Official Title: “A Prospective, Randomized, Double Dummy, Double Blind, Multinational, Multicenter Trial Comparing the Safety and Efficacy of Sequential (Intravenous/Oral) Moxifloxacin 400 mg OD to Intravenous Piperacillin/Tazobactam 4.0/0.5 g Every 8 Hours Followed by Oral Amoxicillin/Clavulanic Acid Tablets 875/125 mg Every 12 Hours for the Treatment of Subjects With Complicated Skin and Skin Structure Infections”

Patients who are considered suitable by their physicians, to take part in this research, will have a physical examination (including an ECG), blood and urine samples taken, as well as a sample of the secretions or tissue around their infection site. In addition, the site of the infection will be photographed. The patients will be randomly assigned one of the treatments:

IV/PO moxifloxacin (drug under evaluation) or IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid (i.e., one of the reference treatments for this kind of infection). The maximum treatment duration will be 21 days, and the minimum will be 7 days.

During the hospitalization, the patients will have a physical examination every day. On Day 3-5 during therapy as well as at the end of treatment, the patients will have repeated examinations. These tests and evaluations will be repeated 14 to 28 days after the end of treatment. During this visit, blood and urine samples will be taken only if judged necessary by the physicians.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: June 2008

Number of arms: 2 (Treatment group 1 (Moxifloxacin IV/oral): Subgroup 1A: Moxifloxacin, 400 mg administered IV once daily and piperacillin/tazobactam placebo administered IV three times daily followed by moxifloxacin 400 mg administered PO once daily and amoxicillin/clavulanic acid oral placebo tablets twice daily. IV administration sequence: moxifloxacin followed by piperacillin/tazobactam placebo.

Subgroup 1B: Moxifloxacin, 400 mg administered IV once daily and piperacillin/tazobactam placebo administered IV three times daily followed by moxifloxacin 400 mg administered PO once daily and amoxicillin/clavulanic acid oral placebo tablets twice daily. IV administration sequence: piperacillin/tazobactam placebo followed by moxifloxacin.

Treatment group 2 (Piperacillin/tazobactam IV/amoxicillin/clavulanic acid tablets):

Subgroup 2A: Piperacillin/tazobactam, 4.0/0.5 g administered IV three times daily and moxifloxacin placebo administered IV od followed by amoxicillin/clavulanic acid oral tablets, 875/125 mg twice daily and moxifloxacin placebo PO od. IV administration sequence:

piperacillin/tazobactam followed by moxifloxacin placebo. Subgroup 2B:

Piperacillin/tazobactam, 4.0/0.5 g administered IV three times daily and moxifloxacin placebo administered IV od followed by amoxicillin/clavulanic acid oral tablets, 875/125 mg twice daily and moxifloxacin placebo PO od. IV administration sequence: moxifloxacin placebo followed by piperacillin/tazobactam. Subjects will be treated for a minimum of 7 days and a maximum of 21 days at the discretion of the investigator.)

Intervention(s) in this Clinical Trial

• Drug: Moxifloxacin intravenous and per os
  • Moxifloxacin, 400 mg administered intravenous once daily followed by Moxifloxacin 400 mg oral tablets once daily
• Drug: Piperacillin/Tazobactam intravenous, Amoxicillin/Clavulanic acid per os
  • Piperacillin/Tazobactam, 4.0/0.5g administered intravenous three times daily followed by amoxicillin/clavulanic acid oral tablets, 875/125mg twice daily.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm 1
• Active Comparator: Arm 2

Primary Measures

• The primary efficacy criterion for this trial is clinical response at the Test-of-Cure Visit
  • Time Frame: Day 14-28 after last dose
    Safety Issue?: No

Secondary Measures

• Clinical response assessed by the investigator on treatment Day 3-5
  • Time Frame: Day 3-5
    Safety Issue?: No
• Clinical response assessed by the investigator at the End Of Therapy (EOT)
  • Time Frame: After last day of treatment
    Safety Issue?: No
• Clinical response assessed by the investigator at the TOC visit
  • Time Frame: 21-48 days after last dose
    Safety Issue?: No
• Bacteriological response
  • Time Frame: Day 3-5, EOT visit, TOC visit
    Safety Issue?: No

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria:

• 1. Written informed consent
• 2. Men or women of 18 years and above with a diagnosis of bacterial skin and skin structure infection that requires
• 1. Hospitalization and 2. Initial parenteral therapy for at least 48 hours and 3. Meets at least one of the following criteria:
• Involvement of deep soft tissue (e.g. fascial, muscle layers)
• 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 (i.e., congestive heart disease), diabetes mellitus, hepatic (i.e., 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:
• 1. Major abscess (es) associated with extensive cellulitis, which requires antibiotic therapy in addition to surgical incision and drainage
• 2. Diabetic foot infection of mild to severe intensity (PEDIS grade 2-4) 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
• 3. 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:
• Involvement of deep soft tissues (e.g. 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:
• 1. Localized pain or tenderness
• 2. 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
• d. Infected ischemic ulcers with at least one of the following conditions:
• Peripheral vascular disease
• Conditions pre-disposing to pressure sores such as paraplegia, peripheral neuropathy
• 5. Presence of at least 3 of the following signs or symptoms:
• 1. Purulent drainage or discharge
• 2. Erythema extending > 1 cm from the wound edge
• 3. Fluctuance
• 4. Pain or tenderness to palpation
• 5. Swelling or induration
• 6. 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
• 7. 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 48 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

Exclusion Criteria:

• 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:
• 1. Necrotizing fasciitis including Fourniers gangrene, ecthyma gangrenosum, streptococcal necrotizing fasciitis and clostridial necrotizing fasciitis
• 2. Burn wound infections
• 3. Secondary infections of a chronic skin disease (e.g. atopic dermatitis)
• 4. Infection of prosthetic materials (e.g. 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
• 5. Infections where a surgical procedure alone is definitive therapy
• 6. 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:
• 1. Known neutropenia (neutrophil count < 1000/µL)
• 2. Known lymphopenia with absolute CD4+ T cell count < 200/mm3
• 3. AIDS-defining event and/or concomitant therapy with HAART
• 4. Chronic treatment (>= 2 weeks) with known immunosuppressant therapy (including treatment with > 15 mg/day of systemic prednisone or equivalent)
• 5. 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
• 9. Known prolongation of the QT interval or concomitant use of drugs reported to increase the QT interval (e.g. Class IA or Class III antiarrhythmics [eg., quinidine, procainamide, amiodarone, sotalol], neuroleptics [e.g. haloperidol], tricyclic antidepressive agents, certain antimicrobials [e.g. pentamidine, halofantrine], certain antihistaminics [e.g. 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 (i.e., 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, e.g. 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
• 21. Previous history of seizure disorders

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Bayer

Overall Clinical Trial Officials and Contacts

Bayer Study Director Study Director Bayer  

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00402727

Study ID Number: 11974

ClinicalTrials.gov Identifier: NCT00402727

Health Authority: Germany: Federal Institute for Drugs and Medical Devices

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