Phase 3 CAP

1
A Phase 2/3 Comparative Study of the Safety
Efficacy of Two Oral Doses of Cethromycin for the
Treatment of Community Acquired Pneumonia
(CAP) S. Bukofzer1, Y. Gu1, D.A. Eiznhamer2,
Z.-Q. Xu2, T.R.J. Jenta2, M.L. Leski2, M.T.
Flavin2 1Abbott Laboratories, Abbott Park, IL,
2Advanced Life Sciences, Woodridge, IL
L-1445
Objectives
Results
Abstract
Background Cethromycin is a potent ketolide
antibacterial agent with activity against
clinically important Gram-positive bacteria,
including many macrolide resistant
strains. Methods This double-blind, randomized,
parallel-group, multi-national, multi-center
study compared the safety and efficacy of a
10-day course of therapy for two doses of
cethromycin (150 mg QD vs. 150 mg BID) in
ambulatory subjects with CAP. Entry criteria
were consistent with published guidelines for the
diagnosis of CAP. Clinical cure was the
improvement of all signs and symptoms of CAP
accompanied by improvement or lack of progression
in chest x-ray abnormalities. Results In this
study, 284 subjects received cethromycin 150 mg
QD and 299 subjects received cethromycin 150 mg
BID. Success rates () are shown in the Table.
No statistically significant difference was
observed between groups in treatment-emergent
gastrointestinal adverse events.
Statistically significant
difference at the plt0.05 level between the two
treatment groups Clin Bact Evaluable
Clinically Bacteriologically Evaluable Conclusi
ons Both cethromycin doses were safe and well
tolerated. Equivalence in the clinical cure
rate, overall bacteriological cure rate and
pathogen eradication rate was demonstrated in the
Intent-to-Treat population, however, higher
clinical cure rates in the clinically evaluable
and clinically and bacteriologically evaluable
population were observed in the 150 mg QD
treatment arm. Community acquired pneumonia
(CAP) is a common respiratory tract infection
that occurs worldwide. In the United States,
approximately 5-6 million cases of CAP occur
annually, the majority of which are treated in
the outpatient setting (1). Initial treatment of
CAP should cover the common typical and atypical
respiratory pathogens known to cause the disease,
such as Streptococcus pneumoniae, Haemophilus
influenzae, Moraxella catarrhalis, Chlamydia
pneumoniae, Mycoplasma pneumoniae, and Legionella
pneumophila (2). Currently, broad spectrum
antibiotics such as the macrolides, penicillins,
quinolones, and cephalosporins are used, however,
the emergence of bacterial resistance to these
and other antimicrobial agents is a worldwide
health problem (3, 4). Thus, antibiotics with
clinical activity against drug resistant
pathogens as well as less prone to foster
resistance are urgently needed. Cethromycin is
an investigational ketolide with an in vitro
bactericidal effect against CAP-causative
pathogens including macrolide-susceptible and
-resistant S. pneumoniae. A Phase II study
(L-1442) comparing 300 mg QD cethromycin versus
600 mg QD cethromycin demonstrated good clinical
cure rates and safety profiles that favored the
lower dose, warranting further investigation of
cethromycin for CAP therapy. 1. Niederman,
M.S., Mandell, L.A., Anzueto, A., Bass, J.B.,
Broughton, W.A., Campbell, G.D., Dean, N., File,
T., Fine, M.J., Gross, P.A., Martinez, F.,
Marrie, T.J., Plouffe, J.F., Ramirez, J., Sarosi,
G.A., Torres, A., Wilson, R., and Yu, V.L.
Guidelines for the management of adults with
community-acquired pneumonia. Diagnosis,
assessment of severity, antimicrobial therapy,
and prevention. Am J Respir Crit Care Med
163(7)1730-54, 2001. 2. Mandell, L.A.,
Bartlett, J.G., Dowell, S.F., File Jr, T.M.,
Musher, D.M., and Whitney, C. Update of practice
guidelines for the management of
community-acquired pneumonia in immunocompetent
adults. IDSA. Clin Infect Dis 37(11)1405-1433,
2003. 3. Lynch, J.P., and Zhanel, G.G. Escalation
of antimicrobial resistance among Streptococcus
pneumoniae implications for therapy. Semin
Respir Crit Care Med 26(6)575-616,
2005. 4. Felmingham, D., Feldman, C., Hryniewicz,
W., Klugman, K., Kohno, S., Low, D.E., Mendes,
C., and Rodloff, A.C. Surveillance of resistance
in bacteria causing community-acquired
respiratory tract infections. Clin Microbiol
Infect 8 Suppl 212-42, 2002.

