Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of patients with acute exacerbation of chronic bronchitis

CLINICAL THERAPEUTICSVVOL. 22, NO. 12,200O

Phase III, Randomized, Double-Blind Study of Clarithromycin Extended-Release and Immediate-Release Formulations in the Treatment of Patients with Acute Exacerbation of Chronic Bronchitis Jay L. Adler, MD,’ William Jannetti, MD,2 David Schneider, MD,3 Jie Zhang, PhD,4 Robert Palmer, MPH,4 and Gerard Notario, MD4 ‘Clinicos Clinical Research, Colorado Springs, Colorado, 2HANA Research Medical Centei; Buena Park, California, 3ChildrenS Hospital, Metairie, Louisiana, and 4Abbott Laboratories, Abbott Park, Illinois

ABSTRACT Background: Clarithromycin has an established efficacy and safety profile in the treatment of respiratory tract infections. Objective: The purpose of this study was to compare the clinical and bacteriologic efficacy and tolerability of clarithromycin extended-release and immediate-release formulations in patients with acute exacerbation of chronic bronchitis (AECB). Methods: In a phase III, randomized, double-blind, parallel-group, multicenter study, patients aged 912 years with signs and symptoms of AECB and a productive cough with purulent sputum received treatment with extended-release (two 500-mg tablets once daily) or immediate-release (one 500-mg tablet twice daily) clarithromycin for 7 days. Assessments were performed before treatment, within 48 hours after treatment, and at the testof-cure visit (study days 19-21). Patients who took ~1 dose of study drug were included in the safety analysis. Results: Of 620 patients randomized and treated, 182 were clinically and bacteriologically assessable (100 in the extended-release group and 82 in the immediate-release group). Treatment groups were well matched with respect to demographic characteristics and medical and social history. At the test-of-cure visit, 83% (83000) of patients in the extended-release and 82% (67/82) of patients in the immediate-release group achieved clinical cure; 86% (85199) and 85% (70/82), respectively, demonstrated bacteriologic cure. Overall pathogen eradication rates were 86% (100/l 16) in the extended-release group and 88% (86/98) in the immediate-release group. The most frequently reported adAccepted for publication October II, 2000. Printed in the USA. Reproduction

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in whole or part is not permitted.

0149-2918100/$19.00

J.L. ADLER ET AL.

verse events were diarrhea (6% in extendedrelease group vs 4% in immediate-release group; no significant difference), taste alterations (4% in each group), and nausea (3% in each group); no clinically meaningful changes in laboratory values or vital signs, as assessed by the investigator, were observed. Conchion: This study suggests that clarithromycin extended-release and immediate-release formulations have equivalent clinical and bacteriologic efftcacy and tolerability in patients with ABCB. Key words: clarithromycin, extendedrelease, immediate-release, acute exacerbation of chronic bronchitis, treatment. (C&z Ther. 2000;22: 1410-1420)

INTRODUCTION Chronic bronchitis may affect 10% to 25% of the adult population. It is estimated that ~12 million people in the United States have chronic bronchitis.’ Exacerbations of chronic bronchitis may be induced by environmental factors (eg, air pollution, smoke) or by bacterial and viral infectious agents. In patients with exacerbation of chronic bronchitis due to a bacterial agent, a pathogen is identified in only 50% of cases2 The most commonly isolated pathogens from patients with acute bacterial exacerbations of chronic bronchitis are Haemaphilus injluenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.24 Because of the recognized inaccuracies of sputum culture and the necessary delays imposed before culture results become available, recent guidelines recommend the initiation of empiric antimicrobial therapy in patients with acute exacerbation of chronic bronchitis (AECB) and suspected bacterial infection.5*6 Patients with AECB who are most likely to benefit from antimi-

