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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, October 2005, p. 4035-4041, Vol. 49, No. 10
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.10.4035-4041.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Department of Family Medicine, McGill University, Montreal, Quebec, Canada,1 Universidad Peruana Cayetano Heredia, Lima, Peru,2 Pfizer Inc., New London, Connecticut3
Received 16 December 2004/ Returned for modification 29 April 2005/ Accepted 20 June 2005
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ABSTRACT |
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INTRODUCTION |
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The newer oral macrolides, including azithromycin, are active against this array of pathogens and are recommended as first-line agents by a number of CAP treatment guidelines (15, 16, 20), generally for outpatients without underlying cardiopulmonary disease or other modifying factors. Oral fluoroquinolones that are active against S. pneumoniae, such as levofloxacin, are also recommended for outpatients with CAP. However, because of their broader spectrum of activity and concerns about increasing rates of resistance arising from excessive use (6, 11), several guidelines advocate restricting use of these "respiratory" fluoroquinolones to patients with cardiopulmonary disease and/or other modifying factors (15, 20) or to those who have recently received antibiotic therapy (16).
Azithromycin has a half-life of approximately 60 h and concentrates within a variety of cells, including fibroblasts, epithelial cells, macrophages, monocytes, and neutrophils (26, 24), thus achieving high and sustained tissue concentrations. These properties allow for shorter dosing regimens than are possible with other antibiotics that have short elimination half-lives. In the United States, azithromycin has been used successfully for the treatment of mild to moderate CAP at a total dose of 1.5 g given orally over 5 days. In Europe and elsewhere, a shorter, 3-day course has proven equally effective (13, 21).
Indeed, a growing body of data suggests that a higher-dose, single-dose regimen may be the most effective means of administering azithromycin. In a preclinical model of otitis media, increasing the dose of azithromycin resulted in more-rapid and more-extensive killing of H. influenzae (1). In models of pneumonia and septicemia, the administration of a single, large dose of azithromycin achieved more-rapid bacterial eradication (D. Girard, S. M. Finegan, C. R. Cimochowski, M. W. Dunne, and A. Giovanis, Abstr. 102nd Am. Soc. Microbiol. Gen. Meet., abstr. A-57, 2002) and improved survival (B. J. Kamicker, C. D. Bertsche, and I. A. Medina. Abstr. 44th Annu. Meet. Intersci. Conf. Antimicrob. Agents Chemother., abstr. B-1181, 2004) than the same dose divided over several days. This so-called "front-loading" of the dose maximizes drug exposure at a time when the bacterial burden is likely to be high, driving up the 24-h area under the concentration-time curve (AUC)/MIC ratio, which is the pharmacokinetic/pharmacodynamic parameter that best predicts efficacy of azithromycin (9). A single-dose pediatric oral suspension of azithromycin (30 mg/kg of body weight) was approved for the treatment of acute otitis media in the United States in 2001.
In considering studies to investigate the efficacy of a higher-dose, single-dose azithromycin regimen in the treatment of CAP in adults, one challenge was the high level of gastrointestinal intolerance (
35%) associated with the currently available 2.0-g oral sachet formulation. The present study investigated the use of a recently developed, novel formulation of azithromycin. This formulation, in which azithromycin is contained within microspheres, allows oral administration of a single, 2.0-g dose, while dramatically improving upon the adverse event profile of the immediate-release sachet formulation. The Cmax value and 24-h AUC achieved after a single 2.0-g dose of azithromycin microspheres are two and three times higher, respectively, than those achieved with the first dose, 500 mg, of either the 3- or 5-day immediate-release regimens that are currently approved in the United States and abroad.
Most patients with CAP are treated as outpatients, in whom compliance with prescribed therapy may be problematic. An added benefit of a single-dose therapy is the opportunity it provides to achieve 100% patient compliance.
The primary objective of this study was to test the hypothesis that a single 2.0-g oral dose of azithromycin microspheres was at least as effective as a 7-day regimen of oral levofloxacin, 500 mg/day, in the treatment of mild to moderate CAP. Secondary objectives included assessments of bacteriologic efficacy and safety.
