Evaluation of Ceftaroline Fosamil Versus Vancomycin Plus Aztreonam in the Treatment of Patients With Skin Infections

A Phase III, Multicentre, Randomised, Double-Blind Comparative Study to Evaluate the Efficacy and Safety of Ceftaroline Fosamil (600 mg Every 8 Hours) Versus Vancomycin Plus Aztreonam in the Treatment of Patients With Complicated Bacterial Skin and Soft Tissue Infections With Evidence of Systemic Inflammatory Response or Underlying Comorbidities

The purpose of this study is to evaluate the effects of Ceftaroline Fosamil versus Vancomycin plus Aztreonam in treatment of patients with complicated bacterial skin and soft tissue infections.

Study Overview

• Status: Completed
• Conditions: Complicated Skin and Soft Tissue Infection
• Intervention / Treatment: Drug: Ceftaroline fosamil; Drug: Vancomycin; Drug: Aztreonam

Detailed Description

A Phase III, Multicentre, Randomised, Double-Blind Comparative Study to Evaluate the Efficacy and Safety of Ceftaroline Fosamil (600 mg every 8 hours) Versus Vancomycin Plus Aztreonam in the Treatment of Patients with Complicated Bacterial Skin and Soft Tissue Infections With Evidence of Systemic Inflammatory Response or Underlying Comorbidities

• Study Type: Interventional
• Enrollment (Actual): 802
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Córdoba, Argentina
    • Research Site
  • Santa Fe, Argentina
    • Research Site
• Australia
  • Parkville, Australia
    • Research Site
• Belgium
  • Bruxelles, Belgium
    • Research Site
• Brazil
  • Belo Horizonte, Brazil
    • Research Site
  • Passo Fundo, Brazil
    • Research Site
  • Salvador, Brazil
    • Research Site
  • São José do Rio Preto, Brazil
    • Research Site
• Bulgaria
  • Pleven, Bulgaria
    • Research Site
  • Ruse, Bulgaria
    • Research Site
  • Sofia, Bulgaria
    • Research Site
• Chile
  • Temuco, Chile
    • Research Site
  • Viña del Mar, Chile
    • Research Site
• China
  • Beijing, China
    • Research Site
  • Changchun, China
    • Research Site
  • Changsha, China
    • Research Site
  • Chengdu, China
    • Research Site
  • Chongqing, China
    • Research Site
  • Fuzhou, China
    • Research Site
  • Guangzhou, China
    • Research Site
  • Haikou, China
    • Research Site
  • Nanning, China
    • Research Site
  • Qingdao, China
    • Research Site
  • Shanghai, China
    • Research Site
  • Shenyang, China
    • Research Site
  • Shijiazhuang, China
    • Research Site
  • Wuhan, China
    • Research Site
  • Xi'an, China
    • Research Site
• Croatia
  • Slavonski Brod, Croatia
    • Research Site
  • Zagreb, Croatia
    • Research Site
• Czechia
  • Jihlava, Czechia
    • Research Site
  • Pardubice, Czechia
    • Research Site
• France
  • Orleans, France
    • Research Site
• Germany
  • Dessau, Germany
    • Research Site
  • Hanau, Germany
    • Research Site
  • Heilbronn, Germany
    • Research Site
• Greece
  • Athens, Greece
    • Research Site
• Hong Kong
  • Kowloon, Hong Kong
    • Research Site
  • Pokfulam, Hong Kong
    • Research Site
• Israel
  • Haifa, Israel
    • Research Site
  • Ramat-Gan, Israel
    • Research Site
  • Safed, Israel
    • Research Site
  • Tel Aviv, Israel
    • Research Site
• Italy
  • Milano, Italy
    • Research Site
• Korea, Republic of
  • Ansan, Korea, Republic of
    • Research Site
  • Deagu, Korea, Republic of
    • Research Site
  • Incheon, Korea, Republic of
    • Research Site
  • Seoul, Korea, Republic of
    • Research Site
  • Won-ju, Korea, Republic of
    • Research Site
• Mexico
  • Guadalajara, Mexico
    • Research Site
• Peru
  • Cusco, Peru
    • Research Site
  • Lima, Peru
    • Research Site
• Philippines
  • Manila, Philippines
    • Research Site
  • Quezon City, Philippines
    • Research Site
• Poland
  • Lublin, Poland
    • Research Site
  • Łódź, Poland
    • Research Site
• Romania
  • Bucharest, Romania
    • Research Site
• Russian Federation
  • Moscow, Russian Federation
    • Research Site
  • Perm, Russian Federation
    • Research Site
  • Saint Petersburg, Russian Federation
    • Research Site
  • Smolensk, Russian Federation
    • Research Site
  • Vsevolozhsk, Russian Federation
    • Research Site
  • Yaroslavl, Russian Federation
    • Research Site
• South Africa
  • Benoni, South Africa
    • Research Site
  • Cape Town, South Africa
    • Research Site
  • Johannesburg, South Africa
    • Research Site
  • Worcester, South Africa
    • Research Site
• Spain
  • Barcelona, Spain
    • Research Site
  • Granada, Spain
    • Research Site
  • Madrid, Spain
    • Research Site
  • Terrassa, Spain
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan
    • Research Site
  • Taipei, Taiwan
    • Research Site
  • Yung Kang City, Taiwan
    • Research Site
• Turkey
  • Ankara, Turkey
    • Research Site
  • Diyarbakir, Turkey
    • Research Site
  • Izmir, Turkey
    • Research Site
• Ukraine
  • Cherkasy, Ukraine
    • Research Site
  • Ivano-Frankivsk, Ukraine
    • Research Site
  • Kharkov, Ukraine
    • Research Site
  • Odesa, Ukraine
    • Research Site
• United States
  • California
    • Chula Vista, California, United States
      • Research Site
  • Florida
    • Orlando, Florida, United States
      • Research Site
    • West Palm Beach, Florida, United States
      • Research Site
  • Indiana
    • Carmel, Indiana, United States
      • Research Site
  • Kentucky
    • Hazard, Kentucky, United States
      • Research Site
  • Massachusetts
    • Springfield, Massachusetts, United States
      • Research Site
  • Michigan
    • Detroit, Michigan, United States
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States
      • Research Site
  • New York
    • Garden City, New York, United States
      • Research Site
  • Texas
    • Bellaire, Texas, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, aged 18 years or older
• Complicated skin and skin structure infection (cSSTI)
• Infection of sufficient severity to warrant hospitalization
• Infection of sufficient severity such that it is expected to require at least 5 days of intravenous antibiotic therapy

