DISPOSITION OF SUBJECTS

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 Abstract Objectives Results 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 p<0.05 level between the two treatment groups Clin & Bact Evaluable = Clinically & Bacteriologically Evaluable Conclusions: 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 2:12-42, 2002. 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. • 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 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 EFFICACY 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 • STUDY DESIGN AND TREATMENT • Double-blind, parallel-group, multi-national, multi-center study • Patients were randomized in a 1:1 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 subject’s usual activities • - Severe The adverse event caused considerable interference with the subject’s 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: • - Probable An adverse event had a strong temporal relationship to study drug or recurred on challenge and another etiology was unlikely or significantly less likely • - Possible An adverse event had a strong temporal relationship to study drug and an alternate etiology was equally or less likely compared to the potential relationship to study drug • - Probably not An adverse event had little or no temporal relationship to the study drug and/or a more likely alternative etiology existed • - Not related An adverse event was due to an underlying or concurrent illness or effect of another drug and was not related to the study drug • PATIENT POPULATION • Primary Diagnosis: Clinical diagnosis of community acquired pneumonia • Key Inclusion Criteria • Males or females ≥18 years of age that had a clinical diagnosis of CAP that was confirmed by a positive chest x-ray and supported by appropriate signs and symptoms • A female must have been non-lactating and at no risk for pregnancy for the following reasons: • - Postmenopausal for at least one year • - Surgically sterile • - If of child bearing potential, the subject must have had a negative pregnancy test and have used a very effective method of birth control throughout the study • Subject must have been a suitable candidate for oral therapy and able to swallow tablets intact • Key Exclusion Criteria • A prior hospitalization within previous four weeks or residence at a chronic care facility • Any underlying condition or disease which would likely interfere with the completion of the course of absorption of study drug therapy or follow-up • Treatment with a long-acting injectable antimicrobial agent within four weeks or other systemic antibiotics within two weeks prior to study drug administration • Patients with known currently active medical conditions likely to interfere with the evaluation of efficacy • Immunocompromised subjects, subjects receiving immunosuppressive agents or subjects with a HIV infection • Females who were pregnant or lactating • Previous treatment with cethromycin • Evidence of history of drug or alcohol abuse within 12 months before study start Background Discussion References Conclusions • 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