| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| complicated skin and skin structure Infections |
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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 | HLT |
| E.1.2 | Classification code | 10040786 |
| E.1.2 | Term | Skin structures and soft tissue infections |
|
| 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 |
The objective of this study is to compare the efficacy and safety of two sequential (IV/PO) treatment regimens for the treatment of adult subjects with cSSSIs:
• Moxifloxacin, 400 mg IV every 24 hours followed by moxifloxacin 400 mg PO every 24 hours.
• Piperacillin/tazobactam, 4.0/0.5 g administered IV three times daily followed by oral amoxicillin/clavulanic acid tablets, 875/125 mg twice daily.
Treatment duration is aimed at minimum of 7 days and a maximum of 21 days.
The primary efficacy criterion for the clinical trial is the clinical response assessed by an independent data review committee (DRC), 14-28 days after the completion of study drug therapy (Test-of-Cure visit [TOC]).
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| E.2.2 | Secondary objectives of the trial |
Secondary efficacy criteria are:
• Clinical response assessed by the investigator on treatment Day 3-5.
• Clinical response assessed by the investigator at the End-of-Therapy (EOT).
• Clinical response assessed by the investigator at the TOC visit.
• Bacteriological response on Day 3-5, at the EOT and TOC visit.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria:
1. Written informed consent.
2. Men or women of age 18 years of age with a diagnosis of bacterial skin and skin structure infection that requires
a. Hospitalization
and
b. Initial parenteral therapy for at least 48 hours
and
c. Meets at least one of the following criteria:
Involvement of deep soft tissue (eg, fascial, muscle layers).(42)
Requirement for a significant surgical intervention including surgical drainage, drainage procedure guided by imaging and/or debridement.
Association with a significant underlying disease that may complicate response to treatment. An underlying disease is considered significant if it includes any of the following conditions that are present at the time of presentation: cancer (except basal- or squamous-cell cancer of the skin), cardiac (ie, congestive heart disease), diabetes mellitus, hepatic (ie, cirrhosis or another form of chronic liver disease), immunologic, renal disease, respiratory, transplantation or vascular disease.
3. Duration of infection < 21 days.
4. Diagnosis of one of the following skin and skin structure infections that requires hospitalization and initial parenteral antibiotic therapy for at least 48 hours:
a. Major abscess(es) associated with extensive cellulitis, which requires antibiotic therapy in addition to surgical incision and drainage.
b. Diabetic foot infection of mild to severe intensity (PEDIS grade 2-4)(43) in the presence or absence of osteomyelitis. Subjects with osteomyelitis may only be enrolled if the infected bone is completely removed by surgery and if residual infection requiring antibiotics is still present following surgery.
c. Wound infection including: post surgical (surgical incision), post-traumatic, human bite/clenched fist and animal bite wound and wound associated with injection drug abuse:
Infections must have occurred within 30 days of a surgical procedure, trauma, animal bite, or human bite, and involve the skin and skin structures at the site of the incision, trauma, or bite.
In addition, post-surgical/trauma wound infections must meet the following criteria (42):
• Involvement of deep soft tissues (eg, fascial and muscle layers) of the incision/trauma.
• At least one of the following criteria:
• Purulent drainage from the deep incision/trauma.
• Identification of an infecting organism from an aseptically obtained culture of fluid or tissue from incision/trauma.
• At least one of the following signs and symptoms:
a. Localized pain or tenderness.
b. Fever (see below).
AND
The incision (in case of post-surgical wound infections) is deliberately opened by a surgeon, unless the culture is negative.
• Abscess or other evidence of infection involving the deep incision/trauma, found on direct examination, during reoperation/operation (in case of trauma), or by histologic or radiologic examination.
• Diagnosis of a deep incisional/post-trauma SSI by a surgeon or attending physician.
Bite wounds/clenched fist infections and wounds associated with injection drug abuse must meet the criteria defining a cSSSI (see point 2c).
d. Infected ischemic ulcers with at least one of the following conditions:
Diabetes mellitus.
Peripheral vascular disease.
Conditions pre-disposing to pressure scores such as paraplegia, peripheral neuropathy.
5. Presence of at least 3 of the following signs or symptoms:
a. Purulent drainage or discharge.
b. Erythema extending > 1 cm from the wound edge.
c. Fluctuance.
d. Pain or tenderness to palpation.
e. Swelling or induration.
f. Fever, defined as body temperature
> 37.5°C (axillary).
> 38°C (orally).
> 38.5°C (tympanically) or
> 39°C (rectally).
