The n e w e ng l a n d j o u r na l of m e dic i n e

original article

The Effect of Telithromycin

in Acute Exacerbations of Asthma
Sebastian L. Johnston, M.D., Ph.D., Francesco Blasi, M.D.,
Peter N. Black, M.B., Ch.B., Richard J. Martin, M.D., David J. Farrell, Ph.D.,
and Richard B. Nieman, M.D., for the TELICAST Investigators*

A BS T R AC T

Background
We conducted a double-blind, randomized, placebo-controlled study to evaluate the From the National Heart and Lung Insti-
efficacy of telithromycin in patients with acute exacerbations of asthma. tute, Imperial College London (S.L.J.); and
G.R. Micro (D.J.F.) both in London; the
University of Milan, Istituto di Ricovero
Methods e cura a Carattere Scientifico Policlinico,
A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an Milan (F.B.); the University of Auckland,
Auckland, New Zealand (P.N.B.); the Na-
acute exacerbation of asthma requiring short-term medical care. The patients were tional Jewish Medical and Research Cen-
randomly assigned to receive 10 days of oral treatment with telithromycin (at a dose ter, Denver (R.J.M.); and Sanofi-Aventis,
of 800 mg daily) or placebo in addition to usual care. Primary efficacy end points Bridgewater, N.J. (R.B.N.). Address reprint
requests to Dr. Johnston at the Depart-
were a change from baseline over the treatment period in symptoms (as recorded ment of Respiratory Medicine, National
by patients in a diary card) and in the peak expiratory flow in the morning at home. Heart and Lung Institute and Wright
The presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was ascertained Fleming Institute of Infection and Immu-
nity, Imperial College London, Norfolk Pl.,
by serologic analysis, polymerase chain reaction, and culture. London W2 1PG, United Kingdom, or at
s.johnston@imperial.ac.uk.
Results
*Other investigators in the Telithromy-
Of the two prespecified primary outcomes, only asthma symptoms showed a signifi- cin, Chlamydophila, and Asthma trial
cantly greater reduction among patients receiving telithromycin than among those (TELICAST) are listed in the Appendix.
receiving placebo. Mean (SD) scores on a test of asthma symptoms (on a 7-point
N Engl J Med 2006;354:1589-600.
scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.01.4 Copyright 2006 Massachusetts Medical Society.
at baseline and 1.71.1 at the end of treatment for the telithromycin group and
2.81.3 at baseline and 2.01.0 at the end of treatment for the placebo group. The
mean decrease in symptom scores during the treatment period was 1.3 for telithro-
mycin 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 pri-
mary 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.)