crobial therapy include those with a history of repeated infections; a comorbid disease such as diabetes, asthma, or heart disease; symptoms such as dyspnea, increased sputum volume, or purulent sputum; or marked airway obstruction. 7-9 Selection of an appropriate empiric antimicrobial agent for treatment of a suspected bacterial infection in patients with AECB requires consideration of the bacteriologic and clinical efficacy and tolerability of the agent as well as dosing convenience. Clarithromycin is an expanded-spectrum macrolide antibiotic that is currently approved for use twice daily in the treatment of upper and lower respiratory tract infections, including bacterial AECB. This agent has good bioavailability (55%) and tissue distribution (lung tissue concentration 8 pg/g). lo Recently, an extendedrelease formulation of clarithromycin was developed to facilitate therapeutic compliance in patients with respiratory tract infections. Pharmacokinetic studies in adults comparing the extended-release formulation (1000 mg once daily) with the immediate-release formulation (500 mg twice daily) of clarithromycin demonstrated that the extended-release tablets produce a statistically significantly lower steadystate peak plasma concentration (C,,,) and longer time to peak concentration (TIIW) (CIW. 2.59 vs 3.51 p,g/mL [P < 0.051; Tmax 7.8 vs 2.1 hours [P < 0.05]). However, the 24-hour area under the concentration-time curve for clarithromycin and its active metabolite, 14-hydroxyclarithromycin, was equivalent for the 2 formulations. ‘I The present study was designed to compare the clinical and bacteriologic efficacy and tolerability of a 7-day course of clarithromycin extended-release (two 500-mg

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CLINICAL THERAPEUTICS’

tablets once daily) with clarithromycin immediate-release (one 500-mg tablet twice daily) in patients with AECB.

PATIENTS

AND METHODS

This phase III, randomized, double-blind, parallel-group, multicenter study was conducted at 87 investigative sites throughout the United States (n = 79) and Canada (n = 8) between March 10, 1998, and February 4, 1999. The study protocol was approved by the institutional review board of each institution, and all patients (or their legal guardians) provided written informed consent before any study-related procedures were performed.

Patient Selection Male and female outpatients aged 812 years with a medical history of chronic bronchitis (defined as cough and sputum production for >2 consecutive years and on most days in a consecutive 3-month period) and a presumptive diagnosis of AECB supported by clinical signs and symptoms were eligible for enrollment. The study protocol specified that the diagnosis of AECB be made on the basis of both clinical and bacteriologic criteria. Clinical signs and symptoms included cough, fever, hoarseness, and wheezing. Eligible patients had a productive cough with purulent sputum (defined as ~25 white blood cells and ~10 squamous epithelial cells per field at 100x magnification) and were able to swallow tablets intact. A placebo arm was considered inappropriate for this trial since current data suggest that patients with AECB derive substantial benefit from antibiotic therapy. I2 Patients were excluded if they had radiologic evidence of pneumonia, active

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tuberculosis, empyema, lung abscess or tumor, acute infiltrates, bronchiectasis, or pleural effusion or consolidation; sinusitis or other infection requiring systemic antibiotic treatment; severe or complicated lower respiratory tract infection or compromised respiratory status; or macrolide allergy. Several of these diseases or conditions may have confounded accurate assessment of efficacy; others, most notably pneumonia and sinusitis, require antibiotic dosing regimens that differ from those used for AECB. Patients were also excluded from the trial if they had used a systemic antibiotic within 3 weeks of study initiation; had received a long-acting injectable antibiotic within 30 days of study initiation or an investigational agent within 4 weeks of study initiation; had significant renal (serum creatinine greater than or equal to the upper limit of normal) or hepatic (alanine aminotransferase, aspartate aminotransferase, or total bilirubin >2 times the upper limit of normal; or alkaline phosphatase >1.25 times the upper limit of normal) impairment; or were pregnant or lactating. The use of terfenadine, astemizole, cisapride, or pimozide (these drugs have known or potential interactions with clarithromycin); oral or parenteral steroids (at a dose equivalent to 2 10 mg/d prednisone); any immunosuppressive drug; other systemic antimicrobial therapy; or any other investigational drug between the initial baseline visit and the test-of-cure visit (study days 19-21) was also prohibited. Theophylline or any theophylline analog, carbamazepine, ergotamine, dihydroergotamine, warfarin, triazolam, phenytoin, or hexobarbital were permitted if patients were clinically monitored for potential adverse events. Female patients could not be at risk for pregnancy.

J.L. ADLER ET AL.

