Clinical trial NCT00402727: Comparison of Sequential IV/PO Moxifloxacin With IV Piperacillin/Tazobactam Followed by PO Amoxicillin/Clavulanic Acid in Patients With a Complicated Skin and Skin Structure Infection
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Abscess
Wound Infection
Diabetic Foot
Ulcer
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2006-11-22
Enrollment: 813
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients, who are considered suitable by their physicians to take part in this research, will have a physical examination (including an Electrocardiogram (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: intravenous (IV)/per oral (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.


Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Men or women of 18 years and above with a diagnosis of bacterial skin and skin structure infection that requires

  * Hospitalization and
  * Initial parenteral therapy for at least 48 hours and
  * 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
* Duration of infection \< 21 days
* Diagnosis of one of the following skin and skin structure infections that requires hospitalization and initial parenteral antibiotic therapy for at least 48 hours:

  * Major abscess(es) associated with extensive cellulitis, which requires antibiotic therapy in addition to surgical incision and drainage
  * Diabetic foot infection of mild to severe intensity (perfusion, extent/size, depth/tissue loss, infection and sensation (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
  * 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:

        * Localized pain or tenderness
        * 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 Skin Structure Infections (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 Complicated Skin and Skin Structure Infections (cSSSI)
  * 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
    * Presence of at least 3 of the following signs or symptoms:

      * Purulent drainage or discharge
      * Erythema extending \> 1 cm from the wound edge
      * Fluctuance
      * Pain or tenderness to palpation
      * Swelling or induration
      * 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
      * C reactive protein (CRP) \>20 mg/L
* 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
* 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:

* 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)
* The following skin and skin structure infections:

  * Necrotizing fasciitis including Fourniers gangrene, ecthyma gangrenosum, streptococcal necrotizing fasciitis and clostridial necrotizing fasciitis
  * Burn wound infections
  * Secondary infections of a chronic skin disease (e.g. atopic dermatitis)
  * 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
  * Infections where a surgical procedure alone is definitive therapy
  * Subjects with uncomplicated skin and skin structure infections including folliculitis and furunculosis, carbunculosis, simple abscesses and superficial cellulitis
* Known hypersensitivity to quinolones and/or any type of beta-lactam antibiotic drugs or any of the excipients
* Previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin-clavulanic acid
* Severe, life threatening disease with a life expectancy of less than 2 months
* Immunosuppression including:

  * Known neutropenia (neutrophil count \< 1000/µL)
  * Known lymphopenia with absolute CD4+ T cell count \< 200/mm3
  * Acquired immunodeficiency syndrome (AIDS)-defining event and/or concomitant therapy with Highly Active Antiretroviral Therapy (HAART)
  * Chronic treatment (\>/= 2 weeks) with known immunosuppressant therapy (including treatment with \> 15 mg/day of systemic prednisone or equivalent)
  * Any other congenital or acquired immune defect or immunosuppression
* Known severe hepatic insufficiency (Child Pugh C) or transaminases increase \> 5 fold upper limit of normal (ULN)
* Known renal impairment with a baseline measured or calculated serum creatinine clearance \< 40 mL/min
* 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 \[cisapride, vincamine IV, depridil, diphemanil\])
* Uncorrected hypokalemia
* Clinically relevant bradycardia
* Clinically relevant heart failure with reduced left ventricular ejection fraction (i.e., below 40%)
* Previous history of symptomatic arrhythmias
* Previous history of tendon disease/disorder with quinolones
* Known or suspected concomitant bacterial infection requiring additional systemic antibacterial treatment, e.g. underlying septic arthritis
* Requiring therapy with probenecid
* 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
* Infection known to be due to a Methicillin-Resistant Staphylococcus Aureus (MRSA), Methicillin-Resistant Staphylococcus Epidermidis (MRSE) or Vancomycin Resistant Enterococcus (VRE) as the single isolated pathogen
* Previous enrolment in this study
* Participation in any clinical investigational drug study within 4 weeks of screening
* Previous history of seizure disorders