n engl j med 354;15 www.nejm.org april 13, 2006 1589

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
K
etolides are a new class of antibi-
otics that are structurally related to macro-
lides1 and have a bactericidal effect against
Chlamydophila pneumoniae and Mycoplasma pneumoni-
ae.2-4 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 Asth-
ma trial (TELICAST) was designed to determine
whether a 10-day course of telithromycin, as com-
pared with placebo, in combination with stan-
dard therapy improves symptoms and peak expi-
ratory flow rates in the morning among patients
with an acute exacerbation of asthma who have no
clinically obvious need for antibiotic treatment.
Me thods
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 pa-
tients 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 pro-
vided 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 Pharmaceu-
tical 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 inpa-
tient hospital setting. Inclusion criteria were in-
1590 n engl j med 354;15
The New England Journal of Medicine
Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
creased wheeze and dyspnea, with a peak expira-
tory 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 im-
mediate intensive care, a known allergic precipi-
tant of the acute episode, a known lower respira-
tory tract disease other than asthma, a smoking
history of 10 or more pack-years, the need for use
of regular oral corticosteroids, antibiotic use with-
in 30 days before enrollment, or an overt infection
requiring specific antibiotic treatment.
Patients were able to continue their usual treat-
ment for asthma including all bronchodilators,
inhaled corticosteroids, antileukotrienes, and the-
ophylline 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 investigators
discretion, which remained unchanged through-
out the study; those requiring oral corticosteroids
for the exacerbation were prescribed a standard-
ized 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 cap-
sules 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 re-
corded diary cards of symptoms and peak expira-
tory flow rate in the morning for six weeks. Pa-
tients 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 mea-
sured with the use of a modified diary-card symp-
tom 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
www.nejm.org april 13, 2006
 telithromycin in acute exacerbations of asthma
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 short-
ness of breath) recorded in the morning. Patients
recorded their peak expiratory flow rates in trip-
licate immediately after waking with the use of a
Mini-Wright peak flow meter (Clement Clarke In-
ternational). Patients also recorded their use of
the study medication, albuterol, and other con-
comitant medications.
Secondary efficacy assessments included in-
clinic pulmonary-function tests (see the Supple-
mentary 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 Sup-
plementary 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 treat-
ment were included in the safety analysis. All ad-
verse 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 clini-
cal judgment and causality.
Statistical Analysis
The end point for power calculation was the day-
time symptom score of patients. The enrollment
of 120 patients per treatment group would pro-
vide the study with a statistical power of 80 per-
cent (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), treat-
ment-by-center interaction, and baseline as covar-
iates. 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 pri-
mary 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
n engl j med 354;15
The New England Journal of Medicine
Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
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 (FEF2575) revealed
a significant treatment-by-center interaction. Lon-
gitudinal analyses were based on the average dur-
ing the six-week study period. The means within
the treatment groups and between-group differ-
ences 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 FEF2575), and for baseline values as co-
variates. 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 pa-
tients recorded during the 10-day treatment pe-
riod were compared by analysis of variance and
analysis of covariance. Analyses included the
mean change in symptom score during the treat-
ment period (with daily observations averaged for
the first 10 days) and the mean change in symp-
toms from baseline to the end of treatment (with
the last observation compared with the baseline
observation).
R e sult s
A total of 278 patients were enrolled in the study
between January 2003 and March 2004 (Fig. 1).
Baseline demographic characteristics were well
balanced between treatment groups (Table 1), as
was the severity of exacerbations in terms of base-
line pulmonary function. In the telithromycin
group, the mean FEV1 was 67.5 percent of the pre-
dicted 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 recommend-
ed by the National Asthma Education and Pre-
vention 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 investiga-
www.nejm.org april 13, 2006 1591
 The n e w e ng l a n d j o u r na l of m e dic i n e

278 Patients enrolled

138 Assigned to placebo
140 Assigned to telithromycin

8 Excluded
2 Erroneously assigned
to placebo
6 Erroneously assigned
to telithromycin

270 Patients underwent

randomization

136 Assigned to placebo 134 Assigned to telithromycin

6 Terminated treatment early

1 Withdrew consent
5 Were lost to follow-up 8 Terminated treatment early
3 Had adverse event
1 Withdrew consent
3 Were lost to follow-up
1 Had other reason
1 Withdrew from analysis
(no baseline diary data)

129 Completed 10 days 126 Completed 10 days

of treatment of treatment
(intention-to-treat population) (intention-to-treat population)

10 Terminated study early 14 Terminated study early

3 Had adverse event 5 Had adverse event
2 Had lack of efficacy 3 Withdrew consent
2 Had protocol violation 5 Were lost to follow-up
3 Were lost to follow-up 1 Had other reason

119 Completed 6 weeks 112 Completed 6 weeks

of follow-up of follow-up

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).

tors), with 34.1 percent of patients in the telithro-
mycin 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 -ago-
nists (a mean of 5.5 puffs per day in the telithro-
mycin 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).

