| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Bacterial Skin and Skin Structure Infections |
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| E.1.1.1 | Medical condition in easily understood language |
| Skin and skin structure infections |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040872 |
| E.1.2 | Term | Skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
| Evaluate the safety and tolerability of ceftaroline versus comparator in pediatric subjects ages 2 months to < 18 years with acute bacterial skin and skin structure infections (ABSSSI) |
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| E.2.2 | Secondary objectives of the trial |
• Evaluate the efficacy of ceftaroline versus comparator in pediatric subjects ages 2 months to < 18 years with ABSSSI
• Evaluate the pharmacokinetics of ceftaroline in pediatric subjects ages 2 months to < 18 years with ABSSSI |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Informed consent in writing from parent(s) or legally acceptable representative(s) and informed assent from subject (if age appropriate according to local requirements)
2. Male or female, 2 months to < 18 years old
3.Presence of ABSSSI requiring IV antibacterial therapy
4.Presence of ABSSSI with measurable margins of erythema (ie, cellulitis), edema, or induration that includes deeper and/or extensive soft tissue involvement* (eg, deep and extensive cellulitis, erysipelas, or major abscess), or requires significant therapeutic surgical intervention** (eg, major abscess or an infected wound [postoperative surgical or traumatic]), defined as:
•Abscess: presence of a loculated fluid collection with erythema (ie, cellulitis), edema, or induration extending from the abscess margin and onset within 7 days before randomization. A “major abscess” either extends to deeper soft tissue or requires significant surgical intervention. Incision and drainage should be conducted within 24 hours after first dose of IV study drug. A minimum margin of erythema (ie, cellulitis), edema, or induration around the abscess is required for a subject to be enrolled in the study;
•Wound infection: presence of either purulent/seropurulent discharge from the surgical/traumatic wound with erythema (ie, cellulitis), edema, or induration surrounding the wound margin. Onset of infection must have occurred within 7 days before randomization and within 30 days following the trauma or surgical procedure. A minimum lesion area of wound infection is required for a subject to be enrolled in the study;
•Cellulitis/erysipelas: presence of advancing erythema, induration/edema, and heat with onset within 7 days before randomization. A minimum area of cellulitis/erysipelas is required for a subject to be enrolled in the study;
*Deeper soft tissue: subdermal tissue, including subcutaneous fat
**Significant surgical intervention: a major invasive therapeutic procedure (not including commonly performed minor procedures such as suture removal, superficial debridement of devitalized tissue, or routine wound care)
5.In addition to erythema (cellulitis), presence of at least 1 of the following local signs and symptoms of acute infection (present for < 10 days):
•Purulent or seropurulent drainage or discharge
•Induration/edema
•Fluctuance
•Heat or localized warmth
AND the presence of at least 1 of the following signs:
•Fever (> 38°C [100.4°F]) or hypothermia (< 35°C [95.0°F]). Temperature should not be measured by the axillary method.
•WBC count > 12,000/mm3
•> 10% immature neutrophils (bands) regardless of total peripheral WBC
•Lymphangitic spread
6.Female subjects who have reached menarche must have a negative urine pregnancy test
7.Female subjects who have reached menarche and are sexually active must be willing to practice sexual abstinence or dual methods of birth control (eg, condom or diaphragm with spermicidal foam or gel) during treatment and for at least 28 days after the last dose of any study drug (IV or PO)
8.Sufficient IV access to receive medication
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| E.4 | Principal exclusion criteria |
1.Documented history of any hypersensitivity or allergic reaction to vancomycin, aztreonam, or any β lactam antimicrobial
2.Uncomplicated skin and soft tissue infections such as simple abscess, impetiginous lesions, superficial or small size cellulitis, furunculosis, carbunculosis, or folliculitis
3.Skin and skin structure infections with a high cure rate after surgical incision alone or after aggressive local skin care
4.Skin and soft tissue infections with any of the following characteristics:
•Known or suspected anaerobic pathogens, Pseudomonas, Proteus, or extended-spectrum β lactamase-producing organisms
•Known or suspected fungal, parasitic, or viral pathogens as the cause for the skin infection
•Decubitus ulcer or diabetic foot infection
•Complicated by osteomyelitis, septic arthritis, or endocarditis
•Burn wound
•Underlying inflammatory skin disease that may obscure determination of response, such as atopic dermatitis
•Human or animal bite
•Rapidly necrotizing process such as necrotizing fasciitis
•Gangrene
•Presence of prosthetic materials
•Need for amputation
5.More than 24 hours of any systemic antibacterial therapy within 96 hours before randomization EXCEPTIONS:
a)Microbiological or clinical treatment failure with a systemic antibiotic other than IV study drugs that was administered for at least 48 hours. Failure must be confirmed by either a microbiological laboratory report or documented worsening clinical signs or symptoms.