• To evaluate the safety and efficacy of a 10-day
  course of therapy with cethromycin, given either
  150 mg QD or 150 mg BID, for the treatment of
  ambulatory CAP patients
• To identify the dose for subsequent confirmatory
  active-controlled trials
• To provide additional evidence of microbiologic
  efficacy

SAFETY In this clinical trial, 284 patients
treated QD received at least one 150 mg dose of
cethromycin, while 299 patients treated BID
received at least one 150 mg dose of cethromycin.
Both the total adverse events and the
drug-related adverse events were similar for the
two groups (Table 5). The majority of the
premature discontinuations due to adverse events
were considered unrelated to the study drug by
the investigator. Table 5. Incidence of
Adverse Events aNot related to study
drug Analysis of drug-related adverse events by
body system indicated no difference between the
groups (Table 6). Table 6. Incidence of
Drug-Related Adverse Eventsa Grouped by Body
System aIncludes Probable and
Possible Adverse Events, excludes Probably Not
and Not Related Adverse Events Both
cethromycin regimens (150 mg QD and BID) were
well tolerated and effective in resolving or
improving clinical signs and symptoms of CAP,
eradicating the target pathogens, and resolving
or improving radiographic evidence of pneumonia.
Although these two treatment regimens
demonstrated non-inferiority in clinical cure
rate among Intent-to-Treat subjects, higher
clinical cure rates were observed among subjects
who received cethromycin 150 mg QD in the
clinically evaluable population and the
clinically and bacteriologically evaluable
population. This study supported the selection
of a QD dosing regimen for further investigation
of cethromycin in treating CAP.
DISPOSITION OF SUBJECTS The study was conducted
from November 30, 2000 to November 6, 2001 and
recruited subjects from 138 centers in the United
States, Austria, Belgium, Brazil, Canada, Costa
Rica, Czech Republic, England, Estonia, Germany,
Greece, Hungary, Lithuania, Poland, Russia, South
Africa, and Spain (Table 1). Table 1.
Disposition of Subjects DEMOGRAPHICS No
statistically significant difference in the
demographics was found between the two treatment
groups (Table 2). Table 2. Demographics in
the Randomized and Treated Population EFF
ICACY The clinical cure rates among the
Intent-to-Treat subject population were
equivalent for the two treatment groups, whereas
statistically significant differences were
observed among the clinically evaluable
population and clinically and bacteriologically
evaluable population, with a higher clinical cure
rate in the 150 mg QD group (Abstract Table). No
statistically significant differences were
observed in bacteriological cure rate, overall
pathogen eradication rate or individual pathogen
eradication rate in any subject population
(Abstract Table and Table 3). Table 3.
Pathogen Eradication Rate in the Clinically and
Bacteriologically Evaluable Population at TOC
Visit aTotal number of pathogens
greater than total number of Clinically and
Bacteriologically Evaluable Subjects because some
patients were infected by more than one
organism Radiographic resolution and success
rates were very similar for both groups in all
subpopulations (Table 4). Table 4.
Radiographic Resolution and Success Rates at TOC
Visit
Patients and Methods
Cethromycin 150 mg QD N () Cethromycin 150 mg BID N ()
Subjects Randomized and Treated 284 (100) 299 (100)
Intent-to-Treat 264 (93) 274 (92)
Clinically Evaluable 231 (81) 246 (82)
Clinical Bacteriologically Evaluable 144 (51) 145 (48)

• STUDY DESIGN AND TREATMENT
• Double-blind, parallel-group, multi-national,
  multi-center study
• Patients were randomized in a 11 ratio to
  receive
• - Cethromycin 150 mg PO, QD and placebo QD for
  10 days
• - Cethromycin 150 mg PO, BID for 10 days
• Subjects were evaluated at five visits
• - At a pre-therapy evaluation one within 48
  hours before enrollment
• - At evaluation two 48-72 after initiation of
  therapy
• - At evaluation three 48-72 hours after the
  last dose
• - At evaluation four at 9-14 days after the
  last dose (Test of Cure Visit TOC)
• - At evaluation five via telephone follow-up
  between Study Days 40-42
• The primary efficacy parameter was clinical
  response at the TOC visit
• Secondary efficacy parameters included
  bacteriological response at the TOC visit and
  clinical and bacteriological response at the
  long-term follow-up visit
• Safety was evaluated throughout the study by
  physical examinations, vital signs, laboratory
  tests, ECGs, and through monitoring of adverse
  events and use of concomitant medications
• Adverse events were classified as one of the
  following
• - Mild The adverse event was transient and
  easily tolerated by the subject
• - Moderate The adverse event caused the
  subject discomfort and interrupted the subjects
  usual activities
• - Severe The adverse event caused
  considerable interference with the subjects
  usual activities and could have been
  incapacitating or life-threatening
• Possible relationships of adverse events to the
  study drug were assessed using the following
  definitions

