Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease

Trial Design

From October 2011 through September 2015, we conducted a multicenter, randomized, double-blind, placebo-controlled phase 4 trial involving patients with GOLD stage 1 or 2 COPD. Patients were identified from community screening at 24 centers in mainland China¹² and were randomly assigned in a 1:1 ratio to receive either tiotropium (at a dose of 18 μg once daily) or matching placebo, administered by means of an inhaler (HandiHaler) once daily for 2 years. Randomization was centralized and conducted with the use of block sizes of four, stratified according to trial site.

The primary end point was the between-group difference in the change from baseline to 24 months in the FEV₁ before bronchodilator use. Secondary end points included the following: between-group difference in the change from baseline to 24 months in the FEV₁ after bronchodilator use; the FVC before and after bronchodilator use at 24 months from baseline; the annual declines in the FEV₁, the FEV₁ as a percentage of the predicted value before and after bronchodilator use, and the FEV₁:FVC ratio from day 30 through month 24; the changes in the COPD Assessment Test (CAT) score (scores range from 0 to 40, with higher scores indicating more severe disease),¹³ the Clinical COPD Questionnaire (CCQ) score (scores range from 0 to 6, with higher scores indicating worse clinical control),¹⁴ and the modified Medical Research Council (mMRC) dyspnea scale score (scores range from 0 to 4, with higher scores indicating more severe breathlessness) from baseline to 24 months; the duration and severity of COPD exacerbations; the time to the first COPD exacerbation; and the use of rescue medications. Further details of the trial design have been published previously.¹² The protocol is available with the full text of this article at NEJM.org.

Patients

The key inclusion criteria were an age of 40 to 85 years and a diagnosis of COPD of GOLD stage 1 or 2, defined as an FEV₁:FVC ratio of less than 0.70 after bronchodilator use plus respiratory symptoms, a history of exposure to risk factors (e.g., smoking, air pollution, biomass combustion), or both and an FEV₁ of 50% or more of the predicted value, measured 20 minutes after the inhalation of 400 μg of albuterol (Ventolin, Glaxo Wellcome).¹⁵ Key exclusion criteria were a COPD exacerbation occurring in the 4 weeks before screening, large-airway disease (e.g., cancer), asthma, and severe systemic disease.¹²

Procedures

Follow-up was scheduled at 1 month and every 3 months thereafter. The data that were collected at each visit included symptom-score assessment, physical examination, adverse events, medication administration, exacerbation information, and smoking status. Laboratory assessments were conducted at baseline and at month 24.

Spirometric values were measured during individual visits (at screening and at months 1, 6, 12, 18, 24, and 25) at approximately the same time of day (within a 4-hour window) at each visit by the same trained technicians according to international standards.¹⁶ Spirometric values that were obtained before bronchodilator use were measured approximately 24 hours after the previous dose of tiotropium or placebo. Spirometry that was performed after bronchodilator use was conducted 20 minutes after the inhalation of 400 μg of albuterol. Short-acting bronchodilators were withheld for at least 6 hours before the next spirometry. The predicted FEV₁ was derived with the use of reference values from the European Coal and Steel Community 1993¹⁷ and by the application of conversion factors (0.95 in men and 0.93 in women).¹⁸

An acute exacerbation of COPD was defined as worsening of at least two major symptoms (cough, sputum volume, sputum purulence, wheezing, or dyspnea) that persisted for at least 48 hours, after the presence of cardiac insufficiency, pulmonary embolism, pneumothorax, pleural effusion, or cardiac arrhythmia had been ruled out.¹⁹ Patients immediately contacted investigators in the case of worsening of respiratory symptoms. The duration, interval, severity, and management of acute exacerbations of COPD were recorded on diary cards and were adjudicated by investigators who graded the severity according to the following categories. A mild event was one that resulted in domiciliary management with COPD medications alone. A moderate event was one that resulted in an outpatient or emergency department visit and the modification of regimen, including antibiotic agents, oral glucocorticoids, or both. A severe event was one that resulted in hospitalization. Assessments of the mMRC dyspnea scale and quality of life (including the CAT and CCQ assessments) were completed at each visit.^13,14

Long-term concomitant use of other maintenance medications for COPD such as bronchodilators was avoided throughout the trial, except for medications that were clinically necessary or that had been initiated before recruitment. Ipratropium was used as rescue medication if needed but was not intended for long-term use (patients were instructed to contact their trial investigator immediately to seek guidance regarding the use of rescue medication, verification of an acute COPD exacerbation, and initiation of treatment associated with the acute exacerbation). Rundo International Pharmaceutical Research and Development was convened to monitor the quality of and check adherence to the trial regimen.