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MATERIALS AND METHODS |
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Study design. This randomized, double-blind, double-dummy study utilized a noninferiority design to compare the efficacy and safety of a 2.0-g dose of azithromycin microspheres with that of levofloxacin, 500 mg given orally (p.o.) daily for 7 days, when used to treat adult patients with mild-to-moderate CAP. Noninferiority would be concluded if the lower limit of the 95% confidence interval around the difference in clinical cure rates (azithromycin microspheres results – levofloxacin results) was greater than –10%. Eligible subjects were randomized 1:1 to receive either a single 2.0-g oral dose of azithromycin microspheres and 7 days of once-daily levofloxacin placebo or a 7-day regimen of levofloxacin, 500 mg daily, and a single dose of azithromycin placebo. The first dose of medication was to be taken under observation in the clinic.
Eligibility criteria.
Males and females, ages 18 years or older, were eligible for enrollment if they had a clinical diagnosis of mild to moderate CAP as demonstrated by a productive cough and two or more of the following signs or symptoms: auscultatory findings such as rales and/or evidence of pulmonary consolidation; dyspnea or tachypnea; elevated body temperature (>38°C orally, >38.5°C tympanically, >39°C rectally, or >37.2°C axillary); elevated total peripheral white blood cell count (>10,000/mm3); or >15% immature neutrophils. Subjects were required to have radiographic evidence of a new pulmonary infiltrate or consolidation that could not be attributed to a process other than pneumonia. Radiographs were read by a radiologist and/or the investigator. Finally, subjects were required to have a Fine mortality risk class of I, I, or III (i.e., a risk score of 
90) (10). For the purposes of this study, the point scoring system for step 2 of the prediction rule was modified as follows: an arterial saturation of 89% by pulse oximetry resulted in a point assignment of +10; arterial blood gases were not done. In addition, a finger-stick glucose test was the only laboratory parameter used in determining the score.
Subjects with evidence of the following were to be excluded from the study: (i) known or suspected hypersensitivity or intolerance to azithromycin, levofloxacin, or other macrolides or fluoroquinolones; (ii) previously diagnosed diseases of immune function, such as baseline absolute neutrophil count of <1,000/mm3, human immunodeficiency virus seropositivity with a CD4 count of <200, or any immunoglobulin or neutrophil disorder; (iii) treatment with more than one dose, or one combination dose, of systemic antibiotic within the previous 7 days; (iv) gastrointestinal disturbances that might affect drug absorption; (v) any medical condition that, in the opinion of the investigator, might interfere with the evaluation of the study drug and/or would make the subject unsuitable for enrollment; (vi) previously diagnosed conditions which tend to mimic or complicate the course and the evaluation of the infectious process, such as bronchiectasis, lung abscess or empyema, active tuberculosis, pulmonary malignancy, cystic fibrosis, or postobstructive pneumonia; (vii) known or suspected renal insufficiency, with a calculated creatinine clearance of less than 50 ml/min; (viii) hospitalization in the previous 14 days or infection acquired in the hospital; (ix) residents of long-term care facilities; (x) current evidence of hepatic disease (i.e., aspartate aminotransferase and/or alanine aminotransferase and/or total bilirubin 
3 times the upper limit of normal; (xi) inability or unwillingness to swallow pills or suspension; (xii) treatment with other investigational drugs within 30 days prior to randomization; and (xiii) prior enrollment in the present study or any other study utilizing azithromycin microspheres. Women who were pregnant or breastfeeding were excluded.
A study subject could be withdrawn from the study at any time for any of the following reasons: an adverse event; persistence or worsening of signs and symptoms of acute infection; an intercurrent illness; decision by the subject not to participate any further; investigator felt that it was in the subject's best interest to do so; study was terminated by the sponsor. Patients who were withdrawn due to persistence or worsening of signs and symptoms of acute infection and received antibiotics to treat the infection were included as clinical failures in the final analysis. In addition, participation of a female subject who became pregnant during study drug dosing was to be discontinued immediately.
Clinical and radiological assessments. Clinical response at test of cure (TOC) was the primary endpoint in this study. Patients were assessed five times during the study: at baseline (day 1), on treatment (days 3 to 5), at the end of treatment (days 8 to 11), at test of cure (days 14 to 21), and at long-term follow-up (days 28 to 35). For the purpose of the per-protocol analyses, the visit windows were extended prior to unblinding to days –1 to 1 for the baseline visit, days 2 to 6 during treatment, days 7 to 12 for end of treatment, days 13 to 24 for TOC, and days 25 to 38 for long-term follow-up. This extension was made to ensure that all clinically relevant data were included in the analyses.