1592 n engl j med 354;15 www.nejm.org april 13, 2006

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
 telithromycin in acute exacerbations of asthma
Efficacy
Primary Outcome Measures
Patients in the telithromycin group had signifi-
cantly greater improvement in asthma symptoms
during the study period than did those in the
placebo group (Fig. 2). The mean (SD) symptom
scores at baseline were 3.01.4 for the telithro-
mycin group and 2.81.3 for the placebo group
in the intention-to-treat population. The telithro-
mycin 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 confi-
dence interval, 0.5 to 0.1; P = 0.004). This dif-
ference 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 dif-
ference, 13.9 percentage points; 95 percent confi-
dence interval, 23.4 to 4.3; P = 0.005). These
parametric analyses were confirmed by a Wilcox-
on rank-sum test (P<0.01).
There was no significant treatment-related dif-
ference 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 min-
ute, as compared with 66.8 liters per minute in
the placebo group (P = 0.28) (Fig. 3).
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 differ-
ence, 22.6 percentage points; 95 percent confi-
dence interval, 36.6 to 7.9; P = 0.003) (Fig. 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).
n engl j med 354;15
The New England Journal of Medicine
Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
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 telithro-
mycin group than in the placebo group (16 per-
cent 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 con-
fidence interval, 0.12 to 0.46; P = 0.001) (Fig. 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 li-
ters per minute between the telithromycin group
and the placebo group (95 percent confidence in-
terval, 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
FEF2575 of 0.40 liter per second (95 percent con-
fidence interval, 0.13 to 0.67; P = 0.004). None of
the pulmonary-function tests showed a signifi-
cant treatment effect by the sixth week of the study
(see the Supplementary Appendix).
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. pneu-
moniae, or both (Table 1). Most criteria for infec-
tion 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 infec-
tion 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 telithro-
mycin 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 differ-
ence 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 pla-
cebo group), the difference was not significant,
www.nejm.org april 13, 2006 1593
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Baseline Characteristics of the Patients.*

Telithromycin Placebo
Characteristic (N = 140) (N = 138)
Demographic characteristics
Age yr
Mean 39.5 39.6
Range 1764 1768
Race or ethnic group no. (%)
White 112 (88.9) 122 (94.6)
Black 3 (2.4) 1 (0.8)
Asian 5 (4.0) 3 (2.3)
Hispanic 1 (0.8) 0
Other 5 (4.0) 3 (2.3)
Sex no. (%)
Male 39 (31.0) 50 (38.8)
Female 87 (69.0) 79 (61.2)
Asthma history
Time since diagnosis yr
Median 13.3 13.1
Range 146 151
Acute exacerbations in the past year no. (%)
0 34 (24.3) 28 (20.3)
1 43 (30.7) 33 (23.9)
23 45 (32.1) 48 (34.8)
>3 18 (12.9) 29 (21.0)
Smoking history
Smoking status no. (%)
Current smoker 22 (15.7) 24 (17.4)
Former smoker 33 (23.6) 31 (22.5)
Never smoked 85 (60.7) 83 (60.1)
Mean no. of pack-years 2.03.2 2.36.3

with a mean 0.58 liter in the telithromycin group

did and those who did not receive investigator-
and 0.46 liter in the placebo group, for a differ-
prescribed oral corticosteroids revealed no signif-
ence of 0.12 liter (95 percent confidence interval,
icant difference in the magnitude of treatment
0.21 to 0.43; P = 0.486). No significant differ-
effect for change from baseline over the treat-
ences in treatment effect on the asthma symp- ment period in symptom scores. Among the 85
tom scores or peak expiratory flow rates were patients who received oral corticosteroids, the
observed between the subgroup that tested posi-mean decrease from baseline was 1.6 points in
tive for infection and the one that tested negative,
the telithromycin group and 1.3 points in the pla-
and neither subgroup showed a significant treat-
cebo group (mean difference, 0.3 point; 95 per-
ment effect. cent confidence interval, 0.6 to 0.1; P = 0.09).
Among the 170 patients who did not receive oral
Post Hoc Analysis corticosteroids, the mean decrease from baseline
A post hoc subgroup comparison of patients who was 1.1 points in the telithromycin group and 0.8

1594 n engl j med 354;15 www.nejm.org april 13, 2006

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
 telithromycin in acute exacerbations of asthma

Table 1. (Continued.)

Telithromycin Placebo
Characteristic (N = 140) (N = 138)
Bacteriologic status no. (%)
Chlamydophila pneumoniaepositive and Mycoplasma 4 (3.7) 1 (0.9)
pneumoniaepositive
C. pneumoniaenegative and M. pneumoniaepositive 4 (3.7) 4 (3.5)
C. pneumoniaepositive and M. pneumoniaenegative 57 (52.3) 67 (58.8)
C. pneumoniaenegative and M. pneumoniaenegative 44 (40.4) 42 (36.8)
Baseline pulmonary function
FEV1 liters 2.180.71 2.300.81
FEV1 % of predicted value 67.521.9 66.919.7
PEF liters/min 276.293.8 302.8114.6
PEF % of predicted value 53.516.9 56.919.0
FVC liters 3.000.84 3.241.04
FEF2575 liters/sec 1.841.10 2.031.21
FEV1:FVC ratio percent 7313 7115
Baseline symptom score and history of asthma medication
Mean summary symptom score in diary 3.01.4 2.81.3
Asthma medication taken in the 30 days before start of study
no. (%)
Inhaled corticosteroids 80 (63.5) 93 (72.1)
Oral corticosteroids 2 (1.6) 3 (2.3)
Long-acting bronchodilator 49 (38.9) 62 (48.1)

* Plusminus values are means SD. FEV1 denotes forced expiratory volume in one second, PEF peak expiratory flow,
FVC forced vital capacity, and FEF2575 forced expiratory flow at 25 to 75 percent of FVC. Percentages may not sum to
100 because of rounding.
Values are given for the 255 patients in the intention-to-treat population (126 in the telithromycin group and 129 in the
placebo group).
Race was self-reported.
Values are given for the 223 patients who underwent microbiologic evaluation (109 in the telithromycin group and 114
in the placebo group).
The majority of positive diagnoses were based on serologic criteria, since no positive cultures and only three positive
polymerase-chain-reaction assays were obtained (one for C. pneumoniae and two for M. pneumoniae).
Summary symptom scores were calculated on the basis of self-reported symptoms and levels of activity, with patients
rating the frequency and severity of their symptoms on a 7-point scale (with 0 denoting no symptoms and 6 denoting
severe symptoms).

point in the placebo group (mean difference, 0.3 be possibly related to treatment in 44 patients,
point; 95 percent confidence interval, 0.6 to including 27 in the telithromycin group (20.5 per-
0.03; P = 0.03. cent) and 17 in the placebo group (13.0 percent)
(P = 0.14). Nausea was significantly more common
Adverse Events in the telithromycin group than in the placebo
A total of 263 patients were able to be included in group (P = 0.01) (Table 2). Elevations in levels of
the safety analysis (132 in the telithromycin group alanine aminotransferase or aspartate amino-
and 131 in the placebo group). The frequency of transferase that were at least three times the up-
adverse events associated with treatment was sim- per limit of normal were observed in two patients
ilar in the two groups (38.6 percent in the telithro- in the telithromycin group and none in the place-
mycin group and 39.7 percent in the placebo group, bo group. Both patients had liver-enzyme levels
P = 0.90), with the majority of events being mild that had been above normal at baseline, includ-
to moderate. Adverse events were considered to ing levels of alanine aminotransferase that were

n engl j med 354;15 www.nejm.org april 13, 2006 1595

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Figure 2. Change in Symptom Scores from Baseline

Telithromycin (N=119)
Mean for telithromycin
6
Improvement
5 mycin and placebo were observed both in the summary
Baseline Symptom Score
to the End of Treatment (Panel A) and the Average
Placebo (N=121)
Scores during Treatment (Panel B) in the Intention-
Mean for placebo
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 telithro-
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

4
scores during treatment (mean difference, 0.3 point;
95 percent confidence interval, 0.5 to 0.1; P = 0.004).

3
2.8 and 3.0 times the upper limit of normal, re-
spectively, at baseline, and 3.0 and 4.9 times the
2 upper limit of normal, respectively, at the end of
treatment. No serious hepatic adverse events were
reported during the study.
1 None of the six serious adverse events reported
during the study and follow-up period were con-
sidered to be treatment related. These events in-
Worsening
0 cluded four cases of an exacerbation of asthma
0 1 2 3 4 5 6
symptoms (two in the telithromycin group and
Symptom Score at End of Treatment Period two in the placebo group) and a case of serious
B
constipation and another of pelvic inflammatory
disease in the telithromycin group.
Telithromycin (N=114) Placebo (N=119)
Mean for telithromycin Mean for placebo
6 Dis cus sion
Improvement

Among adults with acute exacerbations of asth-

ma who were treated with telithromycin, there
5
was a split outcome in the primary end points.
Patients in the telithromycin group had a signifi-
cantly greater improvement in asthma symptoms
Baseline Symptom Score

4
during the 10-day treatment period but did not
have an improvement in peak expiratory flow
3 rates as measured in the morning at home. There
was a significant improvement in a number of
prespecified secondary outcomes with telithromy-
2 cin treatment, including improvement in asthma
symptoms from baseline to the end of treatment,
in the proportion of symptom-free days, and in
1 four assessments of lung function: FEV1, peak ex-
piratory flow (as measured by investigators), FVC,
Worsening and FEF2575. The difference between treatment
0 groups in lung function is of potential clinical
0 1 2 3 4 5 6
significance. However, the difference in symptom
Average Symptom Score during Treatment
scores was small and less than the difference be-
tween groups that was used to calculate the num-
ber 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 analy-

1596 n engl j med 354;15 www.nejm.org april 13, 2006

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
 telithromycin in acute exacerbations of asthma

Figure 3. Change in Peak Expiratory Flow Rates A

from Baseline to the End of Treatment (Panel A) Telithromycin (N=125) Placebo (N=128)
and the Average Rates during Treatment (Panel B),
Mean for telithromycin Mean for placebo
as Recorded by Patients in the Morning in the Intention-
700
to-Treat Population. Worsening
On the basis of modeled data, no significant treatment
differences were observed in the rates from baseline to 600
the end of treatment (mean difference, 3.6 liters per

Baseline Peak Expiratory Flow Rate (liters/min)

minute; 95 percent confidence interval; 32.5 to 25.3;
P = 0.81) or in the average rates during treatment 500
(mean difference, 11.5 liters per minute; 95 percent
confidence interval, 9.4 to 32.5; P = 0.28).
400
sis of the time until patients had a 50 percent
reduction in symptoms revealed significantly fast-
300
er improvement among patients in the telithromy-
cin group than among those in the placebo group
(five days vs. eight days, P = 0.03). If this differ- 200
ence is confirmed by further study, it would be of
clinical importance.
100
The observed effects were achieved in addition
to usual care prescribed for asthma exacerba-
Improvement
tions (including a standardized regimen of oral 0
0 100 200 300 400 500 600 700
prednisone if considered necessary). Although
the study prospectively focused on the efficacy Peak Expiratory Flow Rate at End of Treatment (liters/min)

of telithromycin in the early period (the first 10

B
days) after an exacerbation, a significant improve-
Telithromycin (N=125) Placebo (N=128)
ment in symptoms, though not in pulmonary
Mean for telithromycin Mean for placebo
function, was observed during the 6-week study 700
period. The frequency of adverse events that were Worsening

noted with telithromycin was consistent with that

in previous reports.10 600
Although this placebo-controlled study pro-
Baseline Peak Expiratory Flow Rate (liters/min)

vides evidence regarding the role of treatment

with a specific antibiotic in acute exacerbations 500

of asthma, it does not provide clinical guidance.

A Cochrane systematic review identified only two 400
previous placebo-controlled studies of antibiotics
in acute asthma, neither of which demonstrated
any benefit associated with antibiotic use.11 Both 300
studies enrolled only a small number of hospi-
talized patients (60 adults and 37 children), most
200
of whom showed no sign of bacterial infection,
and both studies used antimicrobial therapy that
was ineffective against atypical bacteria.11 100
The possible role of C. pneumoniae and M. pneu-
moniae in the pathogenesis of asthma remains Improvement
controversial.12 Controlled studies of macrolides 0
0 100 200 300 400 500 600 700
for the treatment of chronic asthma have only
Average Peak Expiratory Flow Rate during Treatment (liters/min)
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,

n engl j med 354;15 www.nejm.org april 13, 2006 1597

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.