OR
Elevated total peripheral white blood cell (WBC) count > 12,000/mm3.
OR
> 15 % immature neutrophils (bands) regardless of total peripheral WBC count.
g. C reactive protein (CRP) > 20 mg/L.
6. Specimen obtained for culture from infected area by needle aspiration of obviously purulent material or by tissue biopsy or by curettage of the surface of ulcer within 24 hours prior to the initiation of study drug therapy.
7. Duration of treatment of the skin/skin structure infection is anticipated to be at least 7 days.
Surgical drainage or debridement of infected wounds or abscesses, if necessary, have to have been completed 48 hours after the initiation of study drug therapy.
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| E.4 | Principal exclusion criteria |
Subjects with any of the following will be excluded from the study:
1. Women, who are pregnant or lactating, or in whom pregnancy can not be excluded (Note: a urine pregnancy test has to be performed for all women of childbearing potential before randomization to the study drug).
2. The following skin and skin structure infections:
a. Necrotizing fasciitis including Fournier’s gangrene, ecthyma gangrenosum, streptococcal necrotizing fasciitis and clostridial necrotizing fasciitis.
b. Burn wound infections.
c. Secondary infections of a chronic skin disease (eg, atopic dermatitis).
d. Infection of prosthetic materials (eg, subcutaneous tissue infection related to a central venous catheter or permanent cardiac pacemaker battery pack). Subjects with removal of a prosthetic device involved in an infection should not be included.
e. Infections where a surgical procedure alone is definitive therapy.
f. Subjects with uncomplicated skin and skin structure infections including folliculitis and furunculosis, carbunculosis, simple abscesses and superficial cellulitis.
3. Known hypersensitivity to quinolones and/or any type of beta-lactam antibiotic drugs or any of the excipients.
4. Previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin-clavulanic acid.
5. Severe, life threatening disease with a life expectancy of less than 2 months.
6. Immunosuppression including:
a. Known neutropenia (neutrophil count < 1000/L).
b. Known lymphopenia with absolute CD4+ T cell count < 200/mm3.
c. AIDS-defining event and/or concomitant therapy with HAART.
d. Chronic treatment ( 2 weeks) with known immunosuppressant therapy (including treatment with > 15 mg/day of systemic prednisone or equivalent).
e. Any other congenital or acquired immune defect or immunosuppression.
7. Known severe hepatic insufficiency (Child Pugh C) or transaminases increase > 5 fold upper limit of normal (ULN).
8. Known renal impairment with a baseline measured or calculated serum creatinine clearance < 40 mL/min (see Cockcroft-Gault formula in Section 10.3).
9. Known prolongation of the QT interval or concomitant use of drugs reported to increase the QT interval (eg, Class IA or Class III antiarrhythmics [eg., quinidine, procainamide, amiodarone, sotalol], neuroleptics [eg., haloperidol], tricyclic antidepressive agents, certain antimicrobials [eg, pentamidine, halofantrine], certain antihistaminics [eg., terfenadine], and other [cisapride, vincamine IV, depridil, diphemanil]).
10. Uncorrected hypokalemia.
11. Clinically relevant bradycardia.
12. Clinically relevant heart failure with reduced left ventricular ejection fraction (ie, below 40%).
13. Previous history of symptomatic arrhythmias.
14. Previous history of tendon disease/disorder with quinolones.
15. Known or suspected concomitant bacterial infection requiring additional systemic antibacterial treatment, eg, underlying septic arthritis.
16. Requiring therapy with probenecid.
17. Treatment with a systemic or topical antibacterial agent for > 24 hours in the previous 7 days preceding study entry unless the subject showed no response or had worsening of clinical signs and symptoms despite 3 or more days of prior therapy and a culture obtained at the time of subject enrollment showed persistence of a pathogen which is susceptible to the study drugs. The prior antimicrobial therapy must not have been a fluoroquinolone or a beta lactam/beta lactamase combination.
18. Infection known to be due to a MRSA, MRSE or VRE as the single isolated pathogen.
19. Previous enrolment in this study.
20. Participation in any clinical investigational drug study within 4 weeks of screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy criterion for this trial is clinical response at the Test-of-Cure Visit 14-28 days after last dose of study medication. The blinded assessment made by the DRC will be considered as the primary evaluation for the clinical response at the TOC visit.
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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 | 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.3 |
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 | 86 |
| 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 | 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
|
| The end of study is defined as clean database |
|
| 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 | 8 |
| 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 | 8 |
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