Antimicrobial

Therapy

Patients who satisfied the inclusion criteria were randomly assigned in a 1: 1 ratio at each study site to receive clarithromycin extended-release (two 500-mg tablets once daily plus placebo for clarithromycin immediate-release) or clarithromycin immediate-release (one 500-mg tablet twice daily plus placebo for clarithromycin extended-release) for 7 days. Patients were instructed to take each dose with food. To assess compliance with the treatment regimen, patients were instructed to return their bottles of study medication (even if empty) at the follow-up visits. Compliance was determined by counting all tablets of active drug. Clinical and Bacteriologic

Assessments

Patients were assessed at the pretreatment visit (within 48 hours of treatment initiation), during which a medical history and physical examination were obtained. Clinical signs and symptoms of cough, sputum production, rales/crackling, egophony, rigors, rhonchilwheezing, substernal pain, pleuritic pain, pleural effusion, headache, coryza, hoarseness, sore throat, dyspnea, and fever (~100°F) were reported as absent or present. If present, the signs and symptoms of cough, sputum production, and dyspnea were rated as mild, moderate, or severe. Volume of sputum production during the previous 24 hours was recorded as 3 oz. Sputum appearance was also assessed (eg, purulent, hemoptic). Clinical response assessments were performed at study days 8 to 10 (within 48 hours of treatment completion) and

study days 19 to 21 (test-of-cure visit). These assessments (clinical cure, clinical failure, or indeterminate) were performed in compliance with the draft US Food and Drug Administration guidelines.i3 Because these new guidelines have eliminated the previously used clinical response “improvement,” efficacy rates in this trial (“clinical cure” rates) were anticipated to be lower than those obtained in previous trials that did not follow the new treatment response guidelines (“clinical success” in those trials included both clinical cure and clinical improvement). In the present trial, the following definitions were used: (1) clinical cure-pretreatment signs and symptoms of infection had resolved or improved (returned to baseline condition) at the test-of-cure visit and no further antimicrobial therapy was needed; (2) clinical failure-pretreatment signs and symptoms of infection did not improve or worsened (new symptoms may also have appeared), and the patient required additional antimicrobial therapy at the test-of-cure visit; and (3) indeterminate-the clinical response to therapy could not be determined. Sputum samples for Gram stain and culture were obtained at the baseline visit to identify the presence and antimicrobial susceptibility of S pneumoniae, H injluenzae, M catarrhalis, Haemophilus

Staphylococcus

aureus,

parainfluenzae,

and other pathogens. Repeat cultures for bacteriologic analysis were performed at the 2 follow-up visits. Sputum samples were obtained by either spontaneous or induced expectoration (using normal saline without preservative as the vehicle) or by transtracheal aspiration. In vitro susceptibility to clarithromycin was determined using breakpoints established by the National Committee for Clinical Laboratory Stan-

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dards.14 The disk-diffusion method, with measurement of the zone of inhibition in millimeters, or the dilution method, with measurement of the minimum inhibitory concentrations in micrograms per milliliter, were used to determine susceptibility. Definitions for bacteriologic responses to treatment were as follows: (1) presumed eradication-in the absence of a repeat sputum culture the patient was presumed to have achieved eradication if the definition of clinical cure was met; (2) eradication-study entry pathogen or pathogens were absent from a repeat sputum culture performed at study days 19 to 21; (3) presumed persistence-in the absence of a repeat sputum culture the initial pathogen or pathogens were presumed to be persistent if the definition of clinical failure was met; (4) persistence-the original pathogen or pathogens were present in culture on study days 19 to 21 or at the time of discontinuation of study therapy; (5) superinfection-a new pathogen or pathogens were present in culture on study days 8 to 10 or 19 to 21 in a symptomatic patient; and (6) indeterminate-assessment was not possible.

Safety Assessments The safety of study medication was monitored by physical examination, including vital signs (pulse, respiration rate, temperature, height, weight, and blood pressure). Laboratory assessments of serum chemistry and hematologic parameters were conducted by a certified central laboratory (Covance Laboratories, Indianapolis, Indiana). Patients were also instructed to contact the investigator or return to the study site at any time during the treatment period if they experienced any adverse event, if their condition had

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not improved, or if signs and symptoms of infection worsened. Laboratory results and adverse events were assessed for severity and relationship to study drug; investigators blinded to the treatment documented their findings on the clinical report form.