Change in FEV1 from Baseline (liters)
0.80
0.70
0.60
Telithromycin
0.50
0.40
0.30
0.20
0.10
0.00
0 1114
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.
Table 2. Adverse Events Occurring among at Least
2 Percent of Patients in the Safety Population.*
Telithromycin
Adverse Event
Diarrhea
Nausea
Upper abdominal
pain
* Comparisons between the treatment groups were per-
formed with Fishers exact test.
immunomodulatory effects, or other mechanisms.
The efficacy of telithromycin through antibacterial
activity is supported by the finding that 61 per-
cent of patients tested positive for infection with
C. pneumoniae, M. pneumoniae, or both and perhaps
by the observation that the effect of telithromy-
cin on FEV1 was significant in patients who tested
positive for infection but not in patients who
tested negative. However, the magnitude of treat-
ment 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 differ-
ences between the groups in terms of the other
study outcomes. The interpretation of the study
results with respect to C. pneumoniae and M. pneu-
moniae infection is problematic because of the
1598
The New England Journal of Medicine
Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
lack of accurate standardized laboratory tests to
diagnose infection with these organisms.15,16 The
P=0.001
0.63
lack of positive results on PCR assay was surpris-
0.60 ing, since we have recently demonstrated increased
0.54
0.51 frequency of detection of C. pneumoniae among
0.50
patients with asthma,17 most likely related to low-
0.34 grade colonization or reactivation.18 Reactivation
occurs in a host with immunologic memory, and
Placebo a low microbial burden is likely; the low rate of
positive results on PCR assay is therefore perhaps
28 (3) 42 (3) understandable. Other factors that could have
Day contributed to the low rate are poor-quality speci-
men collection at centers that do not specialize
in sputum sampling. Further studies will be re-
quired 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 ran-
domized, controlled trials showed no evidence of
improved outcome with a doubling of the dose
Placebo P of inhaled corticosteroids at the onset of an ex-
(N = 132) (N = 131) Value* acerbation.19,20 Although a course of oral corti-
no. (%) costeroids is standard treatment practice, it is
13 (9.8) 5 (3.8) 0.085 remarkable that to our knowledge, there are no
7 (5.3) 0 0.014 published studies comparing oral corticosteroids
with placebo in the treatment of exacerbations
5 (3.8) 2 (1.5) 0.447
of asthma. It is therefore impossible to compare
the magnitude of the differences observed be-
tween telithromycin and placebo in this study
with those resulting from treatment with oral
corticosteroids. Further study is required to re-
veal 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 reli-
able 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 submis-
sion, safety data were summarized regarding 4841
patients in phase 3 controlled efficacy studies and
24,137 patients in a large study comparing telithro-
mycin with amoxicillinclavulanate in the treat-
ment of sinusitis, acute exacerbations of chronic
bronchitis, and pneumonia. In both instances,
among patients with normal liver aminotrans-
ferase levels at entry, the incidence of elevations
of at least three times the upper limit of normal
after treatment was similar among patients re-
ceiving telithromycin and drugs used for com-
n engl j med 354;15 www.nejm.org april 13, 2006
 telithromycin in acute exacerbations of asthma

parison.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 im-
prove its understanding of the frequency of liver-
related adverse events reported for approved anti-
biotics, including telithromycin. Telithromycin has
been licensed for treatment of sinusitis, acute
exacerbations of chronic bronchitis, and pneu-
monia 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 amoxicillinclavulanate).
In conclusion, among adult patients with acute
exacerbations of asthma, telithromycin (at a daily
dose of 800 mg for 10 days) led to an improve-
ment 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 de-
fine 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 hav-
ing received consulting fees from Bayer, Pfizer, Sanofi-Aventis, Al-
tana, and GlaxoSmithKline; lecture fees from Bayer, Sanofi-Aven-
tis, 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-Aven-
tis. Dr. Farrell reports having received consulting fees and grant
support from Sanofi-Aventis. Dr. Nieman was employed by Aven-
tis 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 pa-
tients who participated in the trial.