Clinical assessment was made on the basis of signs and symptoms of CAP. A patient was considered a cure at TOC if signs and symptoms related to the acute infection had resolved or clinical improvement was such that no additional antibiotics were deemed necessary. In addition, the chest X-ray performed at the TOC visit had to be either unchanged or improved.
Failure was defined as either the persistence or worsening of signs and symptoms related to the acute infection for which additional antibiotics were necessary, the appearance of new clinical signs and/or symptoms of pneumonia for which additional antibiotics were necessary, radiological evidence of pneumonia progression during treatment, or death due to pneumonia. In some cases, for instance, when no additional antibiotic was prescribed and some signs or symptoms improved but others did not, a clinical response of cure or failure could not be assigned programmatically. In these instances, the sponsor manually reviewed the subject's data and assigned a response prior to treatment unblinding. Patients with a clinical response of cure at test of cure were also assessed for relapse at long-term follow-up. Relapse was defined as either a return of symptoms after initial resolution or improvement, the appearance of new clinical signs or symptoms without documentation of a new pathogen, the need for alternate antibiotic therapy for worsening signs or symptoms, or the appearance of new signs and symptoms of pneumonia.
Bacteriological assessment. Bacterial response to treatment was a secondary efficacy variable in the study. At the baseline visit, all patients provided a sputum sample, which was sent to a central laboratory for Gram stain. Specimens with <10 epithelial cells per low-power field were cultured, and isolated pathogens were tested for susceptibility to azithromycin and levofloxacin according to the Clinical and Laboratory Standards Institute (formerly National Committee for Clinical Laboratory Standards) procedures. In addition, S. pneumoniae isolates were tested for susceptibility to penicillin and H. influenzae and M. catarrhalis isolates for ß-lactamase production. Genotyping was performed on azithromycin-resistant isolates of S. pneumoniae to determine the presence of the erythromycin ribosomal methylase (erm) gene and/or the macrolide efflux pump (mef) gene. In addition, all subjects submitted a urine specimen for S. pneumoniae antigen testing (BINAX), and blood cultures were collected from those subjects with a positive urine antigen test.
Specimens for detection of M. pneumoniae and C. pneumoniae were sent to the University of Louisville Infectious Diseases Laboratory for testing. Laboratory workup for M. pneumoniae included oropharyngeal swab for PCR detection and culture and acute and convalescent serology by immunofluorescent-antibody assay. Laboratory workup for C. pneumoniae included oropharyngeal swab for PCR detection and acute and convalescent serology by microimmunofluorescent-antibody assay. Seroconversion was considered positive when a fourfold increase in antibody titer, in either immunoglobulin G and/or immunoglobulin M, was seen between the acute- and convalescent-phase serum specimens. There was no testing for Legionella pneumophila performed, since it was felt that this organism was less likely to cause mild or moderate disease.
After the results of the baseline sputum culture were known, the investigator was to take one of the following courses of action, as medically appropriate. Study subjects whose baseline cultures did not grow a pathogen were to continue in the study and be evaluated for clinical response to therapy. Subjects whose baseline culture revealed pathogens susceptible to azithromycin and levofloxacin were to continue in the study and be evaluated for both clinical and bacteriologic response to therapy. Subjects whose baseline culture revealed one or more pathogens resistant to azithromycin or levofloxacin were to continue in the study; if clinically indicated, the investigator could administer alternative antibiotic therapy.
The bacteriologic response at TOC was categorized as eradication or presumed eradication if all initial pathogens were absent or if the subject was considered a cure in the absence of a specimen for culture. The bacteriologic response at TOC was categorized as "persisted" or "presumed persisted" if the original pathogen was still present or if the patient was considered a failure in the absence of a specimen for culture.
Safety assessment. All subjects who received at least one dose of study drug were included in the safety analysis. All subjects in the study were monitored for clinical as well as laboratory adverse events. Adverse events were recorded up to 35 days after therapy, and the investigator assessed their severity and relationship to study medication.
Statistical analysis. The primary objective of the study was to demonstrate noninferiority of azithromycin microspheres to levofloxacin. The primary efficacy variable was the clinical response at TOC in the "clinical per protocol" population. Two-sided 95% confidence intervals were used to estimate the difference in the proportion of cures between the treatment groups, calculated with the normal approximation to the binomial distribution.