Data Analyses Clinically assessable patients were defined as those who met all selection criteria, had taken the study drug for 23 days to qualify for efficacy assessment as a clinical failure, or had taken 280% of the prescribed regimen to qualify as a clinical cure. In addition, clinically assessable patients returned to the study site for their test-of-cure visit (except those deemed to have failed therapy before a scheduled visit). These patients did not take nonstudy systemic antimicrobial agents for another infection and did not have any interfering therapeutic procedures or other potentially confounding interventions during the study period. Clinically and bacteriologically assessable patients-the primary population for analysis-included those who met the criteria for clinical assessment and had 21 target pathogen isolated at the pretreatment assessment. The intent-to-treat population included all randomized patients who took 21 dose of study medication and had a clinical diagnosis of AECB at the pretreatment visit. All patients who received 2 1 dose of study medication were included in the safety analysis.

Statistical Analysis Primary efficacy variables were the rates of clinical cure, bacteriologic cure, and pathogen eradication. The secondary

J.L. ADLER ET AL.

efficacy variable was change from baseline in clinical signs and symptoms. All statistical tests between treatment groups were 2-tailed, with significance level set at P < 0.05. Quantitative variables (weight and age) were analyzed using a l-way analysis of variance, and categorical variables (sex and race) were analyzed using the Fisher exact test. Efficacy variables were summarized by treatment group and analyzed using the Fisher exact test to compare the 2 treatment groups. Binomial 95% CIS were computed for the difference between treatment groups (extended-release minus immediate-release) in efficacy variables. Change from pretreatment to posttreatment in each clinical sign and symptom was summarized by treatment group, compared with the percentage of patients who showed either resolution or improvement, and analyzed using the Fisher exact test. Efficacy variables were further summarized and compared according to subgroup variables (including investigation site, sex, race, age, tobacco use, target pathogen, and other pertinent factors) using the Cochran-Mantel-Haenszel test. Treatment-emergent adverse events were mapped to the Coding Symbols for Thesaurus

of Adverse

Reaction

Terms”

coding system. The incidence of drugrelated adverse events was summarized by treatment group and compared using the Fisher exact test. Events due to concurrent conditions were excluded. For primary clinical or microbiologic effectiveness end points with values of 70% to 79% for the better of 2 agents, a CI that crosses zero and remains within a lower bound delta of -0.20 or less is usually required to establish equivalence.r6 Assuming a standard clinical cure rate of 85%, 240 sub-

jects would provide 80% power to show a 15% difference between the 2 treatment groups.

RESULTS Patient Populations A total of 620 patients were randomized and treated in the study. Of these, 3 17 were treated with clarithromycin extended-release and 303 with clarithromycin immediate-release. An additional 7 patients were enrolled: 6 received study drug but did not return for follow-up visits, and 1 discontinued therapy because of a selection criteria violation. Baseline demographic characteristics of the study population, summarized in Table I, were comparable in the 2 treatment groups, with the exception of the number of episodes of AECB during the previous 12 months. Patients were well matched with respect to pretreatment signs and symptoms of AECB and isolated pathogens, with 2 exceptions. Compared with patients randomized to receive immediate-release clarithromytin, a significantly higher percentage of patients randomized to clarithromycin extended-release had moderate to severe sputum production (81% [24.5/303] vs 86% [272/3 171, P = 0.042) and headache (36% [109/303] vs 45% [143/317], P = 0.019) at the pretreatment visit. At baseline, the most frequently reported signs and symptoms were cough (all 620 patients), purulent sputum (6181620, >99%), rhonchil wheezing (480/620,77%), dyspnea (4591620, 74%), and hoarseness (3561620, 57%). The intent-to-treat population included 585 patients (300 clarithromycin extendedrelease and 285 clarithromycin immediate-

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Table I. Pretreatment

demographic

characteristics

of the study population.