Primary outcomes:
measure: Percentage of Cured Participants as Determined by the Data Review Committee (DRC) at Test of Cure Visit in the Per Protocol (PP) Population
timeFrame: 14 - 28 days after last dose of study medication
Secondary outcomes:
measure: Percentage of Cured Participants as Determined by the Data Review Committee (DRC) at Test of Cure Visit in the Intent to Treat (ITT) Population
timeFrame: 14 - 28 days after last dose of study medication
measure: Percentage of Participants Assessed as Improvements by the Data Review Committee (DRC) at the During Treatment Day 3-5 in the Per Protocol (PP) Population
timeFrame: 3 - 5 days after start of treatment
measure: Percentage of Participants Assessed as Improvements by the Data Review Committee (DRC) at the During Treatment Day 3-5 in the Intent to Treat (ITT) Population
timeFrame: 3 - 5 days after start of treatment
measure: Percentage of Participants Assessed as Resolution by the Data Review Committee (DRC) at End of Therapy in the Per Protocol (PP) Population
timeFrame: after 7 - 21 days of treatment
measure: Percentage of Participants Assessed as Resolution by the Data Review Committee (DRC) at End of Therapy in the Intent to Treat (ITT) Population
timeFrame: after 7 - 21 days of treatment
measure: Percentage of Participants With Bacteriological Success (BS) at 3 to 5 Days After Start of Treatment in the ITT Population With Causative Organisms
timeFrame: 3 - 5 days after start of treatment
measure: Percentage of Participants With Bacteriological Success (BS) at 3 to 5 Days After Start of Treatment in the Microbiological Valid (MBV) Population
timeFrame: 3 - 5 days after start of treatment
measure: Percentage of Participants With Bacteriological Success (BS) After 7 - 21 Days of Treatment in the ITT Population With Causative Organisms
timeFrame: after 7 - 21 days of treatment
measure: Percentage of Participants With Bacteriological Success (BS) After 7 - 21 Days of Treatment in the Microbiological Valid (MBV) Population
timeFrame: after 7 - 21 days of treatment
measure: Percentage of Participants With Bacteriological Success (BS) After 14 - 28 Days After Last Dose of Study Medication in the ITT Population With Causative Organisms
timeFrame: 14 - 28 days after last dose of study medication
measure: Percentage of Participants With Bacteriological Success (BS) After 14 - 28 Days After Last Dose of Study Medication in the Microbiological Valid (MBV) Population
timeFrame: 14 - 28 days after last dose of study medication
Other outcomes:
Locations:
city: Graz
country: Austria
state: Steiermark
city: Graz
country: Austria
city: Wien
country: Austria
city: Bornem
country: Belgium
city: Bruxelles - Brussel
country: Belgium
city: Bruxelles - Brussel
country: Belgium
city: Edegem
country: Belgium
city: Dobrich
country: Bulgaria
city: Pleven
country: Bulgaria
city: Ruse
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Annecy
country: France
city: Avignon
country: France
city: Boulogne Sur Mer
country: France
city: Denain
country: France
city: Grenoble
country: France
city: Le Grau Du Roi
country: France
city: Nevers
country: France
city: Quimper
country: France
city: Tourcoing
country: France
city: Mannheim
country: Germany
state: Baden-Württemberg
city: München
country: Germany
state: Bayern
city: Darmstadt
country: Germany
state: Hessen
city: Wiesbaden
country: Germany
state: Hessen
city: Hannover
country: Germany
state: Niedersachsen
city: Bochum
country: Germany
state: Nordrhein-Westfalen
city: Münster
country: Germany
state: Nordrhein-Westfalen
city: Mainz
country: Germany
state: Rheinland-Pfalz
city: Magdeburg
country: Germany
state: Sachsen-Anhalt
city: Lübeck
country: Germany
state: Schleswig-Holstein
city: Hamburg
country: Germany
city: Athens
