Acute Bacterial Skin and Skin Structure Infections MedDRA version: 13.1 Level: PT Classification code 10040872 Term: Skin infection System Organ Class: 10021881 - Infections and infestations
Conditions
Interventions
Product Name: TR-701 FA
Product Code: TR-701 FA
Pharmaceutical Form: Tablet
CAS Number: 856867-55-5
Current Sponsor code: TR-701 FA
Other descriptive name: free acid phosphate pro-drug for the active
Sponsors
Trius Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Males or females = 18 years old 2. ABSSSI meeting at least 1 of the clinical syndrome definitions listed below and requiring systemic oral antibiotic therapy. Local symptoms must have started within 7 days before the Screening Visit. A. Cellulitis/erysipelas defined as a diffuse skin infection, characterized by all of the following within 24 hours: ? Rapidly spreading areas of erythema of a minimum total lesion surface area of 75 cm2 ? No collection of pus apparent upon visual examination (diagnosis still consistent with cellulitis/erysipelas if pus is collected from the lesion) ? At least 1 of the following signs of infection: ? Induration ? Localized warmth ? Pain or tenderness on palpation ? Swelling ? At least 1 of the following regional or systemic signs of infection: ? Lymph node tenderness and increase in volume or palpable proximal to the primary ABSSSI ? Fever, defined as body temperature = 38°C (100.4°F) oral, = 38.5°C (101.3°F) tympanic, or = 39°C (102.2°F) rectal (observed by a health care provider) ? White blood cell (WBC) count = 10,000 cells/mm3 or 10% immature neutrophils B. Major cutaneous abscess defined as an infection characterized by a collection of pus apparent upon visual examination spreading within the dermis or deeper that is accompanied by all of the following within 24 hours: ? Erythema extending at least 5 cm in the shortest distance from the peripheral margin of the abscess and with a minimum total lesion surface area of 75 cm2 ? At least 1 of the following signs of infection: ? Fluctuance ? Incision and drainage required ? Purulent or seropurulent drainage ? Localized warmth ? Pain or tenderness on palpation ? At least 1 of the following regional or systemic signs of infection: ? Lymph node tenderness and increase in volume or palpable proximal to the primary ABSSSI ? Fever, defined as body temperature = 38°C (100.4°F) oral, = 38.5°C (101.3°F) tympanic, or = 39°C (102.2°F) rectal (observed by a health care provider) ? WBC count = 10,000 cells/mm3 or 10% immature neutrophils C. Wound Infection defined as an infection of any apparent break in the skin characterized by the following: ? Superficial incision surgical site infection (SSI) meeting all of the following criteria: ? Follows clean surgery (elective, not emergency, nontraumatic, primarily closed, no acute inflammation; no break in technique; respiratory, gastrointestinal, biliary, and genitourinary tracts not entered) ? Involves only the skin or subcutaneous tissue around the incision, does not involve fascia ? Occurs within 30 days after procedure ? Original surgical incision = 3 cm ? Purulent drainage (spontaneous or therapeutic) with surrounding erythema extending at least 5 cm in the shortest distance from the peripheral margin of the wound and with a minimum total lesion surface area of 75 cm2 ? At least 1 of the following regional or systemic signs of infection: - Lymph node tenderness and increase in volume or palpable proximal to the primary ABSSSI - Fever, defined as body temperature = 38°C (100.4°F) oral, = 38.5°C (101.3°F) tympanic, or = 39°C (102.2°F) rectal (observed by a health care provider) - WBC count = 10,000 cells/mm3 or 10% immature neutrophils ? Post-traumatic wound (including penetrating trauma [needle, nail, knife]) characterized by all of the following within 24 hours: ? Purulent drainage (spontaneous or the
Exclusion criteria
Exclusion criteria: 1.Uncomplicated skin and skin structure infections such as furuncles, minor abscesses (area of suppuration not surrounded by cellulitis/erysipelas), impetiginous lesions, superficial or limited cellulitis/erysipelas, and minor wound infections (eg, stitch abscesses) 2. Infections associated with, or in close proximity to, a prosthetic device 3. Severe sepsis or septic shock 4. Known bacteremia at time of screening 5. ABSSSI due to or associated with any of the following: ? Suspected or documented gram-negative pathogens in patients with cellulitis/erysipelas or major cutaneous abscess that require an antibiotic with specific gram-negative coverage. Patients with wound infections where gram-negative adjunctive therapy is warranted may be enrolled if they meet the other eligibility criteria ? Diabetic foot infection, gangrene, or perianal abscess ? Concomitant infection at another site not including a secondary ABSSSI lesion (eg, septic arthritis, endocarditis, osteomyelitis) ? Infected burns ? Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial or venous) ? Any evolving necrotizing process (ie, necrotizing fasciitis) ? Infected human or animal bites. However, arthropod (eg, insects, spiders, ‘bugs’) bites are allowed; these are not considered animal bites in this study ? Infections at vascular catheter sites or involving thrombophlebitis ? Incision SSI with any of the following characteristics: ? Follows clean-contaminated surgery (urgent or emergency case that is otherwise clean, elective opening of respiratory, gastrointestinal, biliary, or genitourinary tract with minimal spillage [eg, appendectomy] not encountering infected urine or bile; minor technique break) ? Follows contaminated surgery (nonpurulent inflammation; gross spillage from gastrointestinal tract; entry into biliary or genitourinary tract in the presence of infected bile or urine; major break in technique) ? Follows dirty surgery (purulent inflammation [eg, abscess]; preoperative perforation of respiratory, gastrointestinal, biliary, or genitourinary tract) ? Extends into the fascial or muscle layers, organs, or spaces 6. Use of antibiotics as follows: ? Systemic antibiotic with gram-positive cocci activity for the treatment of any infection within 96 hours before Dose 1 of study drug ? Patients who failed prior therapy for the primary infection site are also excluded from enrollment ? Topical antibiotic on the primary lesion except for antibiotic/antiseptic-coated dressing applied to the clean postsurgical wound 7. Administration of linezolid within 30 days before Dose 1 8. Recent history of opportunistic infections where the underlying cause of these infections is still active (eg, leukemia, transplant, acquired immunodeficiency syndrome [AIDS]) 9. Receiving chronic systemic immunosuppressive therapy such as prednisone doses = 20 mg per day for = 3 of the last 12 months OR therapies that in the Investigator’s judgment could predispose to opportunistic infections 10. Receiving treatment for active tuberculosis 11. Last known CD4 count < 200 cells/mm3 in patients with AIDS 12. Current or anticipated neutropenia with absolute neutrophil count (ANC) < 1000 cells/mm3 13. Severe renal disease defined as creatinine clearance (CrCl) < 30 mL/min estimated by the Cockcroft-Gault formula OR requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous dialysis, or other forms of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to determine the noninferiority (NI) in the early clinical response rate of 6 day oral TR-701 free acid (FA) compared with that of 10-day oral linezolid treatment at 48-72 hours in the Intent-to-Treat (ITT) analysis set in patients with acute bacterial skin and skin structure infections (ABSSSI).;Secondary Objective: The secondary objectives include the following: • To compare the clinical response of 6-day TR-701 FA and 10 day linezolid treatment at 48-72 hours that is sustained at the End of Therapy (EOT) Visit (Day 11) in the ITT and Clinically Evaluable at EOT (CE-EOT) analysis sets • To compare the Investigator’s assessment of clinical success at the Post-Therapy Evaluation (PTE) Visit (7-14 days after the EOT Visit) in the ITT and Clinically Evaluable at PTE (CE- PTE) analysis sets • To compare the Investigator’s assessment of clinical response at the 48-72 Hour and Day 7 Visits in the ITT analysis set • To compare patient-reported pain, by study visit • To evaluate the safety profile of TR-701 FA in comparison with that of linezolid • To assess the population pharmacokinetic (PK) profile of TR-700 ;Primary end point(s): The primary efficacy outcome is the early clinical response rate at the 48-72 Hour Visit in the ITT analysis set. Early clinical response (responder [afebrile with cessation of spread from baseline of the primary ABSSSI lesion], nonresponder) will be determined programmatically from lesion measurements and temperature data recorded on the electronic case report form (e-CRF).;Timepoint(s) of evaluation of this end point: 48-72 Hour Visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary outcome measures are the following: • Sustained clinical response at the EOT Visit in the ITT and CE-EOT analysis sets. Patients assessed as a nonresponder at the 48-72 Hour Visit are considered a clinical failure at the EOT Visit • Investigator’s assessment of clinical success at the PTE Visit in the ITT and CE-PTE analysis sets. Patients assessed as a clinical failure at the EOT Visit are considered a clinical failure at the PTE Visit • Investigator’s assessment of clinical response at the 48-72 Hour and Day 7 Visits • Change from baseline in the pain scores at each time point • Change from baseline in lesion size, assessment of local signs and symptoms, and systemic signs (lymphadenopathy, percentage immature neutrophils, WBC count) Additional Efficacy Outcomes •Per-patient favorable (eradication or presumed eradication) microbiological response at the PTE Visit in the MITT and ME analysis set. Per-patient microbiological response is based on per pathogen outcomes •Per-pathogen microbiological response at the PTE Visit in the MITT and ME analysis sets •Investigator’s assessment of clinical success at the PTE Visit in the MITT and ME analysis sets •Per-pathogen Investigator’s assessment of clinical success at the PTE Visit in the MITT and ME analysis sets Safety Outcomes Safety will be assessed through summaries of AEs, laboratory evaluations (hematology and chemistry), vital signs, ECGs, physical examinations. Pharmacokinetic Analysis The objectives of the population PK analysis are: •To characterize the PK profile of TR-700 in patients, including estimation of typical PK parameters and interindividual and residual variability •To estimate the effects of individual-specific covariate factors of TR-700 PK in this population •To provide individual metrics of TR-700 exposure for modeling probabilities of clinical success, microbiological response, or safety outcomes ;Timepoint(s) of evaluation of this en | — |
Countries
Argentina, Brazil, Canada, Czech Republic, Germany, Hungary, Latvia, Peru, Poland, Romania, Slovakia, Ukraine, United States
Contacts
Public ContactEdward Fang, MD
Trius Therapeutics, Inc.
Outcome results
None listed