Trial Oversight

The trial protocol was approved by the local institutional review board or independent ethics committee at each site, according to the requirement of the Chinese guidelines for Good Clinical Practice. Participants provided written informed consent before enrollment. Statistical analyses were performed by employees of Rundo International Pharmaceutical Research and Development. The funding sources had no role in the design, data analysis, or interpretation of the results in this trial. The sponsor (Boehringer Ingelheim) was given the opportunity to review the manuscript for medical and scientific accuracy as it related to its product (tiotropium) and intellectual property considerations. Albuterol was purchased at full cost. The first and last authors vouch for the accuracy and completeness of the data and analyses reported and for the fidelity of the trial to the protocol. All the authors approved the submission of the manuscript for publication.

Statistical Analysis

We calculated the sample size to detect a difference in the FEV₁ before bronchodilator use between the tiotropium group and the placebo group, assuming a difference of 100 ml and a standard deviation of 350 ml at month 24, with a two-sided significance level of 5% and a power of 90%, taking into account an anticipated withdrawal rate of 35%.^7,9 We estimated that a total of 400 patients per group would be required for the primary analysis.

Confirmatory hypothesis testing was planned only for the primary end point. All the secondary and subgroup analyses are exploratory in nature and were not adjusted for multiple comparisons. Repeated-measures analysis of variance (ANOVA) was used to compare the FEV₁ before and after bronchodilator use at each visit, with values at each follow-up visit as a dependent variable, with the trial-group assignment, baseline FEV₁ values, follow-up visits (categorical variable), interactions between trial group and follow-up visit, and hospital as fixed effects and with participants as random effects. Assuming that trial-group effects varied linearly with the duration of the trial, a random coefficient regression model was used to compare the annual declines in FEV₁, FVC, and the FEV₁:FVC ratio, with the annual declines being expressed as regression coefficients. We used likelihood-based methods to handle missing data for the repeated-measures model and the random-coefficient model. No imputation was deemed to be necessary.

The time to the first acute exacerbation of COPD was compared by means of a log-rank test. The Wilcoxon rank-sum test was applied to assess the interval, duration, and severity of acute exacerbations of COPD. Fisher’s exact test was used for the comparison of differences in the use of rescue medication. The frequency and number of severe acute exacerbations of COPD were compared with the use of a Poisson regression model, with correction for exposure of trial-regimen doses and overdispersion (i.e., presence of greater variability in the data set than the expected heterogeneity in exacerbation rates). Transfer tables were used for the comparison of changes in the mMRC dyspnea scale scores between baseline and the end of the trial. Differences between the changes from baseline to the end of the trial were compared with the use of repeated-measures ANOVA. Subgroup analyses were performed with the use of stratification of COPD according to CAT score (<10 vs. ≥10) and GOLD stage (1 vs. 2) and category (A vs. B). Patients with A or B category disease are considered to be at low risk for an acute exacerbation of COPD; patients with A category disease have few symptoms, and those with B category disease have more symptoms.

The data from patients who underwent randomization and received at least one dose of tiotropium or placebo and had available data regarding efficacy measurement after baseline (i.e., patients who underwent spirometric assessment after bronchodilator use at any scheduled follow-up visit) were included in the full analysis set. The number of exacerbations in each trial group was reported. All the analyses were conducted with the use of SAS software, version 9.2.2 (SAS Institute), and all reported P values are two-sided.

Baseline Demographic Characteristics and Adherence to Trial Regimen

Figure 1. Figure 1. Randomization and Follow-up of Patients with Chronic Obstructive Pulmonary Disease (COPD) of GOLD Stage 1 or 2.

Reasons for discontinuation of the trial did not differ significantly between the two groups. A total of 140 patients (33.2%) in the placebo group withdrew, as did 116 (27.7%) in the tiotropium group (P=0.27). Patients who underwent randomization and received at least one dose of tiotropium or placebo and had available data regarding efficacy measurement after baseline (i.e., patients who underwent spirometric assessment after bronchodilator use at any scheduled follow-up visit) were included in the full analysis set.