Clarithromycin ER (n = 317) Sex, no. (%) Male Female Race, no. (%) White Black Asian Other Age, Y Mean + SD Range Weight, kg Mean + SD Range Tobacco use, no. (%) Non-tobacco user Ex-tobacco user Tobacco user No. of AECB episodes in previous 12 months Mean f SD Range ER =

136 (43) 181 (57)

134 (44) 169 (56)

277 (87)

262 (86)

18 (6) 8 (3) 14 (4)

16 (5) 12 (4) 13 (4)

54.3 + 15.9 14-86

54.6 + 17.2 16-89

82.1 + 22.4 42-195

82.1 f 21.0 44-158

73 (23) 106 (33) 138 (44)

70 (23) 103 (34) 130 (43)

2.9 f 1.6* 1-12

3.2 + 2.0 1-12

extended-release; IR = immediate-release; *P = 0.048.

AECB =

release); 35 patients were excluded from this analysis (17 clarithromycin extendedrelease and 18 clarithromycin immediaterelease) because they did not meet the selection criteria for AECB or because of other protocol violations. The clinically assessable population included 520 patients (26 1 clarithromycin extended-release and 259 immediate-release); 65 patients were excluded from this analysis for protocol violations, missing 21 visit, or using a confounding medication. The clinically and bacteriologically assessable population included 182 patients (100 clarithromycin extended-release and 82 clarithromycin

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Clarithromycin (n = 303)

IR

acute exacerbation of chronic bronchitis.

immediate-release); 374 patients ( 18 1 extended-release and 193 immediaterelease) were excluded because they did not have a target pathogen isolated at pretreatment. (Patients could have been excluded from the clinically and bacteriologically assessable population for 2 1 reason.) Seven percent of treated patients in each treatment group prematurely discontinued their study drug (23/317 in the clarithromycin extended-release group and 201303 in the clarithromycin immediate-release group). The most frequent reason for premature discontinuation of treatment

J.L. ADLER ET AL.

was an adverse event, followed by insufficient clinical improvement and protocol violations.

Treatment Duration and Compliance The mean (*SD) duration of treatment was 7.0 (kO.20) days for patients treated with clarithromycin extended-release and 7.2 (k1.03) days for those treated with clarithromycin immediate-release. A significantly higher percentage of patients treated with the extended-release formulation of clarithromycin took ~80% of the prescribed treatment regimen than did patients treated with the immediaterelease formulation (100% vs 95%, respectively; P = 0.009). This criterion was used to establish the assessable patient populations. Although this difference was statistically significant, it did not influence the efficacy analyses, as the results for the clinically and bacteriologically assessable populations were not different from those of the intent-to-treat populations.

Clinical Response Among clinically and bacteriologically assessable patients, 83% (83/100) in the clarithromycin extended-release group and 82% (67/82) in the clarithromycin immediate-release group were classified as clinical cures at the test-of-cure visit (Table II). Clinical responses were similar in the intent-to-treat analysis. The 95% CI for the difference between clinical cure rates (extended-release vs immediate-release) in the clinically and bacteriologically assessable population and the intent-to-treat population demonstrated that the 2 treatments were equivalent. After adjusting for subgroup efficacy vari-

ables, no statistically significant differences were noted between treatment groups. No statistically significant betweentreatment differences were observed at the test-of-cure visit in the percentage of patients showing resolution or resolution/ improvement in their pretreatment signs and symptoms of AECB, with 1 exception. Compared with patients who received clarithromycin immediate-release, a significantly higher proportion of patients in the clarithromycin extendedrelease group demonstrated resolution of purulent sputum (96% [89/93] vs 85% [64/75]; P = 0.028).

Bacteriologic

Response

Among clinically and bacteriologically assessable patients, 86% (85199) of those who received clarithromycin extendedrelease and 85% (70/82) of those who received the immediate-release formulation had achieved bacteriologic cure at the test-of-cure visit (Table II). The overall pathogen eradication rate was also similar in the 2 treatment groups: pathogen eradication occurred in 86% (100/l 16) of patients in the clarithromycin extendedrelease group and 88% (86198) of the clarithromycin immediate-release group. No significant differences were observed in a comparison of bacterial eradication by isolate (Table II). Results in the intent-totreat analysis were similar. The 95% CI for the differences between groups (extended-release vs immediaterelease) in bacteriologic cure rate (-9.8 to 10.8) and pathogen eradication rate (-10.6 to 7.5) demonstrated that the 2 treatments were equivalent. After adjusting for subgroup efficacy variables, no statistically significant differences were noted between treatment groups.

