The Effect of Telithromycin in Acute Exacerbations of Asthma
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《新英格兰医药杂志》
ABSTRACT
Background We conducted a double-blind, randomized, placebo-controlled study to evaluate the efficacy of telithromycin in patients with acute exacerbations of asthma.
Methods A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an acute exacerbation of asthma requiring short-term medical care. The patients were randomly assigned to receive 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care. Primary efficacy end points were a change from baseline over the treatment period in symptoms (as recorded by patients in a diary card) and in the peak expiratory flow in the morning at home. The presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was ascertained by serologic analysis, polymerase chain reaction, and culture.
Results Of the two prespecified primary outcomes, only asthma symptoms showed a significantly greater reduction among patients receiving telithromycin than among those receiving placebo. Mean (±SD) scores on a test of asthma symptoms (on a 7-point scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.0±1.4 at baseline and 1.7±1.1 at the end of treatment for the telithromycin group and 2.8±1.3 at baseline and 2.0±1.0 at the end of treatment for the placebo group. The mean decrease in symptom scores during the treatment period was 1.3 for telithromycin and 1.0 for placebo (mean difference, –0.3; 95 percent confidence interval, –0.5 to –0.1; P=0.004). There was no significant treatment effect on the other primary outcome measure, a change in morning peak expiratory flow. Nausea was more common among patients in the telithromycin group than in the placebo group (P=0.01). Although 61 percent of patients had evidence of infection with C. pneumoniae, M. pneumoniae, or both, there was no relationship between bacteriologic status and the response to asthma treatment.
Conclusions This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear. (ClinicalTrials.gov number, NCT00273520 .)
Ketolides are a new class of antibiotics that are structurally related to macrolides1 and have a bactericidal effect against Chlamydophila pneumoniae and Mycoplasma pneumoniae.2,3,4 Like macrolides, the ketolide telithromycin (Ketek, Sanofi-Aventis) has immunomodulatory effects both in vitro and in vivo.5,6 It is not known whether treatment with a ketolide could improve treatment of an exacerbation of asthma.
The Telithromycin, Chlamydophila, and Asthma trial (TELICAST) was designed to determine whether a 10-day course of telithromycin, as compared with placebo, in combination with standard therapy improves symptoms and peak expiratory flow rates in the morning among patients with an acute exacerbation of asthma who have no clinically obvious need for antibiotic treatment.
Methods
In this double-blind, parallel-group, randomized, placebo-controlled, multicenter, multinational study, we evaluated the efficacy and safety of oral telithromycin (at a dose of 800 mg daily) for patients with an acute exacerbation of asthma. The study was performed in accordance with the good clinical-practice guidelines recommended by the International Conference on Harmonisation of Technical Requirements and was approved by the ethics committee at each center. All patients provided written informed consent.
The study was designed by two authors from academic institutions and one representative of the sponsor, with input from an advisory board that included all authors. Data were held and analyzed by the contract research organization Pharmaceutical Product Development under guidance from the study sponsor, with input from all authors. An academic author reviewed the statistical-analysis plan. Drs. Johnston and Nieman vouch for the accuracy and completeness of the data reported. All authors had full access to the data, and no limits were placed by the study sponsor with respect to statements made in this report.
Patients
Adults between the ages of 18 and 55 years with diagnosed asthma (>6 months) who requested medical care for an acute exacerbation of asthma were enrolled within 24 hours after presenting to an urgent care clinic, emergency room, or inpatient hospital setting. Inclusion criteria were increased wheeze and dyspnea, with a peak expiratory flow of less than 80 percent of the predicted value, as well as an ability to complete a diary of asthma symptoms, to perform a home test of peak expiratory flow, and to give written informed consent. Exclusion criteria included a need for immediate intensive care, a known allergic precipitant of the acute episode, a known lower respiratory tract disease other than asthma, a smoking history of 10 or more pack-years, the need for use of regular oral corticosteroids, antibiotic use within 30 days before enrollment, or an overt infection requiring specific antibiotic treatment.
Patients were able to continue their usual treatment for asthma — including all bronchodilators, inhaled corticosteroids, antileukotrienes, and theophylline — throughout the study. Patients who began taking an additional inhaled corticosteroid within three days before or after the exacerbation received a dose increment at the investigator's discretion, which remained unchanged throughout the study; those requiring oral corticosteroids for the exacerbation were prescribed a standardized regimen (prednisone at a daily dose of 30 mg for seven days).
Study Design
On a centrally randomized basis with the use of computer-generated codes, patients were assigned in a 1:1 ratio to receive either oral telithromycin (two 400-mg capsules daily) or placebo (two capsules identical in appearance) for 10 days. The baseline study visit occurred within 24 hours after initial presentation. The second visit took place at the end of the treatment period. Patients recorded diary cards of symptoms and peak expiratory flow rate in the morning for six weeks. Patients were not assessed for eligibility before initial presentation.
Efficacy Assessments
The primary efficacy assessments were a change from baseline in asthma-symptom scores and peak expiratory flow rates in the morning during the 10-day treatment period, on the basis of daily diaries of patients. Asthma symptoms were measured with the use of a modified diary-card symptom score in which patients rated the frequency and severity of their symptoms on a 7-point scale (with 0 denoting no symptoms and 6 denoting severe symptoms).7 The diary symptom score was calculated as the average of four daytime activity scores (the frequency of asthma symptoms, the severity of asthma symptoms, the level of activity, and the effect of asthma on activity) recorded in the evening and four individual symptom scores (wheezing, coughing, chest tightness, and shortness of breath) recorded in the morning. Patients recorded their peak expiratory flow rates in triplicate immediately after waking with the use of a Mini-Wright peak flow meter (Clement Clarke International). Patients also recorded their use of the study medication, albuterol, and other concomitant medications.
Secondary efficacy assessments included in-clinic pulmonary-function tests (see the Supplementary Appendix, available with the full text of this article at www.nejm.org). Details about the methods used in the detection of C. pneumoniae and M. pneumoniae are also available in the Supplementary Appendix.
Assessments of Adverse Events and Safety
Safety was assessed by the recording of adverse events and by standard monitoring. Patients who received at least one dose of study medication and had at least one safety assessment during treatment were included in the safety analysis. All adverse events that were spontaneously reported and those identified by an investigator were coded with the use of the Medical Dictionary for Regulatory Activities and were evaluated in terms of severity (mild, moderate, or severe) on the basis of clinical judgment and causality.