We randomly assigned 841 patients with COPD (367 patients with GOLD stage 1 disease and 474 with stage 2) to receive placebo (422 patients) or tiotropium (419) (Figure 1). Among 771 patients who were included in the full analysis set (383 patients in the placebo group and 388 in the tiotropium group), 585 completed the follow-up visits for 2 years. A total of 256 patients withdrew from the trial (140 patients [33.2%] in the placebo group and 116 [27.7%] in the tiotropium group). There were no significant differences in the demographic characteristics or in the reasons for withdrawal (Figure 1, and Table S1 in the Supplementary Appendix, available at NEJM.org). The demographic and clinical characteristics were similar between the patients who withdrew and those who did not withdraw, except for the mean (±SD) CCQ score (1.09±0.79 in patients who withdrew vs. 0.94±0.71 in those who completed the trial, P=0.008) and the CAT score (6.9±5.8 vs. 7.8±6.3, P=0.03) (Table S2 in the Supplementary Appendix).

Table 1. Table 1. Characteristics of the Patients at Baseline (Full Analysis Set).

The baseline values of the patients in the full analysis set were similar in the two groups. The mean age of the patients was 63.9 years in the placebo group and 64.2 years in the tiotropium group, and the median smoking index (the number of packs of cigarettes per day, multiplied by the years of smoking) was 55.1 pack-years and 50.6 pack-years, respectively. The mean FEV₁ before bronchodilator use was 1.82 liters (73.4% of the predicted value) in the placebo group and 1.80 liters (72.6% of the predicted value) in the tiotropium group; the mean FEV₁ after bronchodilator use was 1.94 liters (78.1% of the predicted value) and 1.93 liters (77.9% of the predicted value), respectively. No significant between-group differences were observed in the mMRC dyspnea scale, CAT, or CCQ scores and in the use of concomitant respiratory medications (Table 1).

The mean exposure to the trial regimen was 604 days in the placebo group (adherence rate, 90.5%) and 638 days in the tiotropium group (adherence rate, 93.3%) (P=0.009 for the comparison of mean exposure; P=0.004 for the comparison of adherence rate). The number of times of administration and the number of days of rescue-medication use were greater in the placebo group than in the tiotropium group (P=0.002 and P=0.02, respectively). There was no significant between-group difference with regard to smoking status or the use of other respiratory medications (Table S3 in the Supplementary Appendix).

Lung Function

Figure 2. Figure 2. Mean Forced Expiratory Volume in 1 Second (FEV₁) and Forced Vital Capacity (FVC) before and after Bronchodilator Use and the Risk of Acute Exacerbation of COPD over Time.

Tiotropium resulted in a significantly higher FEV₁ before bronchodilator use than placebo at 24 months, with a between-group difference of 157 ml (95% CI, 123 to 192; P<0.001), and at each visit (ranges of mean differences, 127 to 169 ml in the FEV₁ before bronchodilator use and 71 to 133 ml in the FEV₁ after bronchodilator use; P<0.001 for all comparisons) (Panel A). The FVC was significantly higher in the tiotropium group than in the placebo group (ranges of mean differences, 110 to 164 ml in the FVC before bronchodilator use and 53 to 96 ml in the FVC after bronchodilator use; P<0.05 for all comparisons) (Panel B). I bars indicate ±1 SD. The use of tiotropium resulted in a significantly longer time to the first acute exacerbation of COPD (25th percentile, 522 days; 95% CI, 341 to 649) than placebo (25th percentile, 236 days; 95% CI, 177 to 331). The incidence of an acute exacerbation of COPD was lower with tiotropium than with placebo (Panel C).

Tiotropium resulted in a significantly higher FEV₁ before bronchodilator use than placebo at month 24, with a between-group difference of 157 ml (95% confidence interval [CI], 123 to 192; P<0.001) (Figure 2, and Table S4 in the Supplementary Appendix). At each visit, both the mean FEV₁ (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 and 133 ml after bronchodilator use) and the mean FVC (ranges of mean differences, 110 to 164 ml before bronchodilator use and 53 to 96 ml after bronchodilator use) were significantly higher in the tiotropium group than in the placebo group (P<0.001 for all comparisons of FEV₁ and P<0.05 for all comparisons of FVC at follow-up visits to month 24) (Figure 2, and Table S4 in the Supplementary Appendix).