country: Greece
state: Attica
city: Athens
country: Greece
state: Attica
city: Athens
country: Greece
city: Athens
country: Greece
city: Rio Patras
country: Greece
city: Thessaloniki
country: Greece
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Györ
country: Hungary
city: Kaposvar
country: Hungary
city: Szekesfehervar
country: Hungary
city: Veszprem
country: Hungary
city: Wilton
country: Ireland
state: Cork
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Galway
country: Ireland
city: Sligo
country: Ireland
city: Haifa
country: Israel
city: Tel Hashomer
country: Israel
city: Chieti
country: Italy
city: Milano
country: Italy
city: Pavia
country: Italy
city: Roma
country: Italy
city: Siena
country: Italy
city: Daugavpils
country: Latvia
city: Liepaja
country: Latvia
city: Riga
country: Latvia
city: Riga
country: Latvia
city: Riga
country: Latvia
city: Valmiera
country: Latvia
city: Kaunas
country: Lithuania
city: Siauliai
country: Lithuania
city: Ukmerge
country: Lithuania
city: Vilnius
country: Lithuania
city: Alkmaar
country: Netherlands
city: Eindhoven
country: Netherlands
city: Kraków
country: Poland
city: Lublin
country: Poland
city: Lublin
country: Poland
city: Lublin
country: Poland
city: Poznan
country: Poland
city: Pulawy
country: Poland
city: Warszawa
country: Poland
city: Bucharest
country: Romania
city: Bucharest
country: Romania
city: Bucharest
country: Romania
city: Cluj-Napoca
country: Romania
city: Iasi
country: Romania
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Smolensk
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Johannesburg
country: South Africa
state: Gauteng
city: Pretoria
country: South Africa
state: Gauteng
city: Cape Town
country: South Africa
state: Western Cape
city: Cape Town
country: South Africa
state: Western Cape
city: Cape Town
country: South Africa
state: Western Cape
city: Worcester
country: South Africa
state: Western Cape
city: Oviedo
country: Spain
state: Asturias
city: Terrassa (Barcelona)
country: Spain
state: Catalunya
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Salamanca
country: Spain
city: Ivano-Frankivsk
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Lviv
country: Ukraine
city: Odessa
country: Ukraine
city: Uzhgorod
country: Ukraine
city: London
country: United Kingdom
state: Greater london
city: Winchester
country: United Kingdom
state: Hampshire
city: Inverness
country: United Kingdom
state: Highland
city: Edinburgh
country: United Kingdom
state: Lothian
city: Glasgow
country: United Kingdom
state: Stratchclyde
city: Newcastle Upon Tyne
country: United Kingdom
state: Tyne and Wear
city: Leeds
country: United Kingdom
state: West Yorkshire
city: Manchester
country: United Kingdom
city: York
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Gyssens IC, Dryden M, Kujath P, Nathwani D, Schaper N, Hampel B, Reimnitz P, Alder J, Arvis P. A randomized trial of the efficacy and safety of sequential intravenous/oral moxifloxacin monotherapy versus intravenous piperacillin/tazobactam followed by oral amoxicillin/clavulanate for complicated skin and skin structure infections. J Antimicrob Chemother. 2011 Nov;66(11):2632-42. doi: 10.1093/jac/dkr344. Epub 2011 Sep 6.
citation: Schaper NC, Dryden M, Kujath P, Nathwani D, Arvis P, Reimnitz P, Alder J, Gyssens IC. Efficacy and safety of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of diabetic foot infections: results of the RELIEF study. Infection. 2013 Feb;41(1):175-86. doi: 10.1007/s15010-012-0367-x. Epub 2012 Nov 23.
citation: D'Onofrio V, Monnier AA, Kremer C, Stappers MHT, Netea MG, Gyssens IC. Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections. Eur J Clin Microbiol Infect Dis. 2020 Feb;39(2):353-360. doi: 10.1007/s10096-019-03732-7. Epub 2019 Nov 30.