In order to achieve a power of 80%, the study was designed to enroll 504 subjects in order to have 201 evaluable (clinical per protocol) subjects in each treatment arm, assuming an underlying equivalent clinical response of 85% at TOC and that as many as 20% of subjects would not be evaluable.
There were four patient populations analyzed in this study. The "all treated" population comprised all randomized subjects who took at least one dose of study medication. The "clinically eligible" population, or modified intent-to-treat population, included all treated subject who had a clinical diagnosis of CAP, as specified by the inclusion criteria. The "clinical per protocol" population included those clinically eligible subjects who received at least 6 days of study medication, who came for a TOC assessment in the appropriate time frame, and who did not receive any systemic antibiotics with activity against pathogens likely to cause CAP. Finally, the "bacteriologic per protocol" population comprised those "clinical per protocol" subjects who had a pathogen identified at baseline by either culture, PCR, or serology.
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RESULTS |
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Due to the single-dose nature of the regimen, all subjects treated with azithromycin microspheres were compliant with the full course of active treatment. Ten of the 212 levofloxacin-treated subjects (4.7%) did not complete the full 7-day course of active treatment.
Of the 211 azithromycin microsphere-treated subjects and 212 levofloxacin-treated subjects, 174 (82.5%) and 189 (89.2%), respectively, met criteria for inclusion in the "clinical per protocol" population. The absence of a TOC visit and lack of a clinical or radiographic diagnosis of CAP were the most common reasons for exclusion from the "clinical per protocol" population (Table 2).
Bacteriology at baseline. In the "all treated" patient population, a total of 107 subjects (50.7%) in the azithromycin microspheres group and 112 subjects (52.8%) in the levofloxacin group had at least 1 pathogen identified at baseline (Table 4). The proportions of subjects with single or multiple pathogens were comparable in the two groups. The most commonly identified pathogen overall was C. pneumoniae, followed by Staphylococcus aureus, Haemophilus parainfluenzae, M. pneumoniae, S. pneumoniae, and H. influenzae. The method of diagnosis of atypical pathogens is presented in Table 5. While all C. pneumoniae infections were diagnosed by serology alone, M. pneumoniae was identified by a variety of methodologies. None of the enrolled subjects had documented pneumococcal bacteremia.
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Clinical responses. The clinical cure rate in the "clinical per protocol" population at TOC (days 13 to 24) was 89.7% (156/174) for azithromycin and 93.7% (177/189) for levofloxacin (treatment difference, –4.0%; 95% confidence interval, –9.7%, 1.7%). The clinical responses in the other subject populations are presented in Table 6. Only one subject, in the levofloxacin group, was considered a relapse at the long-term follow-up visit.
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65 years of age were similar between the two groups (36/39 [92.3%] for azithromycin and 40/41 [97.6%] for levofloxacin), as were the response for those with unilobar disease (125/141 [88.7%] for azithromycin and 151/160 [94.4%] for levofloxacin) or multilobar disease (31/33 [93.9%] for azithromycin and 26/29 [89.7%] for levofloxacin). In the "bacteriologic per protocol" population at TOC, clinical success rates for subjects with the most frequently identified pathogens were generally comparable in the two treatment groups, although there were small numbers in some instances: for C. pneumoniae, 94.7% (18/19) for azithromycin and 95.5% (21/22) for levofloxacin; for S. aureus, 100% both for azithromycin (11/11) and for levofloxacin (27/27); for H. parainfluenzae, 100% (11/11) for azithromycin and 73.3% (11/15) for levofloxacin; for S. pneumoniae, 78.6% (11/14) for azithromycin and 83.3% (10/12) for levofloxacin; for M. pneumoniae, 71.4% (5/7) for azithromycin and 100% (18/18) for levofloxacin; for H. influenzae, 93.3% (14/15) for azithromycin and 100% (8/8) for levofloxacin; and for M. catarrhalis, 100% for both azithromycin (7/7) and levofloxacin (2/2).
