E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated Skin and Skin Structure Infections (cSSSI) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052891 |
E.1.2 | Term | Skin bacterial infection |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine the non-inferiority in clinical cure rate of ceftaroline treatment compared with that of vancomycin plus aztreonam treatment at the Test of Cure (TOC) visit in Clinically Evaluable (CE) and Clinically Modified Intent-to-Treat (cMITT) populations of adult subjects with cSSSI. |
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E.2.2 | Secondary objectives of the trial |
· Determine the non-inferiority in microbiologic success (eradication or presumed eradication) rate of ceftaroline treatment compared with that of vancomycin plus aztreonam treatment at the TOC visit · Evaluate the clinical response at the End-of-Therapy (EOT) visit · Evaluate the clinical and microbiological response by pathogen at the TOC visit · Evaluate clinical relapse at the Late Follow-up visit (LFU) visit · Evaluate the microbiological re-infection or recurrence at the LFU visit · Evaluate safety |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age greater than or equal to 18 years 2. Skin and skin structure infection (SSSI) that meets EITHER of the following criteria:Involves deeper soft tissue or requires significant surgical intervention, such as a wound infection (surgical or traumatic), a major abscess, an infected ulcer, or deep and extensive cellulitisORCellulitis or abscess on lower extremity which occurs in subjects with diabetes mellitus or well-documented peripheral vascular disease (PVD) 3. Three or more of the following clinical signs: · Purulent or seropurulent drainage or discharge · Erythema · Fluctuance · Heat or localized warmth · Pain or tenderness to palpation · Fever greater than 38ºC oral (> 38.5ºC rectally or tympanically) or hypothermia (< 35ºC) · White Blood Cell (WBC) count greater than 10,000/mm3 · Greater than 10% immature neutrophils (bands) irrespective of WBC count 4. The subject must require initial hospitalization, or treatment in an emergency room or urgent care setting, by the standard of care. Exception: subjects suitable for outpatient antimicrobial therapy (OPAT) may be enrolled with approval of the Medical Monitor 5. The subject’s infection is expected to require at least 5 days of IV antibiotic therapy. 6. Female subjects of child-bearing potential who are less than 2 years post-menopausal must agree to and comply with using highly effective methods of birth control ( e.g., condom +/- spermicide, combined oral contraceptive, implant, injectable, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in this study. 7. Written informed consent, willingness, and ability to comply with all study procedures. |
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E.4 | Principal exclusion criteria |
1. History of any hypersensitivity or allergic reaction to any ß-lactam antibiotic 2. History of any hypersensitivity or allergic reaction to vancomycin or aztreonam 3. Past or current history of epilepsy or seizure disorder, excluding well-documented febrile seizure of childhood 4. More than 24 hours of treatment with a non-study antimicrobial (other than topical antibiotics) for the treatment of current cSSSI within 96 hours prior to randomization. EXCEPTION: Subjects may be eligible if they meet BOTH of the following conditions: · Clinical evidence of failure following at least 48 hours of prior systemic antibiotic therapy AND · Microbiological evidence of failure 5. Failure of vancomycin or aztreonam as therapy for cSSSI, or prior isolation of an organism with in vitro resistance to vancomycin or aztreonam 6. Uncomplicated SSSI such as simple abscess, impetiginous lesions, superficial cellulitis, furunculosis, carbunculosis, or folliculitis. Skin and skin structure infections with a high cure rate after surgical incision alone or after aggressive local skin care (e.g., surgical site infection with a margin of less than 5 cm of surrounding cellulitis). 7. Skin and skin structure infection with ANY of the following characteristics:· -Known or suspected anaerobic pathogens (e.g., perirectal abscess)· -Known or suspected fungal, parasitic, or viral pathogens· -Known or suspected Pseudomonas aeruginosa as a contributing pathogen· -Involving a decubitus ulcer· -Involving a diabetic foot ulcer or an ulcer associated with PVD that has the following characteristics: o Accompanied with osteomyelitis o Likely to require amputation within 60 days o Likely to require revascularization within 60 days -Requiring significant surgical intervention that cannot be performed within 48 hours after initiating study drug therapy. -Cases of cellulitis with a surface area less than 10 cm2 or a history consistent with clinical improvement or stabilization. -Involving a third-degree burn or a burn covering more than 5% of total body surface area· Involving an underlying inflammatory skin disease that may obscure determination of response -Involving human or animal bites (infections associated with arthropod bites may be allowed) -Involving a rapidly necrotizing process, such as necrotizing fasciitis· -Involving gangrene of any etiology -Complicated by the presence of prosthetic materials that will not be removed, such as central venous catheters, permanent cardiac pacemaker battery packs, or joint replacement prostheses -Likely to require amputation 8. Known or suspected endocarditis, osteomyelitis, or septic arthritis 9. Requirement for concomitant antibacterial or systemic antifungal therapy for any reason EXCEPTIONS: topical antiseptics (e.g., povidone-iodine [Betadine™], chlorhexidine [Hibiclens™], and alcohol and soaps for wound care), topical antifungal therapy, or a single oral dose of any antifungal for treatment of vaginal candidiasis are allowed. 10. Probenecid administration within 3 days prior to initiation of study drug or requirement for concomitant probenecid administration 11. Infections or conditions requiring concomitant systemic corticosteroid therapy at a dose equivalent to or greater than prednisone 40 mg per day 12. Severely impaired renal function (CrCl < 30 mL/min) estimated by the Cockroft-Gault formula 13. Evidence of significant hepatic, hematologic, or immunologic disease determined by the following: · Aspartate aminotransferase (AST, GOT) or ALT (GPT) level greater than 10-fold the upper limit of normal or total bilirubin greater than 3-fold the upper limit of normal · Manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy · Current or anticipated neutropenia (< 500 neutrophils/mm3)· Thrombocytopenia with platelet count less than 60,000 cells/mm3· Known infection with human immunodeficiency virus and either a CD4 count less than or equal to 200 cells/ mm3 or another Acquired Immune Deficiency Syndrome-defining illness · Bone marrow-ablative chemotherapy or radiation therapy within the prior 3 months 14. Evidence of immediate life-threatening disease 15. Life expectancy less than 3 months 16. Women who are pregnant or nursing 17. Participation in any study involving administration of an investigational agent within 30 days prior to randomization into this study 18. Previous participation in a study of ceftaroline 19. Unable or unwilling to adhere to the study-specified procedures and restrictions 20. Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome measure is the per subject clinical cure at the Test-of-Cure (TOC) visit in the Clinically Evaluable (CE) and Clinical Modified Intent-to-Treat (cMITT) populations.
Secondary efficacy endpoints are: Per-subject clinical cure rate at the EOT visit in the CE population Per-subject clinical cure rate at the EOT visit in the cMITT population Per-subject microbiological response at the TOC visit in the microbiological Modified intent-to-Treatment (mMITT) population Per-subject microbiological response at the TOC visit in the Microbiologically Evaluable (ME) population Per-subject relapse at the LFU visit in those subjects who were clinically cured at the TOC visit Per-subject re-infection or recurrence at the LFU visit in those subjects who had a favourable microbiological outcome (eradication or presumed eradication) at the TOC visit.
Safety Endpoints are: Adverse Events Serious Adverse Events Physical Examinations Vital Signs ECG’s Urinalysis Hematology Serum Chemistries Concomitant Medications Concomitant Antimicrobials |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |