| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Classification code | 10049582 |
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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 |
| To compare the clinical efficacy of linezolid to vancomycin in the treatment of complicated skin and soft tissue infections (cSSTI) due to MRSA in adult subjects at the End of Study (EOS) visit. |
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| E.2.2 | Secondary objectives of the trial |
To compare the clinical efficacy, and safety and tolerability of linezolid to vancomycin in the treatment of cSSTI due to MRSA in adult subjects at the End of Treatment (EOT) visit.
To compare the bacteriological efficacy, and safety and tolerability of linezolid to vancomycin in the treatment of cSSTI due to MRSA in adult subjects at the EOT and the EOS visits.
To compare the medical resource utilization of linezolid and vancomycin for this subject population.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male and female subjects with signs or symptoms consistent with infection, and if available, laboratory findings consistent with staphylococcal infection (e.g., Gram stain and culture results). It is not a requirement to have the results of a Gram stain or culture prior to subject enrollment.
2. Subject or his/her legally acceptable representative must give informed consent by signing and dating an informed consent form prior to study entry.
3. Subjects must be at least 18 years of age.
4. Women of childbearing potential must use adequate contraception, defined as hormonal contraception, intrauterine device, or barrier methods (condom or vaginal diaphragm) with spermicide, throughout the study. The pre-study pregnancy test (urine or serum gonadotropin) must be negative. Women who have been surgically sterilized or are at least two years postmenopausal may be enrolled and do not have to use birth control. Women whose method of birth control is hormonal are required to use an additional barrier method during the study.
5. Subjects must be in a hospital environment at the time of first study dose. Non-hospitalized subjects may be enrolled as long as the first dose of study drug is given in a hospital environment. A hospital environment can include an emergency room, long term care facility such as a nursing home or rehabilitation center, or a wound center/infusion center/ambulatory treatment center that is at or attached to the hospital site.
6. Subjects must be expected to survive with effective antibiotic therapy and appropriate supportive care throughout the period of treatment and follow-up.
7. Subjects must be willing to complete all study related activities.
8. Subjects who, after control of their acute infection, are likely to be eligible to be discharged to outpatient therapy. In addition, the following subjects who may require long term hospitalization can be enrolled:
· Trauma and orthopedic patients with infections not involving bone (or if involving bone as per exclusion #8)
· Subjects who are expected to require surgical treatment after the study infection has resolved during the same hospitalization (i.e., skin graft for burn or ulcer)
· Subjects who are randomized to the vancomycin treatment group and the study site's local health practice requires that they stay in the hospital until the end of the treatment period
9. Subjects must have at least two of the specific signs and symptoms of an active skin or soft tissue infection caused by suspected MRSA that involves deep tissues such as subcutaneous tissue, fascia or skeletal muscle. Signs or symptoms may include:
· purulent drainage
· erythema
· swelling/induration
· tenderness to palpation or pain
· local warmth
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| E.4 | Principal exclusion criteria |
1. Subjects who have received an investigational drug during the previous 30 days or five times the plasma half-life (if known), whichever is longer or who have previously participated in any other protocol using linezolid in the past 6 months. Subjects who have previously participated in this trial are also excluded.
2. Subjects of childbearing potential, who are unable to take adequate contraceptive precautions, have a positive pregnancy test result within 24 hours prior to study entry, are otherwise known to be pregnant, or are currently breastfeeding an infant.
3. Subjects with infected devices, where the device is not removed. Subjects with the following infected devices – intravascular catheters/devices, CNS shunts, or peritoneal dialysis (PD) catheters, even if the device is removed, should be excluded.
4. Subjects with a hypersensitivity to vancomycin, teicoplanin, oxazolidinones or any of the excipients in the IV or oral formulation of linezolid.
5. Subjects with MRSA known to be non-susceptible to either of the study drugs before study entry.
6. Subjects who were treated with a previous antibiotic (systemic or topical) with activity against a subject's MRSA isolate (other than linezolid, vancomycin or teicoplanin) with a duration of more than 24 hours unless documented to be a treatment failure (defined as 72 hours of treatment and not responding). Treatment duration is defined as the time during which doses are administered plus time from last dose administered to next scheduled dose. The combined duration of antibiotics with activity against MRSA should not exceed 24 hours if given consecutively in the preceding 72 hours prior to first dose of study drug The treatment duration applies to any of the following timeframes:
· Within the 72-hour pre-enrollment period
· Started prior to the 72-hour pre-enrollment period and extended into this period
· Started during the 72-hour pre-enrollment period and extended into the study drug treatment period
Exception: Subjects who had greater than 24 hours of an antibiotic (other than linezolid, vancomycin or teicoplanin) that can have activity against MRSA, can be enrolled if they can show the following:
· MRSA isolate is non-susceptible to the antibiotic, or
· Institution's pattern of susceptibility indicates that the MRSA isolate is likely to not be susceptible to the antibiotic
· The subject has been treated for > 72 hours and was a documented treatment failure
Certain drugs with variable MRSA activity (e.g. fluoroquinolones, clindamycin, trimethoprim-sulfamethoxazole and tetracycline) may not be excluded if local susceptibility patterns will predict resistance and resistance is subsequently documented (Refer to Section 5.4.1).
7. Subjects who were treated with linezolid, vancomycin or teicoplanin with a treatment duration of more than 24 hours. The treatment duration applies to any of the following timeframes:
· Within the 72-hour pre-enrollment period
· Started prior to the 72-hour pre-enrollment period and extended into this period
· Started during the 72-hour pre-enrollment period and extended into the study drug treatment period
Subjects who were treated previously with linezolid, vancomycin or teicoplanin for the infection under study are excluded if they received a treatment duration of 72 hours or more of treatment and did not respond
8. Subjects with known or suspected necrotizing fasciitis, gas gangrene, gangrene, septic arthritis or osteomyelitis. Subjects may be enrolled if the area of osteomyelitis or gangrene has been or will be (within 72 hours of enrollment) resected (e.g. amputated) and an area of complicated skin/soft tissue infection requiring systemic antibiotic treatment remains. (If gangrene, evidence of critical ischemia must be ruled out as per Exclusion Criteria #9.)
9. Subjects with an infection involving a limb with evidence of critical ischemia in the affected limb defined as any of the following criteria:
· Absent or abnormal Doppler wave forms
· Toe blood pressure of <45 mm Hg
· Ankle brachial index of <0.5
· Critical ischemia as assessed by a vascular surgeon
10. Subjects with rapidly fatal underlying disease not expected to survive to complete the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the clinical outcome at the EOS visit, in subjects with baseline MRSA. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Vancomycin as comparator with Aztreonam(IV) infusion 1-2 grams every 12 hours as required for suspec |
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| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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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End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the trial as stated in the regulatory application.
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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