| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Skin and Skin Structure Infections (cSSSI) |
|
| 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 |
|
| 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 Modified Intent-to-Treat (MITT) populations of adult subjects with cSSSI. |
|
| E.2.2 | Secondary objectives of the trial |
. Evaluate the microbiological success rate at 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 |
|
| 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 cellulitis
o “Deeper soft tissue” is defined as subdermal tissue, including subcutaneous fat; for example, extension of infection to muscle or fascia constitutes evidence of deeper soft tissue involvement.
o “Significant surgical intervention” is defined as a major operative procedure, not including commonly performed minor procedures such as incision and drainage of minor abscesses performed at the bedside, suture removal, needle aspiration, superficial debridement of devitalized tissue, or routine wound care.
o “Wound infection” is defined by the presence of either purulent /seropurulent discharge from the surgical/traumatic wound or greater than or equal to 5 cm of erythema (i.e. cellulitis) surrounding the wound margin.1 Onset must have occurred within 7 days prior to randomization and no later than 30 days following the trauma or surgical procedure.
o“Abscess” is defined by the presence of a loculated fluid collection with greater than or equal to 2 cm of erythema (i.e. cellulitis) extending from the abscess margin and onset within 7 days prior to randomization. A “major abscess” either extends to deeper soft tissue or requires significant surgical intervention.
o “Cellulitis” is defined by the presence of advancing erythema, edema and heat1 with onset within 7 days prior to randomization. “Deep and extensive cellulitis” involves deeper soft tissue and has a surface area of greater than or equal to 10 cm2.
OR
• Cellulitis or abscess on lower extremity which occurs in subjects with diabetes mellitus or well-documented peripheral vascular disease (PVD)
NOTE: Subjects with a history of diabetes mellitus must be taking insulin, insulin analogues, or oral hypoglycemic agents to be eligible for the study. “Well-documented PVD” is defined as arterial or venous vascular disease resulting in ischemia of the lower extremity as manifest by ulceration, poor wound healing, or the absence of readily palpable dorsalis pedis and posterior tibial pulses.2, 3 For purposes of this study, PVD does not include microvascular or lymphatic drainage abnormalities.
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 parenteral antimicrobial therapy (OPAT) may be enrolled if the conditions specified in Section 8.4 are met.
5. The subject’s infection is expected to require at least 5 days of IV antimicrobial 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 plus 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 |
|
| E.4 | Principal exclusion criteria |
Subjects with the following characteristics are excluded:
1. History of any hypersensitivity or allergic reaction to any ß-lactam antimicrobial
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 an antimicrobial (other than topical antimicrobials) for the treatment of current cSSSI within 96 hours prior to randomization.
5. Failure of vancomycin or aztreonam as therapy for the current 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 wound infection with less than 5 cm of erythema surrounding the wound margin).
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 by 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 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, such as atopic dermatitis where inflammation may be prominent for an extended period of time, even after successful bacterial eradication has been achieved
• 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 antimicrobial therapy (including systemic antifungal therapy) for any reason
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 (see Section 9.1)
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, including but not limited to, current or impending respiratory failure, acute heart failure, shock, acute coronary syndrome, unstable arrhythmias, hypertensive emergency, acute hepatic failure, active gastrointestinal bleeding, or acute cerebrovascular events
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 or previously participated in the current 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome measure will be the per subject clinical cure rate at the TOC visit in the CE and MITT populations. Subjects will be considered clinically cured at TOC if they continue to have total resolution of all signs and symptoms of the baseline infection, or improvement of the infection to such an extent that no further antimicrobial therapy is necessary.
Secondary efficacy endpoints are:
• Per-subject clinical cure rate at the TOC visit in the clinical MITT (cMITT) population
• Per-subject clinical cure rate at the EOT visit in the MITT, cMITT, and CE populations
• Per-subject microbiological response at the TOC visit in the microbiological MITT (mMITT) Microbiologically Evaluable (ME) populations
• Per-subject clinical and microbiological response by pathogen at the TOC visit in the mMITT and ME populations
• 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 favorable 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 |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
|
| 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
| |
| 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 |
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