appendix
The following is a list of principal TELICAST investigators: R. Akhras, TMG, Toronto; E. Beck, Praxis, Rudersdorf, Germany; P. Black,
Auckland Hospital, Auckland, New Zealand; B. Bugnas, Cabinet De Pneumologie, Nice, France; P. Carles, Hpital Purpan, Toulouse,
France; S. Centanni, Unita Dipartimentale di Pneumologia, Milan; A. Cheema, Clinical Research Group 2000, Mississauga, Canada;
J. Chien, Finch Midland Medical Centre, Scarborough, Canada; M. Chilvers, TMG, Toronto; J. Corne, Queens Medical Centre, Notting-
ham, United Kingdom; R. Cosentini, Irccs Ospedale Maggiore, Milan; J.-M. Coursier, Hpital Priv dAntony, Antony, France; J. Doug-
las, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; A. Durzo, Primary Care Lung Clinic, Toronto; P. Dzongowski, TMG, Toronto;
D. Elkharrat, Hpital Lariboisire, Paris; J. Eller, Praxis, Berlin; F. Falcone, Ospedale Bellaria di Bologna, Bologna, Italy; F. Fraser, Stoney
Creek Clinical Trials, Stoney Creek, Canada; Y.-D. Gagnon (private practice), Rimouski, Canada; R. Gebhardt (private practice), Berlin;
P. Gibson, John Hunter Hospital, New Lampton Heights, Australia; A. Gillissen, Robert Koch Klinik, Leipzig, Germany; U. Harnest
(private practice), Munich, Germany; M. Humbert, Hpital Antoine Bclre, Clamart, France; G. Jebrak, Hpital Beaujon, Clichy,
France; P. Kardos (private practice), Frankfurt, Germany; J. Karrasch, Peninsula Clinical Research Centre, Kippa Ring, Australia; A.
Kelly, R.J.A. Medicenters Canada, Edmonton, Canada; B. Lasko, Manna Research, Toronto; A. Linnhoff (private practice), Berlin; G.
Matheson, TMG, Toronto; I. Mayers, University of Alberta Hospital, Edmonton, Canada; F. Menivale, Hpital de la Maison Blanche,
Reims, France; G. Mills, Waikato Hospital, Hamilton, New Zealand; A. Morice, Hull Royal Infirmary, Hull, United Kingdom; R. Dal
Negro, Ospedale di Bussolengo, Verona, Italy; M. OMahony, London Road Diagnostic Clinic and Medical Centre, Sarnia, Canada; W.
OMahony (private practice), Corunna, Canada; P.L. Paggiaro, Ospedale di Cisanello, Pisa, Italy; M. Peters, Concord Repatriation General
Hospital, Concord, Australia; C. Powell, Dr. Powell Medical Clinic, Bay Roberts, Canada; A. Prudhomme, C.H.I. Tarbes, France; S.
Salmeron, Fondation Hpital Saint-Joseph, Paris; R. Schnorr (private practice), Berlin; U. Schubart (private practice), Vilsheim, Germany; S.
Sharma, St. Boniface General Hospital, Winnipeg, Canada; C. Tantucci, Universit di Brescia, Brescia, Italy; T. Welte, Otto-von-Guer-
icke-Universitt, Magdeburg, Germany; N. Withers, Royal Devon and Exeter Hospital, Exeter, United Kingdom; and P. Zuck, Hpital
Notre Dame Bon Secours, Metz, France.

References
1. Ackermann G, Rodloff AC. Drugs of
the 21st century: telithromycin (HMR
3647) the first ketolide. J Antimicrob
Chemother 2003;51:497-511.
2. Hammerschlag MR, Roblin PM, Bb-
ar CM. Activity of telithromycin, a new
ketolide antibacterial, against atypical and
intracellular respiratory tract pathogens.
J Antimicrob Chemother 2001;48:Suppl:
25-31.
3. Yamaguchi T, Hirakata Y, Izumikawa
K, et al. In vitro activity of telithromycin
(HMR 3647), a new ketolide, against clin-
ical isolates of Mycoplasma pneumoniae in
Japan. Antimicrob Agents Chemother 2000;
44:1381-2.
4. Roblin PM, Hammerschlag MR. In vitro
activity of a new ketolide antibiotic, HMR
3647, against Chlamydia pneumoniae. Anti-
microb Agents Chemother 1998;42:1515-6.
5. Araujo FG, Slifer TL, Remington JS.
Inhibition of secretion of interleukin-1
and tumor necrosis factor alpha by the
ketolide antibacterial telithromycin. Anti-
microb Agents Chemother 2002;46:3327-
30.
6. Nicolau DP, Tessier PR, Rubenstein I,
Nightingale CH. In vivo immunomodula-
tory profile of telithromycin in a murine
infection model. Clin Microbiol Infect
2003;9:Suppl 1:397. abstract.
7. Santanello NC, Barber BL, Reiss TF,
Friedman BS, Juniper EF, Zhang J. Mea-
surement characteristics of two asthma
symptom diary scales for use in clinical
trials. Eur Respir J 1997;10:646-51.
8. Altman LC, Munk Z, Seltzer J, et al.
A placebo-controlled, dose-ranging study
of montelukast, a cysteinyl leukotriene-