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CLINICAL THERAPEUTICS”

Table II. Bacteriologic and clinical cure rates at the test-of-cure visit, study days 19 to 21 (clinically and bacteriologically assessable population). No. (%) of

Clinical cure rate Within-group 95% CI Bacteriologic cure rate Within-group 95% CI Pathogen eradication rate Within-group 95% CI Eradication rate by protocoldefined bacteria Haemophilus Moraxella

injluenzae

catarrhalis

Streptococcus Haemophilus Staphylococcus

pneumoniae parainjluenzae aureus

Patients

Clarithromycin ER

Clarithromycin

83/100 (83) 74.2 to 89.8

67/82 7 I .6 to 70/82 75.8 to 86/98 79.6 to

85/99* (86) 77.4 to 92.0 100/l 16 (86) 78.6 to 91.9

22/28 (79)

(82) 89.4 (85) 92.2 (88) 93.5

17/22 (77)

IR

P (95% CI) 0.85 (-9.9 to 12.4) >0.99 (-9.8 to 10.8) 0.84 (-10.6 to 7.5)

>0.99 0.35

22/25* (88)

25/26’

(96)

22125 (88)

901

(82)

0.63

24126 (92)

25/28 (89)

>0.99

IO/12 (83)

IO/11 (91)

>0.99

ER = extended-release; IR = immediate-release. *One patient had an indeterminate bacteriologic response and was not included in the calculation of eradication rates.

Study drug-related treatment-emergent adverse events were reported by 22% (70/317) of patients who received clarithromycin extended-release and 17% (52/303) of patients who received the immediate-release formulation. There were no significant differences between treatment groups in the incidence of adverse events. The most frequently occurring (~3%) drug-related adverse events in the clarithromycin extended-release and clarithromycin immediate-release groups were diarrhea (6% and 4%, respectively), altered taste (4% in each treatment group), and nausea (3% in each treatment group). The majority of adverse events were mild to moderate. Serious adverse events were reported by 12 patients (8 treated with clarithromy-

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tin extended-release and 4 treated with clarithromycin immediate-release) during the study. All but 1 of these adverse events were considered to be unrelated or probably unrelated to the study drug; 1 patient in the extended-release group experienced a serious adverse event (atria1 flutter) that was considered possibly related to the study drug. The patient was treated with medication and the event resolved. One death occurred: >30 days after the last dose of study drug, a patient experienced a fatal cardiopulmonary arrest that was considered to be unrelated to the study drug. Nine patients in each treatment group prematurely discontinued treatment because of adverse events, most of which were considered by the investigator to be related to the study drug. Three (33%) of the 9 discontinuations in the clarithromytin extended-release group and 6 (67%)

J.L. ADLER ET AL.

of the 9 discontinuations in the immediaterelease group were attributed to a gastrointestinal adverse event. No clinically meaningful changes in laboratory values or vital signs were observed during the study.

DISCUSSION This study was conducted to compare the rates of bacteriologic cure, pathogen eradication, and clinical cure of 2 formulations of clarithromycin used to treat patients with AECB. Comparable rates of clinical cure (>82%), bacteriologic cure (>85%), and pathogen eradication (>86%) were noted in each treatment group. Significantly more patients in the clarithromycin extended-release treatment group (100%) complied with their therapeutic regimen (~80% of study drug taken, an inclusion requirement for the clinically assessable population) than did patients in the clarithromycin immediate-release treatment group (95%; P = 0.009), despite the fact that both groups took medication twice daily. Thus, the difference in compliance may be related to the increased tolerability of the extended-release formulation. Both formulations of clarithromycin were well tolerated, and drug-related adverse events were usually mild to moderate and were reported at comparable rates in the 2 treatment groups. In both groups, most of the adverse events were related to the gastrointestinal tract, although twice as many patients treated with the immediaterelease formulation discontinued treatment prematurely because of a gastrointestinal adverse event. Macrolide antibiotics are considered first-line treatment for AECB. In the present study of patients with AECB and another study by Murray et all7 of patients

with acute maxillary sinusitis, a new extended-release formulation of clarithromycin that requires only once-daily administration was’assessed. These 2 studies support the efficacy and tolerability of the extended-release formulation of clarithromycin in the treatment of AECB due to H injluenzae, H parainjluenzae, M catarrhalis, or Spneumoniae and acute maxillary sinusitis due to H injZuenzae, M catarrhalis, or S pneumoniae. I8