Exclusion Criteria:

• Received systemic antibacterial drugs for greater than 24 hours within 96 hours prior to first dose of study drug
• Uncomplicated skin and skin structure infections, skin infections suspected to be caused by viral or fungal pathogens
• Diabetic foot infections, decubitus ulcers, ulcers due to peripheral vascular disease
• Infection caused by human or animal bites, sternal wound infections, bone infection or arthritis due to an infection, critical limb ischemia of the affected limb
• Chronic liver disease or severe impaired renal function, severe low white blood cell count, burns on greater than 15% of total body surface area, necrotizing skin infection, amputation required of primary site of infection, sustained shock

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftaroline fosamil; Patients will receive 600 mg of ceftaroline fosamil administered as a 120-minute intravenous infusion very 8 hours. Each dose will be infused in a volume of 250 mL over 120-minutes followed by aztreonam placebo in a volume of 100 mL infused over 30 minutes every 8 hours. In addition vancomycin placebo will be given in a volume of 250 mL infused over 120 minutes every 12 hours. Doses will be adjusted according to the patient's renal function.	Drug: Ceftaroline fosamil; IV ceftaroline 600mg every 8 hours
Active Comparator: Vancomycin plus aztreonam; Patients will receive combination of vancomycin plus aztreonam. Dose of vancomycin will be based on the patient's actual weight and will receive intravenous vancomycin every 12 hours with each dose infused over 120-minutes. Aztreonam dose will be 1 gram intravenously in a volume of 100 mL infused over 30 minutes every 8 hours. In addition, ceftaroline fosamil placebo will be given in a volume of 250 mL infused over 120 minutes every 8 hours. Doses adjusted according to patients renal function	Drug: Vancomycin; IV vancomycin 15mg/kg every 12 hours; Drug: Aztreonam; IV aztreonam 1 g every 8 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response at Test of Cure (TOC) in Modified Intent-to-treat (MITT) Analysis Set	The observed difference in the clinical cure rates at TOC (ceftaroline group minus vancomycin plus aztreonam group) in MITT. Clinical cure rate is measured by comparing the participant's signs and symptoms at TOC visit to those recorded at study baseline.	7 to 20 days after the last dose of study drug
Clinical Response at TOC in Clinically Evaluable (CE) Analysis Set	The observed difference in the clinical cure rates at TOC (ceftaroline group minus vancomycin plus aztreonam group) in CE. Clinical cure rate is measured by comparing the participant's signs and symptoms at TOC visit to those recorded at study baseline.	7 to 20 days after the last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Per Patient Microbiological Response at TOC in Microbiologically Modified-intent-to-treat (mMITT) Analysis Set	Difference in microbiological favorable response rate at TOC in mMITT analysis set. Favorable microbiological response rate is measured by comparing TOC microbiological data to baseline microbiological data. In the absence of TOC microbiological data it is presumed from the clinical response.	7 to 20 days after the last dose of study drug
Per-patient Micro Response at TOC in Microbiologically Evaluable (ME) Analysis Set	Difference in microbiological favorable response rate at TOC in ME. Favourable microbiological response rate is measured by comparing TOC microbiological data to baseline microbiological data. In the absence of TOC microbiological data it is presumed from the clinical response.	7 to 20 days after the last dose of study drug
Clinical Response at End of Treatment (EOT) in MITT Analysis Set	The observed difference in the clinical cure rates at EOT (ceftaroline group minus vancomycin plus aztreonam group) in MITT. Clinical cure rate is measured by comparing the participant's signs and symptoms at EOT visit to those recorded at study baseline.	On day of last dose of study drug (or + 1 day)
Clinical Response at EOT in CE Analysis Set	The observed difference in the clinical cure rates at EOT (ceftaroline group minus vancomycin plus aztreonam group) in CE. Clinical cure rate is measured by comparing the participant's signs and symptoms at EOT visit to those recorded at study baseline.	On day of last dose of study drug (or +1 day)
Clinical Relapse at Late Follow-up (LFU) in CE Patients Who Were Cured at TOC	The observed difference in the clinical relapse rates at LFU (ceftaroline group minus vancomycin plus aztreonam group) in CE. Clinical relapse rate at LFU is measured by comparing a patient's signs and symptoms at late follow-up to those when they were cured at TOC.	21 to 42 days after the last dose of study drug
Early Response at 48 to 72 Hours of Treatment in MITT Analysis Set	The observed difference in the early success rates at 48 to 72 hours of treatment (ceftaroline group minus vancomycin plus aztreonam group) in MITT. Early response rate as measured by comparing the participant's signs and symptoms at the 48-72 hour visit to those recorded at study baseline.	48 to 72 hours after first dose of study drug
Per-pathogen Microbiological Response at TOC by Baseline Pathogen From Site of Skin Infection in ME	Per-pathogen microbiological response at TOC by baseline pathogen from site of skin infection in ME analysis set	7 to 20 days after the last dose of study drug

