PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
For publications based on this study, see associated bibliography.
PROPRIETARY DRUG NAME/INN: Zithromax®/Azithromycin
THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI
PROTOCOL NO.: A0661102
PROTOCOL TITLE: A Multicenter, Randomized, Double-Blind, Double-Dummy
Comparative Trial of Azithromycin SR Versus Levofloxacin for the Treatment of Acute
Exacerbation of Chronic Bronchitis (AECB)
Study Center(s): Study included 84 centers in Brazil (5), Canada (8), Costa Rica (1), Germany
(8), India (6), Lithuania (3), Mexico (1), Netherlands (2), Russian Federation (7), Spain (5),
United Kingdom (4), Venezuela (2), and the United States (32). Sixty-three of these centers
enrolled subjects (including screening failures).
Study Initiation and Completion Dates: 10 January 2003 to 31 March 2004
Phase of Development: Phase 3
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Study Objective(s):
Primary objective: To confirm the hypothesis that a single, 2.0 g dose of azithromycin SR is
clinically non-inferior to 7 days of levofloxacin 500 mg/day (two 250 mg capsules once daily),
when used to treat adults with AECB
Secondary objectives: To assess safety and the bacteriologic efficacy of both treatment regimens
METHODS
Study Design:
This was a randomized, double-blind, double-dummy, active-controlled, multicenter,
international study in which subjects with AECB were assigned to receive oral therapy with
azithromycin SR (a single 2.0 g dose) or levofloxacin (500 mg once daily for 7 days). Enrolled
subjects were stratified into 2 groups based on systemic steroid use at the time of randomization.
Clinical and bacteriologic responses were assessed at the Test of Cure (TOC) visit (14-21 days
post first dose) and Long Term Follow Up (LTFU) visit (28-35 days post first dose). All
subjects who received at least 1 dose of study medication were assessed for safety. All Baseline
pathogens were tested for susceptibility to azithromycin and levofloxacin according to NCCLS
procedures.
CLINICAL STUDY SYNOPSIS
Number of Patients (planned and analyzed):
A total of 530 subjects (265 per treatment arm) were planned for enrollment; 551 subjects were
randomized in the study, and 542 subjects received treatment (268 azithromycin SR, 274
levofloxacin).
Diagnosis and Main Criteria for Inclusion:
Eligible subjects were men or women ≥50 years of age, with a current or past history of smoking
of at least 20 pack-years, a diagnosis of chronic bronchitis (defined as chronic cough and sputum
production on most days for 3 consecutive months for >2 consecutive years), and clinical
evidence of AECB, as demonstrated by the production of purulent sputum (defined by the
presence of >25 polymorphonuclear leukocytes per low power field) and all of the following
signs and symptoms: increased sputum production, increased dyspnea, and increased sputum
purulence. Pack years were calculated by multiplying the average number of cigarette packs
smoked per day times the number of years smoked (eg, 2 packs per day times 15 years equals
30 pack years).
Study Treatment:
Azithromycin SR and matching placebo were supplied as white/off-white powder for oral
suspension in a 100-mL bottle. Azithromycin SR was administered orally as a single 2.0 g dose
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slurry, to be taken at least 1 hour before or 2 hours after a meal. Levofloxacin 250 mg and
matching placebo were supplied as black/blue (gray in Eastern Europe), opaque, hard gelatin
Size #0 capsules in a 60 mL bottle. Each bottle contained 14 capsules.
The study regimens were administered in a double-blind, double-dummy fashion. Subjects
assigned to receive azithromycin SR received their single dose of active azithromycin SR and
2 capsules of levofloxacin placebo on Day 1, and then continued with QD dosing of levofloxacin
placebo for the next 6 days. Subjects assigned to receive levofloxacin received azithromycin SR
placebo and 2 capsules of active levofloxacin on Day 1, and then continued with QD dosing of
active levofloxacin for the next 6 days. The first dose of each study medication was given in an
observed setting such that subjects took the single dose of azithromycin SR/placebo slurry then,
30 minutes later, 2 capsules of levofloxacin/placebo.
Efficacy Evaluations:
The primary efficacy parameter was the sponsor assessment of Clinical Response (clinical cure
rate) in the Clinical Per Protocol population at the TOC visit. The secondary efficacy parameter
was bacteriologic response (eradication rate) at the TOC visit. Additional secondary efficacy
parameters included: Investigator assessment of clinical response at the TOC visit, sponsor
assessment of clinical response by Baseline pathogen at the TOC visit, and clinical and
bacteriologic responses at LTFU. Susceptibilities of Baseline pathogens were also summarized.
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CLINICAL STUDY SYNOPSIS
Safety Evaluations:
Adverse events (AEs) were assessed for all treated subjects. Clinical laboratory tests
(hematology and blood chemistry) and vital signs were collected at Baseline and the End of
Treatment (EOT) visit. Physical examinations were done at Baseline and as deemed necessary
by the investigator at subsequent visits.