CONCLUSION The results of this study suggest that the clinical and bacteriologic efficacy of the extended-release and immediate-release formulations of clarithromycin are equivalent in the treatment of patients with AECB. Analysis of compliance showed that a significantly higher percentage of patients treated with the extended-release formulation of clarithromycin were compliant with their treatment regimen compared with those treated with the immediate-release formulation, which may be related to the increased tolerability of the extendedrelease formulation.

ACKNOWLEDGMENT This multicenter study was initiated and supported by Abbott Laboratories, Abbott Park, Illinois.

Address correspondence to: Jay L. Adler, MD, Clinicos Clinical Research, 2020 West Colorado Avenue, Suite 201, Colorado Springs, CO 80904. REFERENCES I. Reynolds HY. Chronic bronchitis and acute infectious exacerbations. In: Mandell GL,

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Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s

Principles

and Prac-

tice of Infectious Diseases. 5th ed. Philadel-

phia: Churchill Livingstone;

2000:706.

2. Chodosh S. Bronchitis and asthma. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Znfectious Diseases. Philadelphia: WB Saunders; 1992:47648.5. 3. Gump DW, Phillips CA, Forsyth BR, et al. Role of infection in chronic bronchitis. Am Rev Respir Dis. 1976; 113:465474. 4. Kayser FH. Changes in the spectrum of organisms causing respiratory tract infections: A review. Postgrad Med J. 1992;68(Suppl 3):S17-S23. 5. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995;152: S77-S121.

6. Siafakas Optimal chronic (COPD).

NM, Vermeire P, Pride NB, et al. assessment and management of obstructive pulmonary disease Eur Respir J. 1995;8: 1398-l 420.

release clarithromycin tablet at doses of 500 mg and 1000 mg daily. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, Calif. Abstract 1191. 12. Anzueto A. Contemporary Management

Diagnosis

and

of Bronchitis.

town, Pa: Handbooks 2000:86102.

3rd ed. Newin Health Care Co;

13. FDA Guidance for Industry. Acute bacterial exacerbation of chronic bronchitisDeveloping antimicrobial drugs for treatment. Bethesda, Md: US Food and Drug Administration, Center for Drug Evaluation and Research; July 1997/1998. 14. National Committee for Clinical Laboratory Standards. Performance Standards forAntimicrobial

Disk Susceptibility

Tests.

6th ed. Approved Standard M2-A6 (ISBN I-56238-308-6). Wayne, Pa: National Committee for Clinical Laboratory Standards; 1997. 15. COSTART-Coding

Symbols

saurus of Adverse Reaction

for

The-

Terms. 3rd ed.

7. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations. A metaanalysis. JAMA. 1995;273:957-960.

Bethesda, Md: US Food and Drug Administration, Center for Drug Evaluation and Research; 1989.

8. Balter MS, Hyland RH, Low D, et al. Recommendations on the management of chronic bronchitis: A practical guide for Canadian physicians. Can Med Assoc J. 1994;151(10 Suppl):5-23.

16. Division of Anti-infective Products. Clinical development and labeling of antiinfective drug products. 2. Points regarding clinical trial design/conduct. IV. Issues regarding adequacy of trials. Washington, DC: US Food and Drug Administration; October 1992.

9. Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest. 1995;108(Suppl):43S-52s. 10. Peters DH, Clissold SP. Clarithromycin. review

of its antimicrobial

activity,

A

phar-

macokinetic properties, and therapeutic potential. Drugs. 1992;44: 117-l 64. II. Gustavson LE, Cao CX, Semla SJ, Palmer RN. Pharmacokinetics of a new extended-

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17. Murray J, Solomon E, McCluskey D, et al. Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of adult patients with acute maxillary sinusitis. Clin Ther: 2000;22:1421-1432. 18. Biaxin@ [package insert]. Abbott Park, Ill: Abbott Laboratories; October 2000.