Cethromycin 150 mg QD N () Cethromycin 150 mg BID N ()
Number of Subjects 284 (100) 299 (100)
Any Adverse Event 141 (50) 160 (54)
Drug related Adverse Event 64 (23) 74 (25)
Serious Adverse Event 11 (3.9) 16 (5.3)
Premature discontinuation due to Adverse Event 16 (5.6) 11 (3.7)
Deaths 1a (0.4) 1a (0.3)
Evaluation Cethromycin150 mg QD x 10 Days Cethromycin150 mg BID x 10 Days 95 Confidence Intervals
Subject Clinical Cure Rates
Clin Bact Evaluable 96 (138/144) 86 (125/145) 2.8, 16.5
Clinically Evaluable 94 (216/231) 87 (215/246) 0.7, 11.6
Intent-to-Treat 83 (218/264) 81 (222/274) -5.2, 8.3
Subject Bacteriological Cure Rates
Clin Bact Evaluable 94 (135/144) 89 (129/145) -2.0, 11.6
Intent-to-Treat 83 (136/163) 82 (133/162) -7.2, 9.9
Overall Pathogen Eradication Rate
Clin Bact Evaluable 95 (167/176) 90 (162/181) -0.4, 11.2
Intent-to-Treat 85 (168/198) 83 (167/202) -5.3, 9.7
Radiographic Success Rates
Clin Bact Evaluable 94 (133/141) 90 (119/132) -2.6, 10.9
Clinically Evaluable 91 (204/223) 92 (205/224) -5.4, 5.4
Cethromycin 150 mg QD Cethromycin 150 mg BID
Age (yrs) Mean (SD) Range 47.5 17.7 18-88 47.4 16.6 18-86
Race, N () Caucasian Black Other 241 (85) 26 (9) 17 (6) 248 (83) 33 (11) 18 (6)
Sex, N () Female Male 128 (45) 156 (55) 131 (44) 168 (56)
Cethromycin 150 mg QD N () Cethromycin 150 mg BID N ()
Body as a Whole 8 (3) 12 (4)
Cardiovascular 4 (1) 3 (1)
Digestive 38 (13) 41 (14)
Gastrointestinal 31 (11) 31 (10)
Other 11 (4) 16 (5)
Hemic and Lymphatic 4 (1) 7 (2)
Metabolic and Nutritional Disorders 8 (3) 6 (2)
Musculoskeletal 1 (0.4) 1 (0.3)
Nervous 4 (1) 5 (2)
Respiratory 2 (1) 5 (2)
Skin and Appendages 0 3 (1)
Special Senses 9 (3) 16 (5)
Urogenital 3 (1) 4 (1)
Background
Cethromycin 150 mg QD Cethromycin 150 mg BID
Overall Pathogens 95 (167/176a) 90 (162/181a)
H. influenzae 94 (34/36) 79 (33/42)
S. pneumoniae 100 (33/33) 94 (50/53)
M. catarrhalis 92 (12/13) 90 (9/10)
H. parainfluenzae 93 (43/46) 94 (32/34)
S. aureus 100 (6/6) 81 (13/16)
C. pneumoniae 100 (15/15) 88 (7/8)
M. pneumoniae 89 (17/19) 100 (13/13)
L. pneumophila 100 (6/6) 100 (4/4)
Discussion
References
Conclusions
Cethromycin 150 mg QD Cethromycin 150 mg QD Cethromycin 150 mg BID 95 Confidence Intervals
Radiographic resolution rate Radiographic resolution rate
Clinical Bacteriologically Evaluable Subjects Clinical Bacteriologically Evaluable Subjects 59 (83/141) 59 (78/132) -12.3, 11.8
Clin Evaluable Subjects Clin Evaluable Subjects 59 (132/223) 61 (136/224) -10.8, 7.8
Intent-to-Treat Subjects Intent-to-Treat Subjects 51 (134/264) 51 (140/274) -10.8, 7.6
Radiographic success rate Radiographic success rate
Clinical Bacteriologically Evaluable Subjects Clinical Bacteriologically Evaluable Subjects 94 (133/141) 90 (119/132) -2.6, 10.9
Clin Evaluable Subjects Clin Evaluable Subjects 91 (204/223) 92 (205/224) -5.4, 5.4
Intent-to-Treat Subjects Intent-to-Treat Subjects 78 (207/264) 77 (210/274) -5.0, 5.6

• This study demonstrated the efficacy and safety
  of cethromycin, a ketolide, a new class of
  antibiotic, in ambulatory CAP patients
  when dosed either 150 mg QD or BID for 10 days
• Both cethromycin regimens were well tolerated and
  effective in resolving or improving clinical
  signs and symptoms of CAP, eradicating the target
  pathogens, and resolving or improving
  radiographic evidence of pneumonia
• Higher clinical cure rates were observed among
  subjects who received cethromycin 150 mg QD in
  the clinically evaluable and the clinically and
  bacteriologically evaluable subjects
• Clinical cure rates among the Intent-to-Treat
  subjects were equivalent between treatment groups
• This study supported the selection of a QD dosing
  regimen and, thus, pivotal Phase 3 comparator
  trials using 300 mg QD cethromycin in the
  treatment of CAP are currently in progress