Phase III Clinical Trial of Moxifloxacin Hydrochloride in the Treatment of Acute Exacerbations of Chronic Bronchitis in Comparison with Azithromycin

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1 ORIGINAL ARTICLE JIACM 2002; 3(4): Phase III Clinical Trial of Moxifloxacin Hydrochloride in the Treatment of Acute Exacerbations of Chronic Bronchitis in Comparison with Azithromycin SH Talib*, M Arshad**, Hitesh Chauhan***, Renu Jain****, Lalit Vaya***** Abstract A double blind randomised phase III clinical trial was conducted for comparing moxifloxacin to azithromycin in cases of acute exacerbations of chronic bronchitis. The study revealed comparable efficacy of moxifloxacin to azithromycin in alleviating the signs and symptoms of acute exacerbation of chronic bronchitis. The adverse effects, though mild and transient, were higher in the azithromycin group as compared to moxifloxacin group. Key words Moxifloxacin, Azithromycin, Chronic bronchitis. Introduction Acute exacerbation of chronic bronchitis (AECB) usually is associated with common respiratory pathogens, such as Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis and may be particularly severe in debilitated patients, smokers, and the elderly 1,2. Recent data suggests that Chlamydia pneumoniae could also play a role in some patients 3,4. Increasing resistance of organisms to commonly utilised antibiotics presents a challenge in the treatment of AECB. Fluoroquinolones are an alternative mode of treatment since they are not destroyed by beta-lactamase-producing organisms and are therefore effective against gram-negative pathogens, such as H. influenzae and M. catarrhalis. Some quinolones also have activity against S. pneumoniae, including multidrug resistant strains. Moxifloxacin is a new 8-methoxy-fluoroquinolone * Professor and Head, Department of Medicine ** Resident, Department of Medicine *** Biostatistician **** Scientist, Torrent Research Center ***** Chief, Clinical Research and Regulatory Affairs Govt. Medical College and Hospital, Aurangabad , Maharashtra State. antibacterial agent. The minimum inhibitory conncentration for 90% of organisms (MIC90) is less than 0.25 mg/l for commonly isolated community-acquired respiratory tract pathogens including penicillin-susceptible and resistant Streptococcus pneumoniae, Haemophilus sp, and Moraxella catarrhalis and less than 1.0 mg/l for atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. To date, emergence of resistance to moxifloxacin has been uncommon, including selection of resistance under experimental conditions (methicillin-sensitive S. aureus, S. pneumoniae) 5-8. Moxifloxacin has excellent penetration into upper and lower respiratory tissues. Notably, the drug can be administered once a day and is not associated with drug interactions secondary to altered hepatic metabolism. In addition, since its metabolism does not involve the cytochrome P450 system, many common drug interactions are absent. The agent is being investigated in clinical trials and shows promise as a safe and effective once-daily treatment of respiratory infections In addition, its chemical structure and pharmacokinetic and pharmacodynamic properties indicate that it has enhanced potential to minimize emergence of bacterial resistance which should make it an excellent choice for treating respiratory tract infections now, and in the future.

2 Materials and methods This was a double blind, randomised, and comparative study involving patients with AECB randomised 1:1 to receive either moxifloxacin (400mg od for 5 days), or azithromycin (500 mg loading dose on day 1 followed by 250 mg on day 2 through day 5) for 5 days. To maintain the blindness of the study treatment, a placebo was given in moxifloxacin group on day 1 since the azithromycin group received 2 tablets each of 250 mg on day 1. This study was conducted in compliance with independent ethics committee approval and was monitored according to good clinical practices. An informed consent was obtained from each patient. The first patient entered the study in February, 2001, and the last patient completed the study in April Patients were eligible only if they were at least 18 years of age and presenting with AECB. Patients may also have had fever, wheezing, and shortness of breath. A chest radiograph confirming the absence of pulmonary findings consistent with pneumonia was mandatory. Patients with the following conditions were excluded by protocol: pneumonia, known hypersensitivity to 8-methoxy-quinolones, pulmonary disease(s) that precluded evaluation of the therapeutic response, significant hepatic disease or obstruction of the biliary tract, including patients with baseline bilirubin or hepatic enezyme levels (aspartate transaminase, alanine transaminase) that were greater than two times the upper limit of normal, or underlying conditions that could have predisposed to seizures, known HIV infection, a rapidly fatal illness. Female patients of child-bearing potential were not eligible for participation in the study unless they were using reliable contraception. Further exclusion criteria included the following: clinical findings that, in the investigators opinion, warranted parenteral antibiotic therapy, concomitant infections requiring systemic antibacterial therapy, systemic antimicrobial treatment within 3 days prior to study drug administration, prior participation in this study. Because a small increase in corrected QT interval (QTc) is caused by moxifloxacin treatment, patients of congenital prolonged QT syndromes, those on concurrent use of antiarrhythmic agents or other medications known to cause QT prolongation, or those with baseline QTc interval greater than 500 ms were excluded. Baseline visit procedures include verification of inclusion/exclusion criteria, informed consent, medical history, physical examination (including vital signs, height, weight) clinical evaluation of signs and symptoms, ECG, chest radiograph, samples for laboratory analyses (haematology, chemistry, urinalysis). Physical examination, clinical evaluation of signs and symptoms, laboratory analyses, ECG and chest radiograph were repeated at test-of-cure. An assessment of the patient s response to study drug treatment was made at test-of-cure (or premature discontinuation before test-of-cure). Patient compliance with the study drug regimen was assessed during therapy and at test-of-cure assessment, and safety was monitored during treatment and at test-of-cure assessment. Safety parameters included adverse clinical and laboratory events, and changes in ECG, vital signs, and physical examination findings. Adverse events were recorded and classified by the investigator as to severity and relationship to study drug medication. Patients were evaluated at baseline (visit 1), during treatment (visit 2, day 3), and posttreatment (visit 3 or test-of-cure visit, day 7). Efficacy analyses were performed on the all treated and evaluable populations. Clinical response was assessed by the investigator as cure (resolution of all signs and symptoms with no new signs or symptoms associated with the original infection or return of the given finding to the pre-morbid state), improvement (in patients not cured, resolution or reduction of the majority of signs and symptoms with no new signs or symptoms associated with the original infection), failure (no resolution and no reduction of a majority of signs and symptoms; Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December

3 worsening of one or more signs or symptoms, new signs or symptoms associated with the original infection or a new infection, or patient required other antimicrobial therapy for this episode of AECB prior to or at test-of-cure), or indeterminate (inability to assess the patient s signs and symptoms due to lost to follow-up or no information at the test-of-cure visit or on discontinuation prior to test-of-cure). All randomised patients who received complete course of study medication constituted the alltreated population. Patients who met the inclusion/exclusion criteria, had no significant protocol deviation and were treated with more than 80% of the protocol-defined treatment course were included in the clinically evaluable population. Statistical analysis Differences between treatment groups in the distribution of demographic variables and baseline characteristics were subjected to parametric (Unpaired t test) and non-parametric (Chi square or Fisher s exact test) tests. All the categorical types of data were subjected to non-parametric test (Wilcoxan sign rank test for paired data and Wilcoxan rank sum test for unpaired data). Probability values of (p < 0.05) were considered as statistically significant (Here S means significant and NS means non-significant). The severity of symptoms were measured on rank score from 0-3 where 0 denotes absent, 1 = mild, 2 = moderate, and 3 = severe. Observations and results A total of 47 patients were enrolled in the study. The number and percentage of patients in each population for both treatment groups are presented in table I. All the enrolled patients completed the study : 48.94% in the moxifloxacin group and 51.06% in the azithromycin group. There were no statistically significant differences in demographic characteristics between the moxifloxacin and azithromycin groups. In both the moxifloxacin and azithromycin groups, significant changes were observed in the signs and symptoms of AECB between baseline and during therapy, which continued throughout the study (Table II). No significant difference was observed in the sputum characteristics between the two treatment groups at baseline and end of the study visit using chi-square statistical test (Fig. 1). The volume of sputum in both the groups at each visit is represented in fig. 2. Significant changes were observed in other parameters like pulse, RR (respiratory rate), and systolic BP in both the groups during the study period compared to baseline (Table III). Changes in diastolic BP from baseline were not found to be significant statistically in either group at visit 3. Fig. 1 : The sputum characteristics of the two treatment groups during the study period. Fig. 2 : The sputum volume (ml) at different visits in moxifloxacin group (n=23) and azithromycin group (n=24). 362 Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December 2002