n engl j med 354;15 www.nejm.org april 13, 2006 1599

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
 telithromycin in acute exacerbations of asthma

receptor antagonist. J Allergy Clin Immu-
nol 1998;102:50-6.
9. National Asthma Education and Pre-
vention Program. Expert Panel Report:
guidelines for the diagnosis and manage-
ment of asthma update on selected topics
2002. J Allergy Clin Immunol 2002;110:
Suppl 5:S141-S219.
10. Carbon C. A pooled analysis of telithro-
mycin in the treatment of community-
acquired respiratory tract infections in
adults. Infection 2003;31:308-17.
11. Graham V, Lasserson T, Rowe BH.
Antibiotics for acute asthma. Cochrane
Database Syst Rev 2001;3:CD002741.
12. Johnston SL, Martin RJ. Chlamydophila
pneumoniae and Mycoplasma pneumoniae:
a role in asthma pathogenesis? Am J Respir
Crit Care Med 2005;172:1078-89.
13. Black PN, Blasi F, Jenkins CR, et al.
Trial of roxithromycin in subjects with
asthma and serological evidence of infec-
tion with Chlamydia pneumoniae. Am J Respir
Crit Care Med 2001;164:536-41.
14. Kraft M, Cassell GH, Pak J, Martin RJ.
Mycoplasma pneumoniae and Chlamydia pneu-
moniae in asthma: effect of clarithromy-
cin. Chest 2002;121:1782-8.
15. Dowell SF, Peeling RW, Boman J, et al.
Standardizing Chlamydia pneumoniae assays:
recommendations from the Centers for
Disease Control and Prevention (USA) and
the Laboratory Centre for Disease Control
(Canada). Clin Infect Dis 2001;33:492-503.
16. Daxboeck F, Krause R, Wenisch C.
Laboratory diagnosis of Mycoplasma pneu-
moniae infection. Clin Microbiol Infect 2003;
9:263-73.
17. Biscione GL, Corne J, Chauhan AJ,
Johnston SL. Increased frequency of detec-
tion of Chlamydophila pneumoniae in asthma.
Eur Respir J 2004;24:745-9.
18. Wark PA, Johnston SL, Simpson JL,
Hensley MJ, Gibson PG. Chlamydia pneu-
moniae immunoglobulin A reactivation and
airway inflammation in acute asthma. Eur
Respir J 2002;20:834-40.
19. Harrison TW, Oborne J, Newton S,
Tattersfield AE. Doubling the dose of in-
haled corticosteroid to prevent asthma ex-
acerbations: randomised controlled trial.
Lancet 2004;363:271-5.
20. FitzGerald JM, Becker A, Sears MR,
et al. Doubling the dose of budesonide
versus maintenance treatment in asthma
exacerbations. Thorax 2004;59:550-6.
21. Clay KD, Hanson JS, Pope SD, Riss-
miller RW, Purdum PP III, Banks PM.
Brief communication: severe hepatotox-
icity of telithromycin: three case reports
and literature review. Ann Intern Med (in
press). (Accessed March 17, 2006, at http://
www.acponline.org/journals/annals/
hepatotoxicity.htm.)
22. Briefing document for the FDA Anti-
Infective Drug Products Advisory Com-
mittee Meeting, January 2003:96-131. (Ac-
cessed March 17, 2006, at http://www.fda.
gov/ohrms/dockets/ac/03/briefing/
3919B1_01_Aventis-KETEK.pdf.)
23. Food and Drug Administration, Cen-
ter for Drug Evaluation and Research.
Questions and answers on telithromycin
(marketed as Ketek). (Accessed March 17,
2006, at http:// www.fda.gov/cder/drug/
infopage/telithromycin/qa.htm.)
Copyright 2006 Massachusetts Medical Society.

CLINICAL TRIAL REGISTRATION

The Journal encourages investigators to register their clinical trials
in a public trials registry. The members of the International Committee
of Medical Journal Editors plan to consider clinical trials for publication
only if they have been registered (see N Engl J Med 2004;351:1250-1).
The National Library of Medicines www.clinicaltrials.gov is a free registry,
open to all investigators, that meets the committees requirements.

1600 n engl j med 354;15 www.nejm.org april 13, 2006

The New England Journal of Medicine

Downloaded from nejm.org on November 23, 2016. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.