Articles
Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial Nan Shan Zhong*, Tieying Sun*, Chao Zhuo*, George D’Souza, Sang Haak Lee, Nguyen Huu Lan, Chi-Huei Chiang, David Wilson, Fang Sun, Joseph Iaconis, David Melnick
Summary Background Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia. Methods In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III–IV acute communityacquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5–7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8–15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of –10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838. Findings Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8–17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data. Interpretation Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III–IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population. Funding AstraZeneca.
Introduction The morbidity and mortality associated with communityacquired pneumonia of sufficient severity to require hospital admission remain high despite existing management strategies.1,2 Clinical treatment guidelines in the USA,3 Europe,4 and Asian countries5–8 recommend intravenous broad-spectrum cephalosporins such as ceftriaxone, often in combination with a macrolide antibiotic, as a treatment option for such patients. Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in-vitro activity against pathogens that often cause community-acquired pneumonia, including Gram-positive species such as Staphylococcus aureus and Streptococcus pneumoniae, and
non-extended-spectrum β-lactamase (non-ESBL) phenotype Gram-negative species including Klebsiella pneumoniae and Haemophilus influenzae. Compared with other β-lactams, ceftaroline has enhanced in-vitro activity against meticillin-resistant S aureus (MRSA) and penicillin-nonsusceptible S pneumoniae, although ceftaroline fosamil is not currently approved for the treatment of communityacquired pneumonia caused by these pathogens. Ceftaroline fosamil is licensed in Europe for the treatment of adult patients admitted to hospital with communityacquired pneumonia or complicated skin and soft-tissue infection at a dose of 600 mg every 12 h, adjusted for renal function, and for similar indications in several other countries, including the USA.9,10
www.thelancet.com/infection Published online December 22, 2014 http://dx.doi.org/10.1016/S1473-3099(14)71018-7
Lancet Infect Dis 2014 Published Online December 22, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71018-7 See Online/Comment http://dx.doi.org/10.1016/ S1473-3099(14)71063-1 *Contributed equally State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China (Prof N S Zhong MD, Prof C Zhuo MD); Beijing Hospital, Beijing, China (Prof T Sun MD); St John’s Medical College Hospital, Bangalore, India (G D’Souza MD); St Paul’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea (Prof S H Lee MD); Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam (N H Lan MD); Taipei Veterans General Hospital, Taipei, Taiwan (Prof C-H Chiang MD); AstraZeneca, Macclesfield, UK (D Wilson BSc); AstraZeneca China, Shanghai, China (F Sun MD); AstraZeneca, Waltham, MA, USA (J Iaconis PhD); and AstraZeneca Pharmaceuticals, Wilmington, DE, USA (D Melnick MD) Correspondence to: Prof Nan Shan Zhong, State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 501120, China [email protected]
1
Articles
For the study protocol see http://filehosting.pharmacm. com/DownloadService. ashx?client=CTR_MED_7111 &studyid=1374&filename=D372 0C00002_Revised_CSP_1_ (redacted).pdf
Approvals of ceftaroline fosamil for communityacquired pneumonia were based on the results of two multinational, phase 3 clinical trials in predominantly European and North American patients with Pneumonia Outcomes Research Team (PORT) risk class III or IV community-acquired pneumonia (FOCUS 1 and FOCUS 2).11,12 In the individual trials, ceftaroline fosamil was non-inferior to ceftriaxone at the test-of-cure visit (about 1–2 weeks after completion of treatment), with numerically more clinical cures among ceftaroline fosamil-treated patients. In the pooled analysis,13 the lower bound of the 95% CI for the difference was greater than 0%. However, patients of an Asian ethnic origin comprised only about 3% of those enrolled in these two studies;11,12 other clinical trial data in Asian patients have so far been limited to phase 1 pharmacokinetic studies. Thus the efficacy of this drug in the management of communityacquired pneumonia in Asian patients has not previously been assessed. This issue is of particular importance in the context of recent data suggesting differences in the bacterial causes of community-acquired pneumonia between Asian and European or North American populations, including a comparatively greater prominence of Gram-negative bacteria (specifically H influenzae and K pneumoniae) in Asian patients.14,15 S pneumoniae, a leading cause of community-acquired pneumonia, has a different resistance profile, particularly to macrolide antibiotics, in Asia from in Europe and North America.16,17 We aimed to assess the efficacy and safety of ceftaroline fosamil (600 mg every 12 h) compared with ceftriaxone (2 g every 24 h) for the treatment of Asian patients admitted to hospital with community-acquired pneumonia.