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Forest Laboratories
• Investigators: Study Director: David Melnick, MSD, AstraZeneca

Publications and helpful links

General Publications

• Dryden M, Kantecki M, Yan JL, Stone GG, Leister-Tebbe H, Wilcox M. Treatment outcomes of secondary bacteraemia in patients treated with ceftaroline fosamil: pooled results from six phase III clinical trials. J Glob Antimicrob Resist. 2022 Mar;28:108-114. doi: 10.1016/j.jgar.2021.10.027. Epub 2021 Dec 16.
• Cheng K, Pypstra R, Yan JL, Hammond J. Summary of the safety and tolerability of two treatment regimens of ceftaroline fosamil: 600 mg every 8 h versus 600 mg every 12 h. J Antimicrob Chemother. 2019 Apr 1;74(4):1086-1091. doi: 10.1093/jac/dky519.
• Wilcox M, Yan JL, Gonzalez PL, Dryden M, Stone GG, Kantecki M. Impact of Underlying Comorbidities on Outcomes of Patients Treated with Ceftaroline Fosamil for Complicated Skin and Soft Tissue Infections: Pooled Results from Three Phase III Randomized Clinical Trials. Infect Dis Ther. 2022 Feb;11(1):217-230. doi: 10.1007/s40121-021-00557-w. Epub 2021 Nov 6.
• Corey GR, Wilcox MH, Gonzalez J, Jandourek A, Wilson DJ, Friedland HD, Das S, Iaconis J, Dryden M. Ceftaroline fosamil therapy in patients with acute bacterial skin and skin-structure infections with systemic inflammatory signs: A retrospective dose comparison across three pivotal trials. Int J Antimicrob Agents. 2019 Jun;53(6):830-837. doi: 10.1016/j.ijantimicag.2019.01.016. Epub 2019 Feb 1.
• Das S, Li J, Iaconis J, Zhou D, Stone GG, Yan JL, Melnick D. Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections. J Antimicrob Chemother. 2019 Feb 1;74(2):425-431. doi: 10.1093/jac/dky439.
• Dryden M, Zhang Y, Wilson D, Iaconis JP, Gonzalez J. A Phase III, randomized, controlled, non-inferiority trial of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in patients with complicated skin and soft tissue infection with systemic inflammatory response or underlying comorbidities. J Antimicrob Chemother. 2016 Dec;71(12):3575-3584. doi: 10.1093/jac/dkw333. Epub 2016 Sep 1.
• Sanchez-Garcia M, Hammond J, Yan JL, Kantecki M, Ansari W, Dryden M. Baseline Characteristics and Outcomes Among Patients with Complicated Skin and Soft Tissue Infections Admitted to the Intensive Care Unit: Analysis of the Phase 3 COVERS Randomized Trial of Ceftaroline Fosamil Versus Vancomycin Plus Aztreonam. Infect Dis Ther. 2020 Sep;9(3):609-623. doi: 10.1007/s40121-020-00297-3. Epub 2020 Jun 30.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: December 16, 2011
• First Submitted That Met QC Criteria: December 22, 2011
• First Posted (Estimate): December 26, 2011

Study Record Updates

• Last Update Posted (Actual): September 6, 2017
• Last Update Submitted That Met QC Criteria: September 1, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: wound infection; bacterial infection; vancomycin; skin infection; ceftaroline; cellulitis; complicated skin and soft tissue infections (cSSTI); burn infection
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Soft Tissue Infections; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin; Ceftaroline fosamil; Aztreonam
• Other Study ID Numbers: D3720C00001; 2011-004013-16