Table 2. Table 2. Annual Declines in the FEV₁, FVC, Percent of Predicted FEV₁, Percent of Predicted FVC, and FEV₁:FVC Ratio before and after Bronchodilator Use.

From day 30 through month 24, the annual decline in the FEV₁ before bronchodilator use was 38 ml per year in the tiotropium group and 53 ml per year in the placebo group (difference, 15 ml per year; 95% CI, −1 to 31; P=0.06), whereas the annual decline in the FEV₁ after bronchodilator use was 29 ml per year in the tiotropium group versus 51 ml per year in the placebo group (difference, 22 ml per year; 95% CI, 6 to 37; P=0.006). Similar findings were observed for the between-group differences in the percent of the predicted FEV₁ value and in the analyses after adjustment for smoking status, the percent of the predicted FEV₁ value at baseline, age, sex, hospitalization, GOLD stage, and body-mass index (the weight in kilograms divided by the square of the height in meters). The groups did not differ significantly in the FVC, the percent of the predicted FVC value, and the FEV₁:FVC ratio as assessed before and after bronchodilator use (Table 2).

Acute Exacerbations of COPD

A total of 112 patients (28.9%) in the tiotropium group and 150 (39.2%) in the placebo group had an acute exacerbation of COPD. The time to the first acute exacerbation of COPD was longer with tiotropium than with placebo (P<0.001). The 25th-percentile value for the time to the first acute exacerbation of COPD was 522 days (95% CI, 341 to 649) in the tiotropium group and 236 days (95% CI, 177 to 331) in the placebo group. The hazard ratio for the first acute exacerbation of COPD in the tiotropium group, as compared with the placebo group, was 0.60 (95% CI, 0.50 to 0.80; P<0.001) (Figure 2).

Table 3. Table 3. Acute Exacerbations of COPD and Hospitalizations Due to COPD.

The frequency of acute exacerbations of COPD was lower with tiotropium than with placebo (0.27 vs. 0.50 events per patient-year; risk ratio, 0.53; 95% CI, 0.39 to 0.73; P<0.001) (Table 3). Tiotropium also resulted in a lower frequency of hospitalizations per patient per year than placebo (0.03 vs. 0.07 hospitalizations per patient-year, P=0.009) (Table 3).

Quality of Life

Tiotropium was more effective than placebo with regard to mMRC dyspnea scale and CAT scores at all time points except for months 1, 3, and 12. Changes in the CCQ scores also favored tiotropium over placebo at all visits except for month 12. Details are provided in Tables S5, S6, and S7 in the Supplementary Appendix.

Adverse Events

There were no significant between-group differences in the incidence of adverse events, serious adverse events, and death except for mild adverse events, such as oropharyngeal discomfort. Oropharyngeal discomfort, including dry mouth and pharyngeal discomfort, occurred in 63 patients (15.0%) in the tiotropium group, as compared with 28 (6.6%) in the placebo group (P<0.001) (Table S8 in the Supplementary Appendix).

Subgroup Analysis

In this trial, 614 of 841 patients (73.0%) had a CAT score of less than 10, and no significant between-group difference was observed with regard to baseline demographic and clinical characteristics, exposure to the trial regimen, use of other respiratory medication, or smoking status except for the number of times that rescue medication (ipratropium) was administered (Tables S9 and S10 in the Supplementary Appendix). Data on the FEV₁ and FVC values before and after bronchodilator use at individual visits, stratified according to CAT score, are provided in Table S11 in the Supplementary Appendix. In patients with a CAT score of less than 10, the mean decline in the FEV₁ before bronchodilator use was 54 ml per year in the placebo group and 37 ml per year in the tiotropium group, with a difference in the annual decline of 17 ml per year (95% CI, −1 to 35; P=0.07). The mean decline in the FEV₁ after bronchodilator use was 47 ml per year in the placebo group and 28 ml per year in the tiotropium group, with a difference in the annual decline of 20 ml per year (95% CI, 2 to 37; P=0.03) (Table 2). In patients with a CAT score of 10 or more, the between-group difference in the annual decline in the FEV₁ after bronchodilator use was not significant (P=0.07) (Table 2).

Tiotropium prolonged the time to the first acute exacerbation of COPD and decreased the total numbers of all acute exacerbations of COPD and of acute exacerbations of moderate or worse severity in patients with a CAT score of less than 10. In patients with a CAT score of less than 10, the mMRC dyspnea scale score and quality-of-life assessment scores were lower (indicating clinical improvement) in the tiotropium group than in the placebo group at months 15, 21, and 24. Details are provided in Tables S12 through S16 in the Supplementary Appendix.