b)Low-dose tetracycline derivative for acne (eg, doxycycline 50 mg q12h)
6.Requirement for any potentially effective concomitant systemic antibacterial therapy
7.History of seizures, excluding well-documented febrile seizure of childhood
8.Creatinine clearance < 50 mL/min/1.73 m2 as calculated using the updated Schwartz “bedside” formula (Schwartz et al, 2009):
CrCl (mL/min/1.73 m2) = 0.413 × Height (Length) (cm)/
Serum creatinine (mg/dL)
9.Clinical signs or suspicion of meningitis
10.Current septic shock or hemodynamic instability non-responsive to pressor support
11.Evidence of significant hepatic, hematologic, or immunocompromising condition (any of the following):
•Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (× ULN) or total bilirubin level > 2 × ULN
•Known acute viral hepatitis
•Neutropenia (< 500 neutrophils/mm3)
•Thrombocytopenia (< 60,000 platelets/mm3)
•If HIV positive, has CD4 count < 250 cells/mm3 at the last measurement or history of AIDS defining illness
•Bone marrow ablative therapy, including bone marrow transplantation, within the last 12 months
•Bone marrow or solid organ recipients who have had an episode of graft versus host disease or acute rejection episode, respectively, within the last 6 months
•Severe combined immunodeficiency disorder
•Requirement for more than 10 days of systemic corticosteroid therapy (any dose); short courses of corticosteroids, such as those for currently worsening asthma, are permitted
12.Evidence of immediately life-threatening disease, progressively fatal disease, or life expectancy of ≤ 3 months
13.Females who are currently pregnant or breastfeeding
14.Participation in any study involving administration of an investigational agent or device within 30 days before the start of first dose of IV study drug or previously participated in the current study or in another study of ceftaroline fosamil (in which an active agent was received)
15.Unable or unwilling to adhere to the study-specified procedures and restrictions
16.Any condition (eg, cystic fibrosis) that would make the subject, in the opinion of the Investigator, unsuitable for the study (eg, would place a subject at risk or compromise the quality of the data)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measures are safety assessments and include:
• Adverse events (AEs): AEs, serious adverse events (SAEs), deaths, and discontinuations due to AEs will be monitored ; cephalosporin class effects and additional AEs will also be closely monitored (including, but not limited to, seizures, Clostridium difficile-associated diarrhea, allergic reactions, hepatic abnormalities, hemolytic anemia, and changes in renal function)
• Clinical: vital signs (pulse, blood pressure, respiratory rate, temperature)
• Laboratory: complete blood count with differential, direct Coombs test, and chemistry panel
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs and SAEs are reported from signing of informed consent through LFU visit (21 to 35 days after last dose of any study drug [IV or PO]). If the LFU was conducted < 30 days after the last dose of study drug or was not conducted, an effort should be made to obtain AE and SAE information by telephone at least 30 days after the last dose of study drug. Cephalosporin class effects and additional AEs will be closely monitored/followed until resolution or stabilization.
Vital signs and pain scale assessments are collected at baseline, daily while on IV study drug (up to 14 days), and at the EOIV, EOT, TOC, and LFU visits.
Clinical laboratory parameters are collected at the Baseline, Study Day 7 if subject is still on IV study drug at that time, EOIV, TOC visits. |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy end points will include the following (see protocol for more detailed definitions of responses and populations):
• Clinical response at Study Day 3 in the Modified Intent-to-Treat (MITT) Population.
• Clinical outcome at EOIV, EOT, and TOC in the MITT and Clinically Evaluable (CE) Populations
• Clinical and microbiological outcomes by subject and by baseline pathogen at TOC in the Microbiological Modified Intent-to-Treat (mMITT) and Microbiologically Evaluable (ME) Populations
• Clinical relapse at LFU in the MITT Population
• Emergent infections in the mMITT Population
Pharmacokinetics
The PK procedures will be conducted as outlined in the Schedule of Assessments and Procedures (Table 2–1) and include:
• Concentrations of ceftaroline fosamil, ceftaroline, and M-1 in plasma, and if available, in cerebrospinal fluid (CSF; if collected as part of routine medical care).
PK blood samples will be collected after the fourth infusion of ceftaroline fosamil and before oral switch or Study Day 5 (whichever is earlier). Subjects will be randomly assigned (1:1) to one of the following PK sample collection schedules:
• PK Schedule 1: at the end of the ceftaroline fosamil infusion (± 5 minutes) and 3 to 4 hours after the end of the infusion
• PK Schedule 2: 15 minutes to 2 hours after the end of the ceftaroline fosamil infusion and 5 to 7 hours after the end of the infusion (before the start of the next infusion)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
See section E.5.2 above for specific timepoints(s) of evaluation corresponding to each efficacy end point. Two blood samples for pharmacokinetic end points will be collected after the fourth infusion of ceftaroline fosamil and before oral switch or Study Day 5 (whichever is earlier).
Subjects will be randomly assigned (1:1) to one of the following PK sample collection schedules:
•PK Schedule 1: at the end of the ceftaroline fosamil infusion (± 5 minutes) and 3 to 4 hours after the end of the infusion
•PK Schedule 2: 15 minutes to 2 hours after the end of the ceftaroline fosamil infusion and 5 to 7 hours after the end of the infusion (before the start of the next infusion). |
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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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Brazil |
| Chile |
| Georgia |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| South Africa |
| Spain |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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