4 Table I : Demographic data of the efficacy (evaluable study population). Characteristics Moxifloxacin Azithromycin P (N=23) (N=24) value Gender (No.): Male NS Female 4 7 NS Age (mean+/-sd) (years) / / NS Weight (mean+/-sd) (kg.) / /-8.75 NS Height (mean+/-sd) (cms.) / /-7.90 NS Smoking history (No.): Smoker NS Non-smoker NS Population (No.): Rural NS Urban NS NS = Not significant Table II :Changes in signs and symptoms* of AECB observed in both groups during the study period. Moxifloxacin Baseline Day-3 Sig. Day-7 Sig. Mean+/-sd Mean+/-sd Mean+/-sd Temperature / / S / S Cough 2.5+/ /-0.47 S 1.27+/-0.64 S Cough frequency 2.5+/ /-0.47 S 1.27+/-0.46 S Wheeze 1.59+/ /-0.53 S 1.14+/-0.47 S Dyspnoea 2.68+/ /-0.58 S 1.73+/-0.55 S Azithromycin Baseline Day-3 Sig. Day-7 Sig. Mean+/-sd Mean+/-sd Mean+/-sd Temperature ( F) / / S / S Cough 2.78+/ /-0.60 S 1.61+/-0.58 S Cough Frequency 2.74+/ /-0.60 S 1.57+/-0.59 S Wheeze 1.61+/ /-0.54 S 1.04+/-0.21 S Dyspnoea 2.72+/ /-0.52 S 1.96+/-0.56 S Sig. = Test of significance, S = Significant. * The severity of symptoms were measured on rank score from 0-3 where 0 denotes absent, 1 = mild, 2 = moderate, and 3 = severe. Both the drugs were generally well tolerated. There was no incidence of any serious adverse effect throughout the study. Adverse events reported overall, although not significant, were higher in the azithromycin group (20.8%) as compared to moxifloxacin group (8.7%) (Table IV, Fig. 3). The most common adverse events reported were vomiting (4.35%) and nausea (4.35%) in the moxifloxacin group, and rashes (8.33%), itching (4.17%), and giddiness (8.33%) in the azithromycin group. There were no significant laboratory abnormalities observed in either group (Table V). However, total WBC count was significantly lowered in azithromycin Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December

5 Fig. 3 : The adverse events observed in moxifloxacin group and azithromycin group during the study period. group compared to moxifloxacin group. No significant observations were noted in ECG with respect to QTc interval, before and after the treatment in both the groups. None of the patients in moxifloxacin group reported phototoxicity. In the other endpoints, the efficacy index, as the basis of drug effect only (taking efficacy and side effects both into consideration), 47.83% patients in the moxifloxacin group showed excellent improvement compared to 33.33% in the azithromycin group. Moderate and minimal improvements in the moxifloxacin group were in and 8.7% of the patients respectively, in comparison to and 12.5% of the patients in azithromycin group (Table VI, Fig. 4). Thus, physician s overall assessment showed that 91.31% of patients in the moxifloxacin group and 87.49% of patients in the azithromycin group had excellent-to-good response to treatment. Discussion Our findings confirm the results of previous studies Table III : Changes in physical findings in both the groups during the study period. Moxifloxacin Baseline+/-sd Visit 2+/-sd Sig. Visit 3+/-sd. Sig. Pulse (/mt) / /-7.45 S /-6.69 S RR (/mt) / /-5.92 S /-4.07 S BP-Systolic / / S / S BP-Diastolic / /-8.68 NS /-8.16 NS Azithromycin Baseline+/-sd Visit 2 +/-sd Sig. Visit 3+/- sd Sig. Pulse (/mt) / / S / S RR(/mt) / /-4.50 S /-0.07 S BP-Systolic / / S / S BP-Diastolic / /-7.57 S /-7.56 NS Sig. = Test of significance, S = Significant, NS = Non significant. Table IV : Adverse events noted in both the study groups during the study period. Adverse Events Moxifloxacin (No.) Azithromycin (No.) Rash 0 2 Itching 0 1 Giddiness 0 2 Vomiting 1 0 Nausea Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December 2002

6 evaluating the clinical efficacy of moxifloxacin in the treatment of AECB. In this study, with moxifloxacin, AECB responded comparably to azithromycin. At TOC (test-of-cure) assessment the two treatments were equivalent. Three comparative trials have examined the safety and efficacy of moxifloxacin, azithromycin, and clarithromycin for the treatment of acute bacterial exacerbations of chronic bronchitis Eligible patients were 18 years of age or older and had an acute exacerbation of underlying chronic bronchitis, defined as a productive cough for at least three consecutive months during two or more consecutive years. S. pneumoniae, H. influenzae, and M. catarrhalis were the three most common causative pathogens. Patients treated with moxifloxacin 400 mg/day for 5 and 10 days had cure rates of 89-97% and 96% respectively, similar to those of patients receiving azithromycin 500 mg for 1 day followed by 250 mg for 4 days (96%). Fig. 4 : The efficacy index (taking both efficacy and side effects into consideration) of moxifloxacin and azithromycin in the respective study groups. Moxifloxacin and azithromycin were equally well tolerated with no significant difference among regimens. Most adverse events occurred in the first few days of treatment, which were mild and Table V: Laboratory analysis in both the study groups during the study period. Moxifloxacin Baseline+/-sd Visit-3+/-sd Sig. Hb (gm/dl) / /-2.30 NS WBC (/cmm) / / NS Serum creatinine (mg%) 1.13+/ /-0.08 NS Bilirubin (mg%) 0.95+/ /-0.47 NS SGPT (U/L) / /-9.02 NS SGOT (U/L) / /-7.52 NS S. Alk. phos (I/L) / / NS T. proteins (gm%) 6.74+/ /-1.02 NS Azithromycin Baseline+/-sd Visit-3+/-sd Sig. Hb (gm/dl) / /-1.28 NS WBC (/cmm) / / S Serum creatinine (mg%) 1.12+/ /-0.08 NS Bilirubin (mg%) 0.87+/ /-0.45 NS SGPT (U/L) / /-6.80 NS SGOT (U/L) / /-8.93 NS S. Alk. Phos (U/L) / / NS T. proteins (gm%) 6.43+/ /-0.80 NS Sig. = Test of significance, S = Significant, NS = Non significant. Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December