Statistical Analysis
The end point for power calculation was the daytime symptom score of patients. The enrollment of 120 patients per treatment group would provide the study with a statistical power of 80 percent (at P<0.05) to detect a 0.51 point (20 percent) difference between groups in the decrease from a presumed baseline score of 2.56.8
Efficacy end points were analyzed with the use of an analysis-of-covariance model with factors for treatment, study center (investigator), treatment-by-center interaction, and baseline as covariates. Treatment-by-center interaction was removed from the model if it was not significant at a level of 0.15. This was the case for the two primary end points and one secondary end point (in-clinic peak expiratory flow). Analyses of the change from baseline to the end of treatment in the other secondary end points — a change in forced expiratory volume in one second (FEV1), FEV1 as a percentage of the predicted value, forced vital capacity (FVC), and forced expiratory flow at 25 to 75 percent of FVC (FEF25–75) — revealed a significant treatment-by-center interaction. Longitudinal analyses were based on the average during the six-week study period. The means within the treatment groups and between-group differences were estimated by analysis of covariance, and between-group tests were used to compare the effects of telithromycin with those of placebo.
In the models used, the treatment effect was estimated by adjusting for the factors of center, treatment-by-center interaction (for FEV1, FEV1 as expressed as a percentage of predicted value, FVC, and FEF25–75), and for baseline values as covariates. This adjusted model accounts for the difference in the number of patients enrolled at centers. All mean data for efficacy outcomes are presented as least-square means since they result from this adjusted model.
Improvements in asthma symptoms that patients recorded during the 10-day treatment period were compared by analysis of variance and analysis of covariance. Analyses included the mean change in symptom score during the treatment period (with daily observations averaged for the first 10 days) and the mean change in symptoms from baseline to the end of treatment (with the last observation compared with the baseline observation).
Results
A total of 278 patients were enrolled in the study between January 2003 and March 2004 (Figure 1). Baseline demographic characteristics were well balanced between treatment groups (Table 1), as was the severity of exacerbations in terms of baseline pulmonary function. In the telithromycin group, the mean FEV1 was 67.5 percent of the predicted value (as compared with 66.9 percent in the placebo group), and the mean peak expiratory flow was 53.5 percent of the predicted value (as compared with 56.9 percent in the placebo group) (Table 1). These values corresponded to the criteria for moderate-to-severe exacerbations recommended by the National Asthma Education and Prevention Program.9 During the treatment period, patients in the two groups were also well matched with respect to the percentage receiving oral or inhaled corticosteroids (prescribed by investigators), with 34.1 percent of patients in the telithromycin group receiving oral corticosteroids (as compared with 32.6 percent in the placebo group) and 83.3 percent receiving inhaled corticosteroids (as compared with 83.7 percent in the placebo group), as well as the use of short-acting -agonists (a mean of 5.5 puffs per day in the telithromycin group and 5.4 puffs per day in the placebo group). The FEV1:FVC ratio at baseline showed airway obstruction consistent with the presence of asthma (Table 1).
Figure 1. Study Design.
During the initial randomization, 8 of 278 patients were erroneously assigned to an incorrect treatment group and were removed from the study, leaving 270 patients who were randomly assigned to receive either telithromycin (134 patients) or placebo (136 patients).
Table 1. Baseline Characteristics of the Patients.
Efficacy
Primary Outcome Measures
Patients in the telithromycin group had significantly greater improvement in asthma symptoms during the study period than did those in the placebo group (Figure 2). The mean (±SD) symptom scores at baseline were 3.0±1.4 for the telithromycin group and 2.8±1.3 for the placebo group in the intention-to-treat population. The telithromycin group had a mean decrease in symptom scores of 1.3 points during the treatment period, as compared with 1.0 point in the placebo group (mean difference, –0.3 point; 95 percent confidence interval, –0.5 to –0.1; P=0.004). This difference was equal to a 40.4 percent reduction in symptoms for the telithromycin group and a 26.5 percent reduction for the placebo group (mean difference, –13.9 percentage points; 95 percent confidence interval, –23.4 to –4.3; P=0.005). These parametric analyses were confirmed by a Wilcoxon rank-sum test (P<0.01).
Figure 2. Change in Symptom Scores from Baseline to the End of Treatment (Panel A) and the Average Scores during Treatment (Panel B) in the Intention-to-Treat Population.
Symptom scores were obtained from daily diary cards filled out by the patients. On the basis of the modeled data, significant treatment differences between telithromycin and placebo were observed both in the summary symptom scores from baseline to the end of treatment (mean difference, –0.4 point; 95 percent confidence interval, –0.7 to –0.2; P=0.002) and in the average scores during treatment (mean difference, –0.3 point; 95 percent confidence interval, –0.5 to –0.1; P=0.004).
There was no significant treatment-related difference between the groups with respect to peak expiratory flow rates in the morning, as recorded by patients at home. The mean improvement in the telithromycin group was 78.3 liters per minute, as compared with 66.8 liters per minute in the placebo group (P=0.28) (Figure 3).
Figure 3. Change in Peak Expiratory Flow Rates from Baseline to the End of Treatment (Panel A) and the Average Rates during Treatment (Panel B), as Recorded by Patients in the Morning in the Intention-to-Treat Population.
On the basis of modeled data, no significant treatment differences were observed in the rates from baseline to the end of treatment (mean difference, 3.6 liters per minute; 95 percent confidence interval; –32.5 to 25.3; P=0.81) or in the average rates during treatment (mean difference, 11.5 liters per minute; 95 percent confidence interval, –9.4 to 32.5; P=0.28).
Secondary Outcome Measures
The mean decrease in the asthma symptom scores from baseline to the end of treatment was 1.7 points for the telithromycin group and 1.3 points for the placebo group (mean difference, –0.4 point; 95 percent confidence interval, –0.7 to –0.2; P=0.002), equating to a reduction of 51.1 percent for the telithromycin group as compared with 28.5 percent for the placebo group (mean difference, –22.6 percentage points; 95 percent confidence interval, –36.6 to –7.9; P=0.003) (Figure 2).
Patients receiving telithromycin also had some improvement in symptom scores, as compared with the placebo group, during the entire study period, with a mean decrease from baseline of 1.6 points in the telithromycin group and 1.4 points in the placebo group (mean difference, –0.2 point; 95 percent confidence interval, –0.5 to 0.02; P=0.066), which was equal to a 51.1 percent reduction in the telithromycin group and a 38.3 percent reduction in the placebo group (mean difference, –12.8 percentage points; 95 percent confidence interval, –24.8 to –0.9; P=0.04).
During the treatment period, the proportion of symptom-free days (days when all symptom scores in the diary were zero divided by the number of days for which the patient provided scores) was significantly greater in the telithromycin group than in the placebo group (16 percent vs. 8 percent, P=0.006).
Improvement in FEV1 from baseline to the end of treatment was 0.63 liter in the telithromycin group, as compared with 0.34 liter in the placebo group (mean difference, 0.29 liter; 95 percent confidence interval, 0.12 to 0.46; P=0.001) (Figure 4). A significant treatment benefit from baseline to the end of treatment was observed for all in-clinic pulmonary-function tests, with a mean difference in peak expiratory flow rate of 26.9 liters per minute between the telithromycin group and the placebo group (95 percent confidence interval, 1.8 to 52.1; P=0.04), a mean difference in FVC of 0.27 liter (95 percent confidence interval, 0.08 to 0.45; P=0.006), and a mean difference in FEF25–75 of 0.40 liter per second (95 percent confidence interval, 0.13 to 0.67; P=0.004). None of the pulmonary-function tests showed a significant treatment effect by the sixth week of the study (see the Supplementary Appendix).
Figure 4. Mean (±SE) Changes in FEV1 from Baseline at Study Visits among 126 Patients Treated with Telithromycin and 129 Given Placebo.
Values are for the intention-to-treat population.
Status of C. Pneumoniae and M. Pneumoniae at Baseline
A total of 61 percent of patients met at least one criterion for infection with C. pneumoniae, M. pneumoniae, or both (Table 1). Most criteria for infection were serologic, since no positive cultures and only three positive polymerase-chain-reaction (PCR) assays were obtained (one for C. pneumoniae and two for M. pneumoniae).
The magnitude of improvement in FEV1 after treatment with telithromycin was similar in the subgroups with and without evidence of infection with C. pneumoniae, M. pneumoniae, or both at baseline. However, the difference in improvement between treatment groups was only significant in the subgroup of 131 patients in the FEV1 analysis who were positive for infection (61 in the telithromycin group and 70 in the placebo group), with a mean of 0.67 liter in the telithromycin group and 0.38 liter in the placebo group, for a difference of 0.29 liter (95 percent confidence interval, 0.11 to 0.47; P=0.002). Among the 82 patients in the FEV1 analysis who tested negative for infection (41 in the telithromycin group and 41 in the placebo group), the difference was not significant, with a mean 0.58 liter in the telithromycin group and 0.46 liter in the placebo group, for a difference of 0.12 liter (95 percent confidence interval, –0.21 to 0.43; P=0.486). No significant differences in treatment effect on the asthma symptom scores or peak expiratory flow rates were observed between the subgroup that tested positive for infection and the one that tested negative, and neither subgroup showed a significant treatment effect.
Post Hoc Analysis
A post hoc subgroup comparison of patients who did and those who did not receive investigator-prescribed oral corticosteroids revealed no significant difference in the magnitude of treatment effect for change from baseline over the treatment period in symptom scores. Among the 85 patients who received oral corticosteroids, the mean decrease from baseline was 1.6 points in the telithromycin group and 1.3 points in the placebo group (mean difference, –0.3 point; 95 percent confidence interval, –0.6 to 0.1; P=0.09). Among the 170 patients who did not receive oral corticosteroids, the mean decrease from baseline was 1.1 points in the telithromycin group and 0.8 point in the placebo group (mean difference, –0.3 point; 95 percent confidence interval, –0.6 to –0.03; P=0.03).
Adverse Events
A total of 263 patients were able to be included in the safety analysis (132 in the telithromycin group and 131 in the placebo group). The frequency of adverse events associated with treatment was similar in the two groups (38.6 percent in the telithromycin group and 39.7 percent in the placebo group, P=0.90), with the majority of events being mild to moderate. Adverse events were considered to be possibly related to treatment in 44 patients, including 27 in the telithromycin group (20.5 percent) and 17 in the placebo group (13.0 percent) (P=0.14). Nausea was significantly more common in the telithromycin group than in the placebo group (P=0.01) (Table 2). Elevations in levels of alanine aminotransferase or aspartate aminotransferase that were at least three times the upper limit of normal were observed in two patients in the telithromycin group and none in the placebo group. Both patients had liver-enzyme levels that had been above normal at baseline, including levels of alanine aminotransferase that were 2.8 and 3.0 times the upper limit of normal, respectively, at baseline, and 3.0 and 4.9 times the upper limit of normal, respectively, at the end of treatment. No serious hepatic adverse events were reported during the study.
Table 2. Adverse Events Occurring among at Least 2 Percent of Patients in the Safety Population.
None of the six serious adverse events reported during the study and follow-up period were considered to be treatment related. These events included four cases of an exacerbation of asthma symptoms (two in the telithromycin group and two in the placebo group) and a case of serious constipation and another of pelvic inflammatory disease in the telithromycin group.
Discussion
Among adults with acute exacerbations of asthma who were treated with telithromycin, there was a split outcome in the primary end points. Patients in the telithromycin group had a significantly greater improvement in asthma symptoms during the 10-day treatment period but did not have an improvement in peak expiratory flow rates as measured in the morning at home. There was a significant improvement in a number of prespecified secondary outcomes with telithromycin treatment, including improvement in asthma symptoms from baseline to the end of treatment, in the proportion of symptom-free days, and in four assessments of lung function: FEV1, peak expiratory flow (as measured by investigators), FVC, and FEF25–75. The difference between treatment groups in lung function is of potential clinical significance. However, the difference in symptom scores was small and less than the difference between groups that was used to calculate the number of patients needed for the study (an observed decrease of 0.3 point, vs. the decrease used to calculate sample size of 0.5 point). Post hoc analysis of the time until patients had a 50 percent reduction in symptoms revealed significantly faster improvement among patients in the telithromycin group than among those in the placebo group (five days vs. eight days, P=0.03). If this difference is confirmed by further study, it would be of clinical importance.
The observed effects were achieved in addition to "usual care" prescribed for asthma exacerbations (including a standardized regimen of oral prednisone if considered necessary). Although the study prospectively focused on the efficacy of telithromycin in the early period (the first 10 days) after an exacerbation, a significant improvement in symptoms, though not in pulmonary function, was observed during the 6-week study period. The frequency of adverse events that were noted with telithromycin was consistent with that in previous reports.10
Although this placebo-controlled study provides evidence regarding the role of treatment with a specific antibiotic in acute exacerbations of asthma, it does not provide clinical guidance. A Cochrane systematic review identified only two previous placebo-controlled studies of antibiotics in acute asthma, neither of which demonstrated any benefit associated with antibiotic use.11 Both studies enrolled only a small number of hospitalized patients (60 adults and 37 children), most of whom showed no sign of bacterial infection, and both studies used antimicrobial therapy that was ineffective against atypical bacteria.11
The possible role of C. pneumoniae and M. pneumoniae in the pathogenesis of asthma remains controversial.12 Controlled studies of macrolides for the treatment of chronic asthma have only shown small benefit and only in some end points.13,14 The positive effect we observed in acute exacerbations may relate to antibacterial activity against C. pneumoniae and M. pneumoniae, immunomodulatory effects, or other mechanisms. The efficacy of telithromycin through antibacterial activity is supported by the finding that 61 percent of patients tested positive for infection with C. pneumoniae, M. pneumoniae, or both and perhaps by the observation that the effect of telithromycin on FEV1 was significant in patients who tested positive for infection but not in patients who tested negative. However, the magnitude of treatment effects on FEV1 in the group that tested positive for infection was similar to that in the group that tested negative for infection, and the lack of a significant difference in the group that tested negative for infection could simply relate to the smaller number of patients in that group. Furthermore, there were no significant differences between the groups in terms of the other study outcomes. The interpretation of the study results with respect to C. pneumoniae and M. pneumoniae infection is problematic because of the lack of accurate standardized laboratory tests to diagnose infection with these organisms.15,16 The lack of positive results on PCR assay was surprising, since we have recently demonstrated increased frequency of detection of C. pneumoniae among patients with asthma,17 most likely related to low-grade colonization or reactivation.18 Reactivation occurs in a host with immunologic memory, and a low microbial burden is likely; the low rate of positive results on PCR assay is therefore perhaps understandable. Other factors that could have contributed to the low rate are poor-quality specimen collection at centers that do not specialize in sputum sampling. Further studies will be required to elucidate the mechanisms of action of telithromycin.
An assessment of the clinical significance of these observations is difficult because of the lack of information on alternative therapies. Two randomized, controlled trials showed no evidence of improved outcome with a doubling of the dose of inhaled corticosteroids at the onset of an exacerbation.19,20 Although a course of oral corticosteroids is standard treatment practice, it is remarkable that to our knowledge, there are no published studies comparing oral corticosteroids with placebo in the treatment of exacerbations of asthma. It is therefore impossible to compare the magnitude of the differences observed between telithromycin and placebo in this study with those resulting from treatment with oral corticosteroids. Further study is required to reveal the relative magnitude of the two treatment effects.
A recent report has highlighted three cases of severe liver injury among patients treated with telithromycin.21 Our study is too small to give reliable information regarding extremely rare adverse events. However, the safety of telithromycin was considered in detail in a submission to the Food and Drug Administration (FDA). In this submission, safety data were summarized regarding 4841 patients in phase 3 controlled efficacy studies and 24,137 patients in a large study comparing telithromycin with amoxicillin–clavulanate in the treatment of sinusitis, acute exacerbations of chronic bronchitis, and pneumonia. In both instances, among patients with normal liver aminotransferase levels at entry, the incidence of elevations of at least three times the upper limit of normal after treatment was similar among patients receiving telithromycin and drugs used for comparison.22 The FDA had received reports of the three cases recently published as part of the MedWatch reporting system. In June 2005, the Office of Drug Safety looked at adverse events associated with telithromycin, including hepatic adverse events, and concluded that there was no new information that changed its assessment of the hepatic safety.23 Although it is difficult to determine the actual frequency of adverse events from voluntary reporting systems, such as the MedWatch program, the FDA is continuing to improve its understanding of the frequency of liver-related adverse events reported for approved antibiotics, including telithromycin. Telithromycin has been licensed for treatment of sinusitis, acute exacerbations of chronic bronchitis, and pneumonia since 2001, and an estimated 22 million courses of treatment have been prescribed. Severe hepatic events have been reported with most antibiotics used in the treatment of community-acquired respiratory tract infections, including macrolides, fluoroquinolones, and some -lactams (including amoxicillin–clavulanate).
In conclusion, among adult patients with acute exacerbations of asthma, telithromycin (at a daily dose of 800 mg for 10 days) led to an improvement in symptoms and in lung-function tests performed in the clinic but not in home-measured peak expiratory flow rates. Further studies are required to confirm these results, to further define patient populations who are most likely to benefit from the treatment, and to elucidate the mechanisms of action.
Dr. Johnston reports having received consulting fees from Sanofi-Aventis, Pfizer, and GlaxoSmithKline. Dr. Blasi reports having received consulting fees from Bayer, Pfizer, Sanofi-Aventis, Altana, and GlaxoSmithKline; lecture fees from Bayer, Sanofi-Aventis, Pfizer, Abbott, Altana, and GlaxoSmithKline; and grant support from GlaxoSmithKline, Pfizer, Altana, and Abbott. Drs. Black and Martin report having received consulting fees from Sanofi-Aventis. Dr. Farrell reports having received consulting fees and grant support from Sanofi-Aventis. Dr. Nieman was employed by Aventis Pharmaceuticals at the time of the study, is currently employed by Berlex (U.S. affiliate of Schering AG), and currently has equity and stock options in Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
We are indebted to Cheryl Pinto of PPD in Morrisville, N.C., for statistical advice; to Shannon Jackson of PPD and Jennifer Pluim of Sanofi-Aventis, for study management; and to the patients who participated in the trial.
* Other investigators in the Telithromycin, Chlamydophila, and Asthma trial (TELICAST) are listed in the Appendix.
Source Information
From the National Heart and Lung Institute, Imperial College London (S.L.J.); and G.R. Micro (D.J.F.) — both in London; the University of Milan, Istituto di Ricovero e cura a Carattere Scientifico Policlinico, Milan (F.B.); the University of Auckland, Auckland, New Zealand (P.N.B.); the National Jewish Medical and Research Center, Denver (R.J.M.); and Sanofi-Aventis, Bridgewater, N.J. (R.B.N.).
Address reprint requests to Dr. Johnston at the Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Pl., London W2 1PG, United Kingdom, or at s.johnston@imperial.ac.uk.