Methods Study design and participants In this prospective, multicentre, double-blind, activecomparator, randomised phase 3, non-inferiority with nested superiority trial patients with community-acquired pneumonia from 64 centres in China (23), India (13), South Korea (16), Taiwan (seven), and Vietnam (five) were randomly assigned to receive ceftaroline fosamil or ceftriaxone. Eligible patients were adults with radiographically confirmed pneumonia, defined as new or progressive pulmonary infiltrates on chest radiograph or CT scan consistent with bacterial pneumonia, acute illness (duration ≤7 days) with at least three clinical signs or symptoms of pneumonia, and PORT risk class III or IV disease (ie, PORT score >70 and ≤130)18 that required hospital admission and intravenous antibiotic treatment. Key exclusion criteria included PORT scores of 70 or less (risk class I and II) or greater than 130 (risk class V); requirement for admission to intensive care; pneumonia from a suspected source other than community-acquired bacterial pathogens (eg, ventilator-associated pneumonia, hospital-acquired pneumonia, visible or gross aspiration 2
pneumonia, or suspected viral, fungal, or mycobacterial infection of the lung); non-infectious causes of pulmonary infiltrates; treatment with other systemic antimicrobial drug for community-acquired pneumonia in the 96 h before randomisation (apart from a single dose of an oral or intravenous short-acting antibiotic for communityacquired pneumonia; or unequivocal clinical evidence of treatment failure after 48 h or more of previous systemic antimicrobial treatment with isolation of an organism resistant to the previous treatment); microbiologically documented infection with a pathogen regarded as nonsusceptible to ceftaroline and ceftriaxone (eg, Pseudomonas aeruginosa) or non-susceptible to ceftriaxone (eg, MRSA). A full list of inclusion and exclusion criteria is included in the study protocol, which is available online. The protocol was approved by independent ethics committees or institutional review boards at all study sites, and the study was done in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent.
Randomisation and masking After screening and enrolment, we used a centralised telephone and web-based system to assign a unique randomisation code for each enrolled patient, ensuring concealment of the randomisation sequence. Patients were assigned to receive either intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5–7 days. Randomisation was stratified by geographical area (China, India, South Korea, Taiwan, and Vietnam), with block sizes of four, to ensure roughly 1:1 assignment to each treatment group. Additionally, we used the randomisation system to enable the clinical team to monitor disease severity to ensure that at least 25% of randomly assigned patients were PORT risk class IV. Patients and the investigators and study staff who did patient enrolment and administered study treatment were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. Pharmacists and study site staff who were not masked to treatment allocation obtained each patient’s unique randomisation code and ensured that administration of study drugs occurred within 24 h of baseline assessments.