7 transient in nature. Rash, itching, giddiness, nausea, and vomiting were the most frequent drug related complaints with both the drugs. No patient was withdrawn from the study because of these side effects. Indeed, the safety profile of moxifloxacin was similar to that of azithromycin. There was no phototoxicity in the moxifloxacin group, as it is believed that the methoxy group at the 8-position on moxifloxacin confers decreased phototoxicity. ECG records at baseline and after treatment did not show any evidence of increased QTc intervals in either group. Table VI : Efficacy index* of moxifloxacin and azithromycin in the study groups. Efficacy index Moxifloxacin Azithromycin Excellent 11 (47.83%) 8 (33.33%) Good 10 (43.48%) 13 (54.16%) Fair 2 (8.7%) 3 (12.5%) Poor 0 0 * Efficacy index is assessed on the basis of drug effect only taking both efficacy and side effects into consideration. Global evaluation of response to therapy, which reflects the overall assessment on the combined parameters of efficacy and safety, suggested that the percentage of patients benefiting overall were higher in the moxifloxacin group than in the azithromycin group. Hence, one can conclude that moxifloxacin with once daily doses of 400 mg provided comparable efficacy and improvement in the signs and symptoms of AECB with mild and transient side effects. comparison with currently available antimicrobials against respiratory tract pathogens. J Antimicrob Chemother 1996; 37: Rodnick JE, Gude JK. The use of antibiotics in acute bronchitis and acute bacterial exacerbations of chronic bronchitis. West J Med 1988; 149: Bauernfeind A. Comparison of the antibacterial activities of the quinolones BAY , gatifloxacian (AM1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J Antimicrob Chemother 1997; 41: Fass RJ. In vitro activity of BAY , a new 8- methoxyquinolone. Antimicrob Agents Chemother 1997; 41: Woodcock JM, Andrews JM, Boswell FJ et al. In vitro activity of BAY , a new fluoroquinolone. Antimicrob Agents Chemother 1997; 41: Bebear CM, Renaudin H, Boudjadja A et al. In vitro activity of BAY , a new fluroquinolone, against mycoplasmas. Antimicrob Agents Chemother. 1998; 42: Burke T, Villanueva C, Mariano H et al. Comparison of moxifloxacin and cerfuroxime axetil in the treatment of acute maxillary sinusitis. Clin Ther 1999; 21: Chodosh S, DeAbate CA, Haverstock D et al. Short course moxifloxain therapy for treatment of acute bacterial exacerbation of chronic bronchitis. Respir Med 2000; 94: Mathew CP, Warner JH, Heyd A et al. Short course moxifloxacin vs. azithromycin in the treatment of acute exacerbation of chronic brochitis. Paper preseented at American Thoracic Society International Meeting. Toronto, Canada 2000; 5-10 (Abstract). 12. Wilson R, Kubin R, Ballin I et al. Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1999; 44: Church D, Haverstock D, Heyd A. Moxifloxacin: a review of its safety profile based on worldwide clinical trials. Paper presented at ASHP Annual Meeting. Philadelphia, PA 2000; June 4-7. Acknowledgement Torrent Research Centre for generous supplies of drugs. References 1. Sachs FL. Chronic bronchitis. In: Pennington JE ed. Respiratory infections, Diagnosis & management. New York: Raven Press, 1983; Gedds AM. Cefpodoxime proxetil in the treatment of lower respiratory tract infections. Drugs 1991; 42: Baquero F, Canton R. In vitro activity of sparfloxain in 366 Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December 2002