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Background We conducted a double-blind, randomized, placebo-controlled study to evaluate the efficacy of telithromycin in patients with acute exacerbations of asthma.
Methods A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an acute exacerbation of asthma requiring short-term medical care. The patients were randomly assigned to receive 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care. Primary efficacy end points were a change from baseline over the treatment period in symptoms (as recorded by patients in a diary card) and in the peak expiratory flow in the morning at home. The presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was ascertained by serologic analysis, polymerase chain reaction, and culture.
Results Of the two prespecified primary outcomes, only asthma symptoms showed a significantly greater reduction among patients receiving telithromycin than among those receiving placebo. Mean (±SD) scores on a test of asthma symptoms (on a 7-point scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.0±1.4 at baseline and 1.7±1.1 at the end of treatment for the telithromycin group and 2.8±1.3 at baseline and 2.0±1.0 at the end of treatment for the placebo group. The mean decrease in symptom scores during the treatment period was 1.3 for telithromycin and 1.0 for placebo (mean difference, –0.3; 95 percent confidence interval, –0.5 to –0.1; P=0.004). There was no significant treatment effect on the other primary outcome measure, a change in morning peak expiratory flow. Nausea was more common among patients in the telithromycin group than in the placebo group (P=0.01). Although 61 percent of patients had evidence of infection with C. pneumoniae, M. pneumoniae, or both, there was no relationship between bacteriologic status and the response to asthma treatment.
Conclusions This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear. (ClinicalTrials.gov number, NCT00273520 .)
Ketolides are a new class of antibiotics that are structurally related to macrolides1 and have a bactericidal effect against Chlamydophila pneumoniae and Mycoplasma pneumoniae.2,3,4 Like macrolides, the ketolide telithromycin (Ketek, Sanofi-Aventis) has immunomodulatory effects both in vitro and in vivo.5,6 It is not known whether treatment with a ketolide could improve treatment of an exacerbation of asthma.
The Telithromycin, Chlamydophila, and Asthma trial (TELICAST) was designed to determine whether a 10-day course of telithromycin, as compared with placebo, in combination with standard therapy improves symptoms and peak expiratory flow rates in the morning among patients with an acute exacerbation of asthma who have no clinically obvious need for antibiotic treatment.
Methods
In this double-blind, parallel-group, randomized, placebo-controlled, multicenter, multinational study, we evaluated the efficacy and safety of oral telithromycin (at a dose of 800 mg daily) for patients with an acute exacerbation of asthma. The study was performed in accordance with the good clinical-practice guidelines recommended by the International Conference on Harmonisation of Technical Requirements and was approved by the ethics committee at each center. All patients provided written informed consent.
The study was designed by two authors from academic institutions and one representative of the sponsor, with input from an advisory board that included all authors. Data were held and analyzed by the contract research organization Pharmaceutical Product Development under guidance from the study sponsor, with input from all authors. An academic author reviewed the statistical-analysis plan. Drs. Johnston and Nieman vouch for the accuracy and completeness of the data reported. All authors had full access to the data, and no limits were placed by the study sponsor with respect to statements made in this report.
Patients
Adults between the ages of 18 and 55 years with diagnosed asthma (>6 months) who requested medical care for an acute exacerbation of asthma were enrolled within 24 hours after presenting to an urgent care clinic, emergency room, or inpatient hospital setting. Inclusion criteria were increased wheeze and dyspnea, with a peak expiratory flow of less than 80 percent of the predicted value, as well as an ability to complete a diary of asthma symptoms, to perform a home test of peak expiratory flow, and to give written informed consent. Exclusion criteria included a need for immediate intensive care, a known allergic precipitant of the acute episode, a known lower respiratory tract disease other than asthma, a smoking history of 10 or more pack-years, the need for use of regular oral corticosteroids, antibiotic use within 30 days before enrollment, or an overt infection requiring specific antibiotic treatment.
Patients were able to continue their usual treatment for asthma — including all bronchodilators, inhaled corticosteroids, antileukotrienes, and theophylline — throughout the study. Patients who began taking an additional inhaled corticosteroid within three days before or after the exacerbation received a dose increment at the investigator's discretion, which remained unchanged throughout the study; those requiring oral corticosteroids for the exacerbation were prescribed a standardized regimen (prednisone at a daily dose of 30 mg for seven days).
Study Design
On a centrally randomized basis with the use of computer-generated codes, patients were assigned in a 1:1 ratio to receive either oral telithromycin (two 400-mg capsules daily) or placebo (two capsules identical in appearance) for 10 days. The baseline study visit occurred within 24 hours after initial presentation. The second visit took place at the end of the treatment period. Patients recorded diary cards of symptoms and peak expiratory flow rate in the morning for six weeks. Patients were not assessed for eligibility before initial presentation.
Efficacy Assessments
The primary efficacy assessments were a change from baseline in asthma-symptom scores and peak expiratory flow rates in the morning during the 10-day treatment period, on the basis of daily diaries of patients. Asthma symptoms were measured with the use of a modified diary-card symptom score in which patients rated the frequency and severity of their symptoms on a 7-point scale (with 0 denoting no symptoms and 6 denoting severe symptoms).7 The diary symptom score was calculated as the average of four daytime activity scores (the frequency of asthma symptoms, the severity of asthma symptoms, the level of activity, and the effect of asthma on activity) recorded in the evening and four individual symptom scores (wheezing, coughing, chest tightness, and shortness of breath) recorded in the morning. Patients recorded their peak expiratory flow rates in triplicate immediately after waking with the use of a Mini-Wright peak flow meter (Clement Clarke International). Patients also recorded their use of the study medication, albuterol, and other concomitant medications.
Secondary efficacy assessments included in-clinic pulmonary-function tests (see the Supplementary Appendix, available with the full text of this article at www.nejm.org). Details about the methods used in the detection of C. pneumoniae and M. pneumoniae are also available in the Supplementary Appendix.
Assessments of Adverse Events and Safety
Safety was assessed by the recording of adverse events and by standard monitoring. Patients who received at least one dose of study medication and had at least one safety assessment during treatment were included in the safety analysis. All adverse events that were spontaneously reported and those identified by an investigator were coded with the use of the Medical Dictionary for Regulatory Activities and were evaluated in terms of severity (mild, moderate, or severe) on the basis of clinical judgment and causality.