Statistical Methods:
Efficacy: The primary efficacy analysis compared clinical cure rates (based on sponsor-assessed
clinical response) of the azithromycin SR and levofloxacin regimens at the TOC visit
(Day 14-21) in the Clinical Per Protocol population. A 95% confidence interval (CI) for the
difference in cure rates was constructed based on normal approximation to the binomial
distribution with stratification for systemic steroid use. There was no adjustment for centers.
Azithromycin SR was considered non-inferior to levofloxacin if the lower limit of the 95% CI
for the difference in cure rates (azithromycin SR minus levofloxacin) was greater than -10%.
The CI for the difference in overall bacteriologic eradication rates was constructed using the
normal approximation to the binomial distribution and accounted for steroid use stratification.
Success for bacteriologic endpoints was based on combining the categories of eradication and
presumed eradication. For all other secondary efficacy endpoints, frequency tables for each
response were provided.
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Clinical Per Protocol Subjects were All Treated Subjects who had a diagnosis of chronic
bronchitis and clinical evidence of AECB, a negative chest radiograph for pneumonia, and who
received: at least 6 days of dosing of study medication (including both active and placebo doses),
no concomitant systemic antibiotic with activity against key AECB pathogens, and an
assessment in the appropriate visit window. Bacteriologic Per Protocol Subjects were Clinical
Per Protocol Subjects with a Baseline bacterial pathogen identified by culture.
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CLINICAL STUDY SYNOPSIS
RESULTS
Table S1 Subject Disposition and Demography:
Evaluation Group, N (%) of Subjectsa Azithromycin SR Levofloxacin
Screened 621
All Randomized 551
All Treated 268 274
Completed Study 249 (92.9) 251 (91.6)
Discontinued from Study 19 (7.1) 23 (8.4)
Evaluated for Primary Efficacyb 220 (82.1) 218 (79.6)
Analyzed for Safety:
Adverse Events 268 (100.0) 274 (100.0)
Laboratory Datac 258 (96.3) 260 (94.9)
a
Percentages are based on the All Treated Subjects.
b
Clinical Per Protocol Population at the TOC visit.
c
Number of treated subjects with at least one laboratory observation during the study.
Treatment groups were generally similar with respect to Baseline characteristics. An overview
of subject disposition and demography is shown in Table S1. Approximately 69% of all treated
subjects were men. The majority of subjects were white (60%), with a mean age of 62 years for
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both treatment groups. Systemic steroid use was similar (10%) in each group. In addition,
duration (in years) of the subjects’ underlying disease (chronic bronchitis), mean duration of
current exacerbation, and Baseline signs and symptoms were similar between treatment groups.
Treatment groups were similar with respect to the number and type of pathogens isolated at
Baseline, with M. catarrhalis and S. pneumoniae being the most common isolates. The number
of discontinuations was similar between the azithromycin SR treatment group (7.1%) and the
levofloxacin treatment group (8.4%). Reasons for discontinuation are listed in Table S2.
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CLINICAL STUDY SYNOPSIS
Table S2 Discontinuations From Study (All Treated Subjects)
Number (%) of Subjects Azithromycin SR Levofloxacin
N = 268 N = 274
Subject Died 0 (0.0) 2 (0.7)
Discontinuations
Related to Study Druga 7 (2.6) 7 (2.6)
Adverse Eventb 1 (0.4) 2 (0.7)
Lack of efficacy 6 (2.2) 5 (1.8)
Not Related to Study Druga 12 (4.5) 14 (5.1)
Adverse Eventb 2 (0.7) 7 (2.6)
Other 2 (0.7) 1 (0.4)
Subject Defaultedc 8 (3.0) 6 (2.2)
Total 19 (7.1) 23 (8.4)
a
Relationship to Study Drug is derived as Related if reason for discontinuation is Insufficient Clinical
Response (Lack of Efficacy), or due to a treatment-related adverse event; otherwise, Relationship is
derived as Not Related.
b
Includes only subjects who discontinued due to an adverse event (AE) according to their completed
subject summary CRF.
c
Includes subjects who discontinued due to the following reasons: Lost to Follow-Up or Subject No
Longer Willing to Participate in Study.
Baseline susceptibility: The majority of isolates were susceptible to both azithromycin and
levofloxacin, as shown below in Table S3.
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Table S3 Susceptibility of Specific Baseline Pathogens, Number of Pathogens
(All Randomized Subjects Without Regard to Treatment Group)
Susceptibilitya to Azithromycin Susceptibilitya to Levofloxacin
Baseline Pathogens Total S I R Not Total S I R Not
Testedb Testedb
H. influenzae 46 46 0 0 0 46 46 0 0 0
M. catarrhalis 57 0 0 0 57 57 0 0 0 57
S. aureus 32 20 0 12 0 32 27 4 1 0
S. pneumoniae 56 45 0 11 0 56 55 0 1 0
H. parainfluenzae 28 27 0 0 1 28 28 0 0 0
S = Susceptible, I = Intermediate, R = Resistant; susceptibility based upon current breakpoints per organism
for azithromycin and levofloxacin, Pathogens: Haemophilus influenzae (H. influenzae), Moraxella
catarrhalis (M. catarrhalis), Staphylococcus aureus (S. aureus), Streptococcus pneumoniae
(S. pneumoniae), and Haemophilus parainfluenzae (H. parainfluenzae).
a
Susceptibility results based on MIC and/or disk diffusion testing; disk result used only if MIC result
missing.
b
Not tested includes pathogens for which no NCCLS breakpoint criteria have been established.