Procedures To maintain masking of treatment allocation from the patients and the treating clinicians, patients assigned to ceftriaxone received a 30 min infusion containing 2 g ceftriaxone followed by a matching placebo infusion, and a further two placebo infusions 12 h later. Each dose of ceftaroline fosamil was split into two consecutive 30 min (300 mg) infusions, with doses given every 12 h. For patients with moderate renal impairment (creatinine clearance less than 50 mL/min but greater than 30 mL/min, as estimated by the Cockcroft-Gault formula), ceftaroline
www.thelancet.com/infection Published online December 22, 2014 http://dx.doi.org/10.1016/S1473-3099(14)71018-7
Articles
fosamil dosing could be adjusted at any time by pharmacists or study staff not masked to treatment allocation to two consecutive 30 min infusions of ceftaroline fosamil 200 mg (for a total of 400 mg) every 12 h and readjusted if renal function improved (creatinine clearance >50 mL/min). Ceftriaxone doses do not require adjustment for patients with creatinine clearance greater than 30 mL/min. If a patient in either treatment group had creatinine clearance of 30 mL/min or less, investigators were asked to contact the funder’s study physician for direction. Patients received their allocated treatment for 5–7 days (exact treatment time at the investigators’ discretion), and were followed up for 21–35 days after the end of treatment. Planned assessments were done at appropriate timepoints throughout the study. These included assessment of clinical signs and symptoms of community-acquired pneumonia and physical and laboratory examinations (at baseline, treatment days 1–4, end of treatment [same day as the last day of treatment or the subsequent morning if the last dose of study treatment was given at night], test-of-cure visit [8–15 days after last dose of study drug]), and late follow-up visit [21–35 days after the last dose of study drug); vital signs (every scheduled visit apart from the late follow-up visit); chest radiograph or CT-scan (at baseline and test-of-cure visit); and monitoring of adverse events and serious adverse events (up to the late follow-up visit). The safety population included all randomly assigned patients who received at least one dose of study drug. The modified intention-to-treat population included all patients who received any study drug and who had PORT risk class III or IV community-acquired pneumonia. The microbiological modified intention-to-treat population included patients in the modified intention-to-treat population who had at least one bacterial pathogen identified at baseline (excluding Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila). The clinically evaluable population consisted of all patients in the modified intention-to-treat population who met predefined evaluability criteria, including meeting the minimum disease criteria for community-acquired pneumonia and having sufficient information to determine clinical outcome. Reasons for exclusion from the clinically evaluable population included serological evidence at baseline of acute infection with an atypical pathogen (eg, M pneumoniae or C pneumoniae) or an indeterminate immunoglobulin M (IgM) serology for mycoplasma unless a bacterial pathogen other than the atypical one was also isolated from the baseline culture of respiratory secretions; evidence of L pneumophila infection; isolation from baseline sputum cultures of a pathogen regarded as inherently resistant to either or both study treatments as the sole causative pathogen (eg, Acinetobacter spp, Burkholderia spp, ESBL-positive Escherichia coli or K pneumoniae, MRSA, or Pseudomonas spp). The microbiologically evaluable population consisted
of all patients who met all criteria for both the microbiological modified intention-to-treat population and the clinically evaluable population. Clinical cure was defined as total resolution of all signs and symptoms of community-acquired pneumonia or improvement to such an extent that further antimicrobial treatment was unnecessary (ie, absence of fever for at least 24 h continuously and substantial improvement in other signs and symptoms). Clinical failure was defined as persistence, incomplete clinical resolution, or worsening in signs and symptoms of communityacquired pneumonia that required alternative antimicrobial treatment; a treatment-limiting adverse event that led to discontinuation of the study drug, with patient requiring alternative antimicrobial treatment for community-acquired pneumonia; or death by any cause within 28 days of the end of treatment. Clinical failure at the end of treatment was carried forward to test of cure for efficacy analyses. Indeterminate clinical outcomes were recorded in the modified intention-to-treat population if incomplete study data were available for the assessment of efficacy (including treatment change before completion of at least 48 h of study treatment) or if patients were lost to follow-up. Adverse events and serious adverse events were classified by system organ class and preferred term by use of the Medical Dictionary for Regulatory Activities version 16.0. Specimens of sputum, pleural fluid, and blood were obtained for microbiological analysis at baseline and, if medically indicated, throughout the study treatment and follow-up periods. Local laboratories and a central laboratory (Covance Central Laboratory Services, Indianapolis, IN, USA) were used for the microbiological assessments. Pathogens isolated by a local laboratory were sent to the central laboratory for confirmation of genus and species and susceptibility testing by CLSI (Clinical and Laboratory Standards Institute) broth microdilution. All sera samples were processed through the central laboratory for diagnosis of atypical pathogen infections. Urine samples were obtained at baseline for S pneumoniae and L pneumophila antigen testing, and blood samples were obtained at baseline and late followup for serological testing. Identification of acute infection by atypical pathogens was done by serological methods, and by urinary antigen test for L pneumophila. Patients were regarded as infected with M pneumoniae if a fourtimes or greater increase in M pneumoniae immunoglobulin G (IgG) titre was detected between a negative acute (baseline) serology test (IgG titre
Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial Nan Shan Zhong*, Tieying Sun*, Chao Zhuo*, George D’Souza, Sang Haak Lee, Nguyen Huu Lan, Chi-Huei Chiang, David Wilson, Fang Sun, Joseph Iaconis, David Melnick
Summary Background Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia. Methods In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III–IV acute communityacquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5–7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8–15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of –10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838. Findings Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8–17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data. Interpretation Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III–IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population. Funding AstraZeneca.