Statistical Analysis
The end point for power calculation was the daytime symptom score of patients. The enrollment of 120 patients per treatment group would provide the study with a statistical power of 80 percent (at P<0.05) to detect a 0.51 point (20 percent) difference between groups in the decrease from a presumed baseline score of 2.56.8
Efficacy end points were analyzed with the use of an analysis-of-covariance model with factors for treatment, study center (investigator), treatment-by-center interaction, and baseline as covariates. Treatment-by-center interaction was removed from the model if it was not significant at a level of 0.15. This was the case for the two primary end points and one secondary end point (in-clinic peak expiratory flow). Analyses of the change from baseline to the end of treatment in the other secondary end points — a change in forced expiratory volume in one second (FEV1), FEV1 as a percentage of the predicted value, forced vital capacity (FVC), and forced expiratory flow at 25 to 75 percent of FVC (FEF25–75) — revealed a significant treatment-by-center interaction. Longitudinal analyses were based on the average during the six-week study period. The means within the treatment groups and between-group differences were estimated by analysis of covariance, and between-group tests were used to compare the effects of telithromycin with those of placebo.
In the models used, the treatment effect was estimated by adjusting for the factors of center, treatment-by-center interaction (for FEV1, FEV1 as expressed as a percentage of predicted value, FVC, and FEF25–75), and for baseline values as covariates. This adjusted model accounts for the difference in the number of patients enrolled at centers. All mean data for efficacy outcomes are presented as least-square means since they result from this adjusted model.
Improvements in asthma symptoms that patients recorded during the 10-day treatment period were compared by analysis of variance and analysis of covariance. Analyses included the mean change in symptom score during the treatment period (with daily observations averaged for the first 10 days) and the mean change in symptoms from baseline to the end of treatment (with the last observation compared with the baseline observation).
Results
A total of 278 patients were enrolled in the study between January 2003 and March 2004 (Figure 1). Baseline demographic characteristics were well balanced between treatment groups (Table 1), as was the severity of exacerbations in terms of baseline pulmonary function. In the telithromycin group, the mean FEV1 was 67.5 percent of the predicted value (as compared with 66.9 percent in the placebo group), and the mean peak expiratory flow was 53.5 percent of the predicted value (as compared with 56.9 percent in the placebo group) (Table 1). These values corresponded to the criteria for moderate-to-severe exacerbations recommended by the National Asthma Education and Prevention Program.9 During the treatment period, patients in the two groups were also well matched with respect to the percentage receiving oral or inhaled corticosteroids (prescribed by investigators), with 34.1 percent of patients in the telithromycin group receiving oral corticosteroids (as compared with 32.6 percent in the placebo group) and 83.3 percent receiving inhaled corticosteroids (as compared with 83.7 percent in the placebo group), as well as the use of short-acting -agonists (a mean of 5.5 puffs per day in the telithromycin group and 5.4 puffs per day in the placebo group). The FEV1:FVC ratio at baseline showed airway obstruction consistent with the presence of asthma (Table 1).
Figure 1. Study Design.
During the initial randomization, 8 of 278 patients were erroneously assigned to an incorrect treatment group and were removed from the study, leaving 270 patients who were randomly assigned to receive either telithromycin (134 patients) or placebo (136 patients).
Table 1. Baseline Characteristics of the Patients.
Efficacy
Primary Outcome Measures
Patients in the telithromycin group had significantly greater improvement in asthma symptoms during the study period than did those in the placebo group (Figure 2). The mean (±SD) symptom scores at baseline were 3.0±1.4 for the telithromycin group and 2.8±1.3 for the placebo group in the intention-to-treat population. The telithromycin group had a mean decrease in symptom scores of 1.3 points during the treatment period, as compared with 1.0 point in the placebo group (mean difference, –0.3 point; 95 percent confidence interval, –0.5 to –0.1; P=0.004). This difference was equal to a 40.4 percent reduction in symptoms for the telithromycin group and a 26.5 percent reduction for the placebo group (mean difference, –13.9 percentage points; 95 percent confidence interval, –23.4 to –4.3; P=0.005). These parametric analyses were confirmed by a Wilcoxon rank-sum test (P<0.01).
Figure 2. Change in Symptom Scores from Baseline to the End of Treatment (Panel A) and the Average Scores during Treatment (Panel B) in the Intention-to-Treat Population.
Symptom scores were obtained from daily diary cards filled out by the patients. On the basis of the modeled data, significant treatment differences between telithromycin and placebo were observed both in the summary symptom scores from baseline to the end of treatment (mean difference, –0.4 point; 95 percent confidence interval, –0.7 to –0.2; P=0.002) and in the average scores during treatment (mean difference, –0.3 point; 95 percent confidence interval, –0.5 to –0.1; P=0.004).
There was no significant treatment-related difference between the groups with respect to peak expiratory flow rates in the morning, as recorded by patients at home. The mean improvement in the telithromycin group was 78.3 liters per minute, as compared with 66.8 liters per minute in the placebo group (P=0.28) (Figure 3).
Figure 3. Change in Peak Expiratory Flow Rates from Baseline to the End of Treatment (Panel A) and the Average Rates during Treatment (Panel B), as Recorded by Patients in the Morning in the Intention-to-Treat Population.
On the basis of modeled data, no significant treatment differences were observed in the rates from baseline to the end of treatment (mean difference, 3.6 liters per minute; 95 percent confidence interval; –32.5 to 25.3; P=0.81) or in the average rates during treatment (mean difference, 11.5 liters per minute; 95 percent confidence interval, –9.4 to 32.5; P=0.28).
Secondary Outcome Measures
The mean decrease in the asthma symptom scores from baseline to the end of treatment was 1.7 points for the telithromycin group and 1.3 points for the placebo group (mean difference, –0.4 point; 95 percent confidence interval, –0.7 to –0.2; P=0.002), equating to a reduction of 51.1 percent for the telithromycin group as compared with 28.5 percent for the placebo group (mean difference, –22.6 percentage points; 95 percent confidence interval, –36.6 to –7.9; P=0.003) (Figure 2).
Patients receiving telithromycin also had some improvement in symptom scores, as compared with the placebo group, during the entire study period, with a mean decrease from baseline of 1.6 points in the telithromycin group and 1.4 points in the placebo group (mean difference, –0.2 point; 95 percent confidence interval, –0.5 to 0.02; P=0.066), which was equal to a 51.1 percent reduction in the telithromycin group and a 38.3 percent reduction in the placebo group (mean difference, –12.8 percentage points; 95 percent confidence interval, –24.8 to –0.9; P=0.04).