Efficacy Results:
Primary Efficacy Results:
Subjects in the Clinical Per Protocol population treated with azithromycin SR had a clinical cure
rate at TOC of 93.6% compared with 92.7% for subjects treated with levofloxacin. The 95% CI
around the difference in cure rates at TOC was -3.4% to 5.5%. The lower limit of this CI was
greater than -10%, indicating that azithromycin SR therapy was non-inferior to levofloxacin
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CLINICAL STUDY SYNOPSIS
therapy in the treatment of AECB. Of those subjects who were assessed as clinical cure at TOC,
over 98% of the subjects in both treatment groups remained a clinical cure at the LTFU visit. A
summary of clinical response is shown in the Table S4.
Table S4 Summary of Clinical Response (Clinical Per Protocol Subjects)
Number (%) of Subjects
Azithromycin SR Levofloxacin 95% CIa
Subjects at TOC 220 218
Cure 206 (93.6) 202 (92.7) -3.4, 5.5
Failure 14 (6.4) 16 (7.3)
Subjects at LTFU 197 193
Cure 194 (98.5) 190 (98.4)
Relapse 3 (1.5) 3 (1.6)
Clinical response is sponsor assessed.
TOC=Test of Cure; LTFU=Long Term Follow-Up.
a
95% confidence interval for the treatment difference in cure rates; note that a lower limit > -10%
indicates non-inferiority.
In general, there were no remarkable differences between treatment groups in clinical cure rates
by gender, age, race, or steroid-use in the Clinical Per Protocol population.
Secondary Efficacy Results:
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Cure rates based upon the investigators’ assessment of clinical response for subjects in the
Clinical Per Protocol population at the TOC visit (shown in Table S5) were very similar to those
based upon the sponsor assessment of clinical response (shown in Table S6).
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CLINICAL STUDY SYNOPSIS
Table S5 Investigator Assessment of Clinical Response at TOC (Clinical Per Protocol
Subjects)
Investigator Assessment of Response, Azithromycin SR Levofloxacin
n (%) N = 220 N = 218
Cure 207 (94.1) 201 (92.2)
Failure 11 (5.0) 14 (6.4)
Signs/Symptoms persisted/worsened 9 (4.1) 11 (5.0)
New signs/symptoms 0 ─ 2 (0.9)
Developed pneumonia 2 (0.9) 1 (0.5)
Not Done 0 ─ 0 ─
Missing 2 (0.9) 3 (1.4)
TOC = Test of Cure.
Table S6 Sponsor Assessment of Clinical Response (Clinical Per Protocol Subjects),
Number (%) of Subjects
Azithromycin SR Levofloxacin Difference 95% CIa
Subjects at EOT 215 215
Cure 209 (97.2) 207 (96.3) — —
Failure 6 (2.8) 8 (3.7)
Subjects at TOC 220 218
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Cure 206 (93.6) 202 (92.7) 1.0 -3.4, 5.5
Failure 14 (6.4) 16 (7.3)
Subjects at LTFUb 197 193
Cure 194 (98.5) 190 (98.4) — —
Relapse 3 (1.5) 3 (1.6)
a
95% confidence interval for the difference in cure rates between treatment groups; a lower limit of > -10%
indicates non-inferiority.
b
LTFU includes subjects who are cured at TOC and have LTFU assessments.
EOT=End of Treatment; TOC=Test of Cure; LTFU=Long Term Follow-Up.
Clinical cure rates for all treated subjects are shown below in Table S8.
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CLINICAL STUDY SYNOPSIS
Table S7 Clinical Cure Rates at TOC by Baseline Characteristics: All Treated Subjects
Number Cured / Number of Subjects (%)
Characteristics Azithromycin SR Levofloxacin Total
N = 268 N = 274 N = 542
Gender
Male 162 / 177 (91.5) 174 / 196 (88.8) 336 / 373 (90.1)
Female 82 / 91 (90.1) 68 / 78 (87.2) 150 / 169 (88.8)
Age (years)
90%) in azithromycin SR-treated subjects who had documented
infection with S. pneumoniae, H. influenzae, or M. catarrhalis at Baseline. Treatment-related
adverse events occurred more frequently in azithromycin SR-treated subjects (24%) as compared
with levofloxacin-treated subjects (15%). Most events were mild or moderate digestive system
events. Single-dose treatment with azithromycin SR is safe and effective in the treatment of
AECB in adults.
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Based on a report completed on: 23 July 2004
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