Introduction The morbidity and mortality associated with communityacquired pneumonia of sufficient severity to require hospital admission remain high despite existing management strategies.1,2 Clinical treatment guidelines in the USA,3 Europe,4 and Asian countries5–8 recommend intravenous broad-spectrum cephalosporins such as ceftriaxone, often in combination with a macrolide antibiotic, as a treatment option for such patients. Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in-vitro activity against pathogens that often cause community-acquired pneumonia, including Gram-positive species such as Staphylococcus aureus and Streptococcus pneumoniae, and
non-extended-spectrum β-lactamase (non-ESBL) phenotype Gram-negative species including Klebsiella pneumoniae and Haemophilus influenzae. Compared with other β-lactams, ceftaroline has enhanced in-vitro activity against meticillin-resistant S aureus (MRSA) and penicillin-nonsusceptible S pneumoniae, although ceftaroline fosamil is not currently approved for the treatment of communityacquired pneumonia caused by these pathogens. Ceftaroline fosamil is licensed in Europe for the treatment of adult patients admitted to hospital with communityacquired pneumonia or complicated skin and soft-tissue infection at a dose of 600 mg every 12 h, adjusted for renal function, and for similar indications in several other countries, including the USA.9,10
www.thelancet.com/infection Published online December 22, 2014 http://dx.doi.org/10.1016/S1473-3099(14)71018-7
Lancet Infect Dis 2014 Published Online December 22, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71018-7 See Online/Comment http://dx.doi.org/10.1016/ S1473-3099(14)71063-1 *Contributed equally State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China (Prof N S Zhong MD, Prof C Zhuo MD); Beijing Hospital, Beijing, China (Prof T Sun MD); St John’s Medical College Hospital, Bangalore, India (G D’Souza MD); St Paul’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea (Prof S H Lee MD); Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam (N H Lan MD); Taipei Veterans General Hospital, Taipei, Taiwan (Prof C-H Chiang MD); AstraZeneca, Macclesfield, UK (D Wilson BSc); AstraZeneca China, Shanghai, China (F Sun MD); AstraZeneca, Waltham, MA, USA (J Iaconis PhD); and AstraZeneca Pharmaceuticals, Wilmington, DE, USA (D Melnick MD) Correspondence to: Prof Nan Shan Zhong, State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 501120, China [email protected]
1
Articles
For the study protocol see http://filehosting.pharmacm. com/DownloadService. ashx?client=CTR_MED_7111 &studyid=1374&filename=D372 0C00002_Revised_CSP_1_ (redacted).pdf
Approvals of ceftaroline fosamil for communityacquired pneumonia were based on the results of two multinational, phase 3 clinical trials in predominantly European and North American patients with Pneumonia Outcomes Research Team (PORT) risk class III or IV community-acquired pneumonia (FOCUS 1 and FOCUS 2).11,12 In the individual trials, ceftaroline fosamil was non-inferior to ceftriaxone at the test-of-cure visit (about 1–2 weeks after completion of treatment), with numerically more clinical cures among ceftaroline fosamil-treated patients. In the pooled analysis,13 the lower bound of the 95% CI for the difference was greater than 0%. However, patients of an Asian ethnic origin comprised only about 3% of those enrolled in these two studies;11,12 other clinical trial data in Asian patients have so far been limited to phase 1 pharmacokinetic studies. Thus the efficacy of this drug in the management of communityacquired pneumonia in Asian patients has not previously been assessed. This issue is of particular importance in the context of recent data suggesting differences in the bacterial causes of community-acquired pneumonia between Asian and European or North American populations, including a comparatively greater prominence of Gram-negative bacteria (specifically H influenzae and K pneumoniae) in Asian patients.14,15 S pneumoniae, a leading cause of community-acquired pneumonia, has a different resistance profile, particularly to macrolide antibiotics, in Asia from in Europe and North America.16,17 We aimed to assess the efficacy and safety of ceftaroline fosamil (600 mg every 12 h) compared with ceftriaxone (2 g every 24 h) for the treatment of Asian patients admitted to hospital with community-acquired pneumonia.