Subgroup analyses that were stratified according to GOLD stage and category (1 vs. 2 and A vs. B) showed results that were similar to those in the overall analysis. Details are provided in Tables S17 through S23 in the Supplementary Appendix.

We investigated the efficacy and safety of tiotropium in a large cohort of patients who had GOLD stage 1 or stage 2 COPD. Tiotropium resulted in a significantly higher FEV₁ than placebo at 24 months and ameliorated the annual decline in the FEV₁ assessed after bronchodilator use but not the FEV₁ assessed before bronchodilator use. Moreover, tiotropium resulted in a lower frequency of acute exacerbations of COPD than placebo and improved quality of life in patients with GOLD stage 1 or 2 COPD. Similar results were found in patients who had a CAT score of less than 10.

Clinical trials with medication intervention in patients with GOLD stage 1 COPD or a CAT score of less than 10 are scarce, with some data available from post hoc subgroup analyses.^9,11,20 Our multicenter trial involved patients with GOLD stage 1 or 2 COPD and enrolled more than 40% of patients with stage 1 disease and more than 70% of patients with a CAT score of less than 10, mainly from the community by means of a COPD screening program. At baseline, the majority of patients had a low frequency of acute exacerbations of COPD and had received minimal medications.

Attempts to decrease the progression rate of COPD with tiotropium have not been fully successful. In a subgroup analysis of the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, tiotropium resulted in an annual decline in the FEV₁ after bronchodilator use in patients with GOLD stage 2 COPD that was less than the decline in patients who received placebo. However, the mean between-group differences were small and not clinically significant (6 ml per year).⁹ In our trial, we recruited only patients with mild or moderate COPD, which might have contributed to the differences in findings between the two trials. Previous reports have shown that in previously untreated patients with COPD, tiotropium led to an annual decline in the FEV₁ that was slower than that with placebo.²⁰ In another study involving patients with mild-to-moderate COPD, the FEV₁ after bronchodilator use was significantly greater after 12 weeks of tiotropium than after placebo, which suggests that tiotropium might be effective for mild COPD.¹⁰ However, in a real-world retrospective cohort study involving patients with early-stage COPD (FEV₁ ≥70% of the predicted value), tiotropium did not lead to a significantly slower decline than placebo in the FEV₁ (decline in FEV₁ before bronchodilator use, 30.4 ml per year in the tiotropium group and 21.9 ml per year in the placebo group; decline in FEV₁ after bronchodilator use, 23.9 ml per year and 22.5 ml per year, respectively).²¹ This finding could be due to the retrospective study design and the small sample size.

The case definition for COPD that we used was an FEV₁:FVC ratio of less than 0.70 after bronchodilator use plus respiratory symptoms, a history of exposure to risk factors (e.g., smoking, air pollution, biomass combustion), or both.^15,22,23 Patients with early-stage COPD remain asymptomatic but have a rapid decline in lung function.^24-26 In our trial, all the participants met the diagnostic definition of COPD in terms of risk factors and spirometric results, and in patients with a CAT score of less than 10, tiotropium resulted in an annual decline in the FEV₁ after bronchodilator use that was less than the decline observed with placebo. It is not known whether the prevention of COPD-related loss of lung function that was associated with tiotropium has any effect on the underlying disease mechanisms in COPD. If it does not, then the benefit that we observed may simply delay the development of more severe disease rather than prevent it.

The prevention of acute exacerbations of COPD has been listed explicitly as a cardinal goal for patients who have COPD of any grade of severity.¹⁵ Tiotropium resulted in a significantly lower frequency of acute COPD exacerbations than placebo, which reaffirms previous reports.^7,9,20 Finally, our trial showed no remarkable differences with regard to side effects (e.g., cardiovascular effects, urinary tract disease) that have been associated with tiotropium as compared with placebo, except for dry mouth or pharyngeal discomfort.

In conclusion, this trial showed that tiotropium was effective in improving lung function and quality of life and resulted in a lower frequency of acute COPD exacerbations than placebo among patients with GOLD stage 1 or 2 disease. Whether early intervention with tiotropium alters the long-term course of COPD remains an open question.