During the treatment period, the proportion of symptom-free days (days when all symptom scores in the diary were zero divided by the number of days for which the patient provided scores) was significantly greater in the telithromycin group than in the placebo group (16 percent vs. 8 percent, P=0.006).
Improvement in FEV1 from baseline to the end of treatment was 0.63 liter in the telithromycin group, as compared with 0.34 liter in the placebo group (mean difference, 0.29 liter; 95 percent confidence interval, 0.12 to 0.46; P=0.001) (Figure 4). A significant treatment benefit from baseline to the end of treatment was observed for all in-clinic pulmonary-function tests, with a mean difference in peak expiratory flow rate of 26.9 liters per minute between the telithromycin group and the placebo group (95 percent confidence interval, 1.8 to 52.1; P=0.04), a mean difference in FVC of 0.27 liter (95 percent confidence interval, 0.08 to 0.45; P=0.006), and a mean difference in FEF25–75 of 0.40 liter per second (95 percent confidence interval, 0.13 to 0.67; P=0.004). None of the pulmonary-function tests showed a significant treatment effect by the sixth week of the study (see the Supplementary Appendix).
Figure 4. Mean (±SE) Changes in FEV1 from Baseline at Study Visits among 126 Patients Treated with Telithromycin and 129 Given Placebo.
Values are for the intention-to-treat population.
Status of C. Pneumoniae and M. Pneumoniae at Baseline
A total of 61 percent of patients met at least one criterion for infection with C. pneumoniae, M. pneumoniae, or both (Table 1). Most criteria for infection were serologic, since no positive cultures and only three positive polymerase-chain-reaction (PCR) assays were obtained (one for C. pneumoniae and two for M. pneumoniae).
The magnitude of improvement in FEV1 after treatment with telithromycin was similar in the subgroups with and without evidence of infection with C. pneumoniae, M. pneumoniae, or both at baseline. However, the difference in improvement between treatment groups was only significant in the subgroup of 131 patients in the FEV1 analysis who were positive for infection (61 in the telithromycin group and 70 in the placebo group), with a mean of 0.67 liter in the telithromycin group and 0.38 liter in the placebo group, for a difference of 0.29 liter (95 percent confidence interval, 0.11 to 0.47; P=0.002). Among the 82 patients in the FEV1 analysis who tested negative for infection (41 in the telithromycin group and 41 in the placebo group), the difference was not significant, with a mean 0.58 liter in the telithromycin group and 0.46 liter in the placebo group, for a difference of 0.12 liter (95 percent confidence interval, –0.21 to 0.43; P=0.486). No significant differences in treatment effect on the asthma symptom scores or peak expiratory flow rates were observed between the subgroup that tested positive for infection and the one that tested negative, and neither subgroup showed a significant treatment effect.
Post Hoc Analysis
A post hoc subgroup comparison of patients who did and those who did not receive investigator-prescribed oral corticosteroids revealed no significant difference in the magnitude of treatment effect for change from baseline over the treatment period in symptom scores. Among the 85 patients who received oral corticosteroids, the mean decrease from baseline was 1.6 points in the telithromycin group and 1.3 points in the placebo group (mean difference, –0.3 point; 95 percent confidence interval, –0.6 to 0.1; P=0.09). Among the 170 patients who did not receive oral corticosteroids, the mean decrease from baseline was 1.1 points in the telithromycin group and 0.8 point in the placebo group (mean difference, –0.3 point; 95 percent confidence interval, –0.6 to –0.03; P=0.03).
Adverse Events
A total of 263 patients were able to be included in the safety analysis (132 in the telithromycin group and 131 in the placebo group). The frequency of adverse events associated with treatment was similar in the two groups (38.6 percent in the telithromycin group and 39.7 percent in the placebo group, P=0.90), with the majority of events being mild to moderate. Adverse events were considered to be possibly related to treatment in 44 patients, including 27 in the telithromycin group (20.5 percent) and 17 in the placebo group (13.0 percent) (P=0.14). Nausea was significantly more common in the telithromycin group than in the placebo group (P=0.01) (Table 2). Elevations in levels of alanine aminotransferase or aspartate aminotransferase that were at least three times the upper limit of normal were observed in two patients in the telithromycin group and none in the placebo group. Both patients had liver-enzyme levels that had been above normal at baseline, including levels of alanine aminotransferase that were 2.8 and 3.0 times the upper limit of normal, respectively, at baseline, and 3.0 and 4.9 times the upper limit of normal, respectively, at the end of treatment. No serious hepatic adverse events were reported during the study.
Table 2. Adverse Events Occurring among at Least 2 Percent of Patients in the Safety Population.
None of the six serious adverse events reported during the study and follow-up period were considered to be treatment related. These events included four cases of an exacerbation of asthma symptoms (two in the telithromycin group and two in the placebo group) and a case of serious constipation and another of pelvic inflammatory disease in the telithromycin group.
Discussion
Among adults with acute exacerbations of asthma who were treated with telithromycin, there was a split outcome in the primary end points. Patients in the telithromycin group had a significantly greater improvement in asthma symptoms during the 10-day treatment period but did not have an improvement in peak expiratory flow rates as measured in the morning at home. There was a significant improvement in a number of prespecified secondary outcomes with telithromycin treatment, including improvement in asthma symptoms from baseline to the end of treatment, in the proportion of symptom-free days, and in four assessments of lung function: FEV1, peak expiratory flow (as measured by investigators), FVC, and FEF25–75. The difference between treatment groups in lung function is of potential clinical significance. However, the difference in symptom scores was small and less than the difference between groups that was used to calculate the number of patients needed for the study (an observed decrease of 0.3 point, vs. the decrease used to calculate sample size of 0.5 point). Post hoc analysis of the time until patients had a 50 percent reduction in symptoms revealed significantly faster improvement among patients in the telithromycin group than among those in the placebo group (five days vs. eight days, P=0.03). If this difference is confirmed by further study, it would be of clinical importance.