Methods Study design and participants In this prospective, multicentre, double-blind, activecomparator, randomised phase 3, non-inferiority with nested superiority trial patients with community-acquired pneumonia from 64 centres in China (23), India (13), South Korea (16), Taiwan (seven), and Vietnam (five) were randomly assigned to receive ceftaroline fosamil or ceftriaxone. Eligible patients were adults with radiographically confirmed pneumonia, defined as new or progressive pulmonary infiltrates on chest radiograph or CT scan consistent with bacterial pneumonia, acute illness (duration ≤7 days) with at least three clinical signs or symptoms of pneumonia, and PORT risk class III or IV disease (ie, PORT score >70 and ≤130)18 that required hospital admission and intravenous antibiotic treatment. Key exclusion criteria included PORT scores of 70 or less (risk class I and II) or greater than 130 (risk class V); requirement for admission to intensive care; pneumonia from a suspected source other than community-acquired bacterial pathogens (eg, ventilator-associated pneumonia, hospital-acquired pneumonia, visible or gross aspiration 2
pneumonia, or suspected viral, fungal, or mycobacterial infection of the lung); non-infectious causes of pulmonary infiltrates; treatment with other systemic antimicrobial drug for community-acquired pneumonia in the 96 h before randomisation (apart from a single dose of an oral or intravenous short-acting antibiotic for communityacquired pneumonia; or unequivocal clinical evidence of treatment failure after 48 h or more of previous systemic antimicrobial treatment with isolation of an organism resistant to the previous treatment); microbiologically documented infection with a pathogen regarded as nonsusceptible to ceftaroline and ceftriaxone (eg, Pseudomonas aeruginosa) or non-susceptible to ceftriaxone (eg, MRSA). A full list of inclusion and exclusion criteria is included in the study protocol, which is available online. The protocol was approved by independent ethics committees or institutional review boards at all study sites, and the study was done in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent.
Randomisation and masking After screening and enrolment, we used a centralised telephone and web-based system to assign a unique randomisation code for each enrolled patient, ensuring concealment of the randomisation sequence. Patients were assigned to receive either intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5–7 days. Randomisation was stratified by geographical area (China, India, South Korea, Taiwan, and Vietnam), with block sizes of four, to ensure roughly 1:1 assignment to each treatment group. Additionally, we used the randomisation system to enable the clinical team to monitor disease severity to ensure that at least 25% of randomly assigned patients were PORT risk class IV. Patients and the investigators and study staff who did patient enrolment and administered study treatment were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. Pharmacists and study site staff who were not masked to treatment allocation obtained each patient’s unique randomisation code and ensured that administration of study drugs occurred within 24 h of baseline assessments.
