoke. Long-acting inhaled bronchodilators, which include the long-acting beta-adrenoceptor agonists salmeterol, for moterol, arformoterol, and indacaterol, and the long-acting- muscarinic receptor antagonist tiotropium continue to be the mainstay of the current management of COPD.
In 2008, COPD moved from the sixth- to the third-leading cause of death in the US. This increase is thought to have been driven by the aging population, smoking epidemic, and reduced mortality from other common causes of death. Data analyzed from a 2011 Behavioral Risk Factor Surveillance System survey suggest that 6.3% of US adults (an estimated 15 million) have been diagnosed with the disease.
Pulmonary inflammation, airway remodeling and vascular remodeling are the basic pathological features, and pulmonary vascular remodeling is an important reason for the continuous progression of pulmonary hypertension and the formation of pulmonary heart disease. At present, little is known about the mechanism of pulmonary vascular remodeling, and there is no effective reversal of drugs. Therefore, in-depth study of its mechanism and finding a drug that can effectively intervene pulmonary vascular remodeling is the key to treating COPD, reducing pulmonary hypertension, and delaying pulmonary heart disease.
Case Study
In the clinical trials of drugs, in addition to disease as the main factors, in order to ensure the drug efficacy of the symptomatic, drug use process should also be based on the patient and different. The patient's race, habits and so on will affect the efficacy, so according to the specificity of the experiment to choose clinical trial patients are very critical. Previous studies of roflumilast have predominantly involved Caucasian populations. However, ethnic differences may contribute to differences in drug responses and cause unexpected therapeutic and adverse effects. Thus, further study is necessary to determine the efficacy and safety of roflumilast in Korean COPD patients.
Another challenge in clinical trials is statistical analysis of data, which has many medical statistical methods, each applicable to different data. The statistical methods used in clinical trials must be carefully selected based on the data. In this report, comparisons between groups were assessed using Student’s t-test or the Mann-Whitney U test for continuous variables except for lung function endpoints, or x2 or Fisher’s exact test for categorical variables. Efficacy data were analyzed by intention to treat (ITT) in randomized patients receiving at least one dose of study medication. The per-protocol (PP) population was comprised of patients in the ITT population who had no documented major study protocol violations. Lung function changes were analyzed using a repeated-measures analysis of covariance (ANCOVA) for all visits from base-line to the final scheduled visit at week 12. Additionally, supportive analyses were performed using an ANCOVA model with the last observation carried forward.
Using the above strategy, we recruited appropriate patients to evaluate the efficacy and safety of roflumilast in a Korean population and compared the efficacy among subgroups based on the Korean COPD classification guidelines.
Design:
This double-blinded, placebo-controlled, parallel-group, phase III trial of roflumilast conducted in 35 outpatient centers in South Korea Hong Kong, Malaysia, Philippines, and Taiwan.
Participants:
A total of 260 Korean COPD patients were recruited. Of these patients, 207 (male, n=206) were randomized to roflumilast (n=102) or placebo (n=105) and included in the ITT and safety analyses.
Key inclusion criteria included adults aged ≥40 years with a history of COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (post-bronchodilator FEV1/forced vital capacity ≤70%, post-broncho-dilator FEV1 30–80% predicted, and FEV1 increase ≤15% and/or ≤200 mL after receiving 400 μg salbutamol).
Length of enrollment period:
12 weeks
Interventions:
Eligible patients were stratified according to smoking status and then randomized to receive either roflumilast (500 μg) or placebo once daily. A single-blind 4-week run-in period was followed by a double-blind 12-week treatment period.
Main outcomes:
- LSMean post-bronchodilator FEV1
- Adverse events
- Types and frequency of AEs
Results:
A total of 260 Korean COPD patients were recruited. Of these patients, 207 (male, n=206) were randomized to roflumilast (n=102) or placebo (n=105) and included in the ITT and safety analyses. All but one randomized patient were male. A total of 72 patients in the roflumilast group and 74 patients in the placebo group had post-bronchodilator FEV1 <60% predicted. Of the 207 randomized patients, 181 completed the study, and 164 were included in the PP analyses (roflumilast, n=79; placebo, n=85). Of the 164 patients, the mean (SD) age was 66.9 (7.3) years, the mean body mass index was 22.6 (2.8) kg/m2, and the mean post-bronchodilator FEV1 was 51.7% (13.9) of the predicted value, respectively. No significant differences in baseline demographic characteristics or spirometric parameters were observed between groups (Table 1).
Table 1. Baseline Characteristics of Korean COPD Patients in the JADE Study
COPD, chronic obstructive pulmonary disease; BD, bronchodilator; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second.
n (%), categorical data; mean (SD), continuous data.
*Percentages are based on the number of patients in the respective treatment group. n, number of patients in the respective treatment group or category.
The primary endpoint (LSMean post-bronchodilator FEV1) increased by 43 mL in patients receiving roflumilast and decreased by 60 mL in those receiving placebo after 12 weeks of treatment (Table 2). The inter-treatment difference of 103 mL was statistically significant (p<0.0001), demonstrating the superiority of roflumilast for improving post-bronchodilator FEV1 in patients with COPD. Similar analyses of LSMean pre-broncho-dilator FEV1 also demonstrated the superiority of roflumilast over placebo (inter-treatment difference: 119 mL, 95% CI 61–153 mL, p<0.001).
Table 2. Change of FEV1 (L) for all Korean COPD Patients and Each Sub-Group
During the treatment period, a higher percentage of patients in the roflumilast group (69.6%) reported AEs than did those in the placebo group (45.7%). AEs related to study medication were reported from 25 patients (24.5%) in the roflumilast group and from five (4.8%) in the placebo group. Eight patients (7.8%) in the roflumilast group and two (1.9%) in the placebo group discontinued the study due to AEs. Serious AEs were reported from nine patients (8.8%) in the roflumilast group and from two (1.0%) in the placebo group. No deaths occurred during the treatment period in either group. The most common AEs were upper respiratory tract infection, diarrhea, weight loss, and anorexia (Table 3). Routine physical examinations and laboratory tests, including complete blood count, blood chemistry and urine analyses, and electrocardiograms, did not reveal any clinically relevant AEs. The mean change in body weight from baseline to last study visit was -2.0 (2.4) kg in the roflumilast group and +0.1 (2.0) kg in the placebo group (LSMean difference, -2.07, p<0.001).
Table 3. Incidence of Adverse Events Affecting at Least 3% of Patients among All Korean COPD Patients
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References:
1. Lee, J. S., et al. (2016) ‘Efficacy and safety of roflumilast in Korean patients with COPD’, Yonsei Medical Journal, 57(4), 928-935.
2. Rabe, K. F. (2011) ’Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease’, British Journal of Pharmacology, 163(1), 53-67.
3. Lee, J. S., et al. (2013) ‘Longitudinal lung volume changes in patients with chronic obstructive pulmonary disease’, Lung, 191(4), 405-412.