Bacteriologic responses. Among subjects in the "bacteriologic per protocol" population, the overall bacteriologic response rates (eradication or presumed eradication) for azithromycin and levofloxacin were 90.7% (97/107) and 92.3% (120/130), respectively (treatment difference, –1.7%; 95% confidence interval, –8.8%, 5.5%). In the azithromycin microsphere arm, there were eight pathogens for which the bacteriologic response was "presumed persisted": one H. influenzae isolate (azithromycin MIC of 1), two S. pneumoniae isolates (azithromycin MICs of 4 and 0.12), one C. pneumoniae isolate (azithromycin MIC not tested), two M. pneumoniae isolates (MIC not tested), and two Enterobacter spp. (azithromycin MIC of >4); the subjects with these pathogens were clinical failures. In addition, two Enterobacter spp. (azithromycin MIC of >4) were documented to persist in subjects that were considered clinical cures. In the levofloxacin arm, there were eight pathogens for which the bacteriologic response was "presumed persisted": two S. pneumoniae isolates (levofloxacin MIC of 1), one C. pneumoniae isolate (levofloxacin MIC not tested), four Haemophilus parainfluenzae isolates (levofloxacin MICs, 0.015 [three isolates] and 0.06), and one Klebsiella oxytoca isolate (levofloxacin MIC of 0.03); the subjects with these pathogens were clinical failures. In addition, two isolates were documented to persist: one Klebsiella oxytoca isolate (levofloxacin MIC of 0.03) in a subject who was a clinical failure and one Pseudomonas spp. (levofloxacin MIC of 2) in a subject that was a clinical cure.
A total of seven azithromycin-resistant S. pneumoniae isolates were identified in the study, five in subjects in the azithromycin group (Table 7). Four of these subjects were in the "bacteriologic per protocol" population; two were considered clinical cures, and two were failures. One of the failures had an S. pneumoniae isolate with high-level azithromycin resistance (MIC of >256 µg/ml; erm(B) genotype); despite clinical failure, the organism was documented to be eradicated in a follow-up sputum culture obtained at the TOC visit. The single subject in the "clinically eligible" population was considered a cure. This subject, who also had S. aureus identified at baseline, had S. pneumoniae with an azithromycin MIC of 4 µg/ml; the isolate tested negative for both the mef and erm(B) genes, suggesting that resistance, in this instance, may have been conferred by a point mutation.
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Serious adverse events occurred in eight (3.8%) azithromycin-treated patients and six (2.8%) of those receiving levofloxacin. None of the events were considered treatment-related. Six subjects (two treated with azithromycin and four treated with levofloxacin) were hospitalized for worsening pneumonia; two of the levofloxacin subjects ultimately died of causes other than pneumonia: one of cardiorespiratory arrest and one of respiratory failure, lung abscess, and pulmonary hemorrhage on study day 87. Bronchial alveolar lavage and suctioned endotracheal specimens from the subject with respiratory failure obtained nearest to the reported onset date of pulmonary abscesses (study day 17) grew Aspergillus spp. One azithromycin-treated subject died of heart failure that was considered unrelated to study medication.
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DISCUSSION |
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It is unclear what effect having a smaller than anticipated number of "clinical per protocol" subjects had on the power of the study to detect noninferiority. While the smaller sample size decreased this power, the observed clinical response rates suggest that the actual clinical responses are greater than 85%, which would have increased the power.
While the mean age in this study was between 48 and 49, roughly one quarter of enrolled subjects were 65 years of age; both treatment regimens were effective in this particular population. As one might expect in a study targeting mild to moderate pneumonia, most subjects had unilobar disease; however, those subjects with multilobar involvement responded well to both therapies.
Causative pathogens were identified in just over 50% of patients in both treatment arms, which is similar to the rates reported in other CAP studies (2, 17). Interestingly, the most frequently identified typical pathogen was S. aureus (43 isolates total; 9 from Canada, 2 from India, 4 from Lithuania, 14 from Peru, 2 from Russia, and 12 from the United States). Of the 43 subjects with S. aureus identified in their baseline sputum cultures, 20 had >25 polymorphonuclear cells per low-power field. While community-acquired methicillin-resistant S. aureus (MRSA) infections have occurred with increasing frequency in the last few years (25; J. C. Hageman, J. Francis, and T. M. Uyeki, Abstr. Infect. Dis. Soc. Am. 42nd Annu. Meet., abstr. LB-8, 2004), only 2 of the 43 S. aureus isolates identified in this study were methicillin resistant. Neither of the 2 methicillin-resistant S. aureus isolates had antibiograms suggestive of true community acquisition. Both were resistant to amoxicillin/clavulanate, azithromycin, clarithromycin, cefuroxime, and penicillin; and they were both susceptible to levofloxacin.