Procedures To maintain masking of treatment allocation from the patients and the treating clinicians, patients assigned to ceftriaxone received a 30 min infusion containing 2 g ceftriaxone followed by a matching placebo infusion, and a further two placebo infusions 12 h later. Each dose of ceftaroline fosamil was split into two consecutive 30 min (300 mg) infusions, with doses given every 12 h. For patients with moderate renal impairment (creatinine clearance less than 50 mL/min but greater than 30 mL/min, as estimated by the Cockcroft-Gault formula), ceftaroline
www.thelancet.com/infection Published online December 22, 2014 http://dx.doi.org/10.1016/S1473-3099(14)71018-7
Articles
fosamil dosing could be adjusted at any time by pharmacists or study staff not masked to treatment allocation to two consecutive 30 min infusions of ceftaroline fosamil 200 mg (for a total of 400 mg) every 12 h and readjusted if renal function improved (creatinine clearance >50 mL/min). Ceftriaxone doses do not require adjustment for patients with creatinine clearance greater than 30 mL/min. If a patient in either treatment group had creatinine clearance of 30 mL/min or less, investigators were asked to contact the funder’s study physician for direction. Patients received their allocated treatment for 5–7 days (exact treatment time at the investigators’ discretion), and were followed up for 21–35 days after the end of treatment. Planned assessments were done at appropriate timepoints throughout the study. These included assessment of clinical signs and symptoms of community-acquired pneumonia and physical and laboratory examinations (at baseline, treatment days 1–4, end of treatment [same day as the last day of treatment or the subsequent morning if the last dose of study treatment was given at night], test-of-cure visit [8–15 days after last dose of study drug]), and late follow-up visit [21–35 days after the last dose of study drug); vital signs (every scheduled visit apart from the late follow-up visit); chest radiograph or CT-scan (at baseline and test-of-cure visit); and monitoring of adverse events and serious adverse events (up to the late follow-up visit). The safety population included all randomly assigned patients who received at least one dose of study drug. The modified intention-to-treat population included all patients who received any study drug and who had PORT risk class III or IV community-acquired pneumonia. The microbiological modified intention-to-treat population included patients in the modified intention-to-treat population who had at least one bacterial pathogen identified at baseline (excluding Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila). The clinically evaluable population consisted of all patients in the modified intention-to-treat population who met predefined evaluability criteria, including meeting the minimum disease criteria for community-acquired pneumonia and having sufficient information to determine clinical outcome. Reasons for exclusion from the clinically evaluable population included serological evidence at baseline of acute infection with an atypical pathogen (eg, M pneumoniae or C pneumoniae) or an indeterminate immunoglobulin M (IgM) serology for mycoplasma unless a bacterial pathogen other than the atypical one was also isolated from the baseline culture of respiratory secretions; evidence of L pneumophila infection; isolation from baseline sputum cultures of a pathogen regarded as inherently resistant to either or both study treatments as the sole causative pathogen (eg, Acinetobacter spp, Burkholderia spp, ESBL-positive Escherichia coli or K pneumoniae, MRSA, or Pseudomonas spp). The microbiologically evaluable population consisted
of all patients who met all criteria for both the microbiological modified intention-to-treat population and the clinically evaluable population. Clinical cure was defined as total resolution of all signs and symptoms of community-acquired pneumonia or improvement to such an extent that further antimicrobial treatment was unnecessary (ie, absence of fever for at least 24 h continuously and substantial improvement in other signs and symptoms). Clinical failure was defined as persistence, incomplete clinical resolution, or worsening in signs and symptoms of communityacquired pneumonia that required alternative antimicrobial treatment; a treatment-limiting adverse event that led to discontinuation of the study drug, with patient requiring alternative antimicrobial treatment for community-acquired pneumonia; or death by any cause within 28 days of the end of treatment. Clinical failure at the end of treatment was carried forward to test of cure for efficacy analyses. Indeterminate clinical outcomes were recorded in the modified intention-to-treat population if incomplete study data were available for the assessment of efficacy (including treatment change before completion of at least 48 h of study treatment) or if patients were lost to follow-up. Adverse events and serious adverse events were classified by system organ class and preferred term by use of the Medical Dictionary for Regulatory Activities version 16.0. Specimens of sputum, pleural fluid, and blood were obtained for microbiological analysis at baseline and, if medically indicated, throughout the study treatment and follow-up periods. Local laboratories and a central laboratory (Covance Central Laboratory Services, Indianapolis, IN, USA) were used for the microbiological assessments. Pathogens isolated by a local laboratory were sent to the central laboratory for confirmation of genus and species and susceptibility testing by CLSI (Clinical and Laboratory Standards Institute) broth microdilution. All sera samples were processed through the central laboratory for diagnosis of atypical pathogen infections. Urine samples were obtained at baseline for S pneumoniae and L pneumophila antigen testing, and blood samples were obtained at baseline and late followup for serological testing. Identification of acute infection by atypical pathogens was done by serological methods, and by urinary antigen test for L pneumophila. Patients were regarded as infected with M pneumoniae if a fourtimes or greater increase in M pneumoniae immunoglobulin G (IgG) titre was detected between a negative acute (baseline) serology test (IgG titre