The observed effects were achieved in addition to "usual care" prescribed for asthma exacerbations (including a standardized regimen of oral prednisone if considered necessary). Although the study prospectively focused on the efficacy of telithromycin in the early period (the first 10 days) after an exacerbation, a significant improvement in symptoms, though not in pulmonary function, was observed during the 6-week study period. The frequency of adverse events that were noted with telithromycin was consistent with that in previous reports.10
Although this placebo-controlled study provides evidence regarding the role of treatment with a specific antibiotic in acute exacerbations of asthma, it does not provide clinical guidance. A Cochrane systematic review identified only two previous placebo-controlled studies of antibiotics in acute asthma, neither of which demonstrated any benefit associated with antibiotic use.11 Both studies enrolled only a small number of hospitalized patients (60 adults and 37 children), most of whom showed no sign of bacterial infection, and both studies used antimicrobial therapy that was ineffective against atypical bacteria.11
The possible role of C. pneumoniae and M. pneumoniae in the pathogenesis of asthma remains controversial.12 Controlled studies of macrolides for the treatment of chronic asthma have only shown small benefit and only in some end points.13,14 The positive effect we observed in acute exacerbations may relate to antibacterial activity against C. pneumoniae and M. pneumoniae, immunomodulatory effects, or other mechanisms. The efficacy of telithromycin through antibacterial activity is supported by the finding that 61 percent of patients tested positive for infection with C. pneumoniae, M. pneumoniae, or both and perhaps by the observation that the effect of telithromycin on FEV1 was significant in patients who tested positive for infection but not in patients who tested negative. However, the magnitude of treatment effects on FEV1 in the group that tested positive for infection was similar to that in the group that tested negative for infection, and the lack of a significant difference in the group that tested negative for infection could simply relate to the smaller number of patients in that group. Furthermore, there were no significant differences between the groups in terms of the other study outcomes. The interpretation of the study results with respect to C. pneumoniae and M. pneumoniae infection is problematic because of the lack of accurate standardized laboratory tests to diagnose infection with these organisms.15,16 The lack of positive results on PCR assay was surprising, since we have recently demonstrated increased frequency of detection of C. pneumoniae among patients with asthma,17 most likely related to low-grade colonization or reactivation.18 Reactivation occurs in a host with immunologic memory, and a low microbial burden is likely; the low rate of positive results on PCR assay is therefore perhaps understandable. Other factors that could have contributed to the low rate are poor-quality specimen collection at centers that do not specialize in sputum sampling. Further studies will be required to elucidate the mechanisms of action of telithromycin.
An assessment of the clinical significance of these observations is difficult because of the lack of information on alternative therapies. Two randomized, controlled trials showed no evidence of improved outcome with a doubling of the dose of inhaled corticosteroids at the onset of an exacerbation.19,20 Although a course of oral corticosteroids is standard treatment practice, it is remarkable that to our knowledge, there are no published studies comparing oral corticosteroids with placebo in the treatment of exacerbations of asthma. It is therefore impossible to compare the magnitude of the differences observed between telithromycin and placebo in this study with those resulting from treatment with oral corticosteroids. Further study is required to reveal the relative magnitude of the two treatment effects.
A recent report has highlighted three cases of severe liver injury among patients treated with telithromycin.21 Our study is too small to give reliable information regarding extremely rare adverse events. However, the safety of telithromycin was considered in detail in a submission to the Food and Drug Administration (FDA). In this submission, safety data were summarized regarding 4841 patients in phase 3 controlled efficacy studies and 24,137 patients in a large study comparing telithromycin with amoxicillin–clavulanate in the treatment of sinusitis, acute exacerbations of chronic bronchitis, and pneumonia. In both instances, among patients with normal liver aminotransferase levels at entry, the incidence of elevations of at least three times the upper limit of normal after treatment was similar among patients receiving telithromycin and drugs used for comparison.22 The FDA had received reports of the three cases recently published as part of the MedWatch reporting system. In June 2005, the Office of Drug Safety looked at adverse events associated with telithromycin, including hepatic adverse events, and concluded that there was no new information that changed its assessment of the hepatic safety.23 Although it is difficult to determine the actual frequency of adverse events from voluntary reporting systems, such as the MedWatch program, the FDA is continuing to improve its understanding of the frequency of liver-related adverse events reported for approved antibiotics, including telithromycin. Telithromycin has been licensed for treatment of sinusitis, acute exacerbations of chronic bronchitis, and pneumonia since 2001, and an estimated 22 million courses of treatment have been prescribed. Severe hepatic events have been reported with most antibiotics used in the treatment of community-acquired respiratory tract infections, including macrolides, fluoroquinolones, and some -lactams (including amoxicillin–clavulanate).
In conclusion, among adult patients with acute exacerbations of asthma, telithromycin (at a daily dose of 800 mg for 10 days) led to an improvement in symptoms and in lung-function tests performed in the clinic but not in home-measured peak expiratory flow rates. Further studies are required to confirm these results, to further define patient populations who are most likely to benefit from the treatment, and to elucidate the mechanisms of action.
Dr. Johnston reports having received consulting fees from Sanofi-Aventis, Pfizer, and GlaxoSmithKline. Dr. Blasi reports having received consulting fees from Bayer, Pfizer, Sanofi-Aventis, Altana, and GlaxoSmithKline; lecture fees from Bayer, Sanofi-Aventis, Pfizer, Abbott, Altana, and GlaxoSmithKline; and grant support from GlaxoSmithKline, Pfizer, Altana, and Abbott. Drs. Black and Martin report having received consulting fees from Sanofi-Aventis. Dr. Farrell reports having received consulting fees and grant support from Sanofi-Aventis. Dr. Nieman was employed by Aventis Pharmaceuticals at the time of the study, is currently employed by Berlex (U.S. affiliate of Schering AG), and currently has equity and stock options in Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
We are indebted to Cheryl Pinto of PPD in Morrisville, N.C., for statistical advice; to Shannon Jackson of PPD and Jennifer Pluim of Sanofi-Aventis, for study management; and to the patients who participated in the trial.
* Other investigators in the Telithromycin, Chlamydophila, and Asthma trial (TELICAST) are listed in the Appendix.
Source Information
From the National Heart and Lung Institute, Imperial College London (S.L.J.); and G.R. Micro (D.J.F.) — both in London; the University of Milan, Istituto di Ricovero e cura a Carattere Scientifico Policlinico, Milan (F.B.); the University of Auckland, Auckland, New Zealand (P.N.B.); the National Jewish Medical and Research Center, Denver (R.J.M.); and Sanofi-Aventis, Bridgewater, N.J. (R.B.N.).
Address reprint requests to Dr. Johnston at the Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Pl., London W2 1PG, United Kingdom, or at s.johnston@imperial.ac.uk.
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