While 25% (7/28) of the S. pneumoniae isolates collected in this study were resistant to azithromycin, this translated to only 1.8% (7/394) of clinically eligible subjects overall having resistant S. pneumoniae as the cause of their episode of CAP. Moreover, three of the five azithromycin-treated subjects with resistant S. pneumoniae were considered clinical cures. Of note, these subjects were not infected with isolates of the (erm)B genotype, which confers high-level resistance to azithromycin and other macrolides. While the number of resistant S. pneumoniae isolates collected in this study is too small to allow any firm conclusions regarding efficacy, administering 2.0 g of azithromycin microspheres as a single dose is likely to result in concentrations of azithromycin in lung tissue and fluid that would be effective against S. pneumoniae with low-level macrolide resistance. A trial examining the lung pharmacokinetics of the single-dose azithromycin microsphere regimen is currently under way to provide data to support this hypothesis.
The single 2.0-g dose of azithromycin microspheres was well tolerated. While the incidence of treatment-related diarrhea (12.3%) was higher in the azithromycin treatment arm than in the amoxicillin/clavulanate arm, it is lower than the rate of treatment-related diarrhea reported in a study of the recently approved 3-day azithromycin regimen for bacterial sinusitis (17.0%) (12). The overall difference in treatment-related adverse events between treatments was primarily due to diarrhea, since the number of patients with adverse events other than diarrhea was only slightly higher for azithromycin-treated patients.
In the present study, all azithromycin microsphere patients were fully compliant with active treatment, whereas 4.7% of levofloxacin-treated patients did not complete the entire 7-day course of active treatment. Studies have shown that short-course antibiotic therapy can improve patient compliance (7). Other studies have shown that improving compliance can lead to faster resolution of symptoms (8). A meta-analysis of several studies on bacterial upper respiratory tract infections, which included acute otitis media, acute bacterial sinusitis, and streptococcal pharyngitis, concluded that shorter courses of antibiotics have the potential to increase patient compliance with therapy, decrease adverse events (by decreasing drug exposure), decrease the emergence of resistant strains, and reduce cost (22, 23).
Surveys consistently show that compliance declines in relation to the frequency and duration of antibiotic therapy (4, 27). Once symptoms begin to resolve within the first few days of treatment, patients often stop taking antibiotic therapy, thereby increasing the risk of treatment failure. Thus, the availability of single-dose antibiotic therapy may enhance compliance, thereby maximizing efficacy while minimizing the emergence of resistance.
Another compliance-related advantage of single-dose azithromycin microspheres is the potential for use as directly observed therapy. This option may be valuable in the clinic or emergency department, where compliance may be in doubt or barriers to filling prescriptions may exist.
The pneumonia severity index developed by the Pneumonia Outcomes Research Team stratifies patients into five risk classes, with 30-day mortality rates highest in class V (10). While most clinicians would agree that patients with class IV or V disease should be hospitalized, a notable proportion of subjects who are treated as inpatients have class I, II, or III disease (10, 18). A recently conducted, randomized trial confirmed that outpatient care of patients with risk classes II and III was as safe and effective as inpatient care (5); the patients in that study received levofloxacin. While treatment guidelines generally advocate the use of the respiratory fluoroquinolones for the treatment of CAP in patients with comorbidities or recent antibiotic use (15, 16, 20), studies have shown that inappropriate use of fluoroquinolone in the outpatient setting is common (14), which in turn could contribute to the development of resistance.
The present study has demonstrated that a single 2.0-g dose of azithromycin microspheres was at least as effective and well tolerated as a 7-day course of levofloxacin when used to treat mild to moderate CAP in adults. This novel formulation represents a safe and effective therapy for subjects for whom outpatient treatment is appropriate, including those with Fine class II and III disease, while providing the added benefit of maximum patient compliance.
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ACKNOWLEDGMENTS |
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The clinical trial was funded by Pfizer Inc. D. E. Lewis, D. Jorgensen, and J. D. Breen are employed by Pfizer Inc. J. D'Ignazio and M. A. Camere participated as investigators in the trial.
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FOOTNOTES |
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