A Study to Assess Objective Endpoint Measurements of Response in Bacterial Skin Infections

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare clinical response to the measurement techniques of several objective measures of clinical efficacy for use in future ABSSSI (Acute Bacterial Skin and Skin Structure Infection) clinical trials

Official Title
-----------------
A Phase 2 Exploratory Study of Objective Endpoints in Subjects With Acute Bacterial Skin and Skin Structure Infections Treated With Delafloxacin, Vancomycin, or Linezolid

Conditions
-----------------
Skin and Subcutaneous Tissue Bacterial Infections

Intervention / Treatment
-----------------
* Drug: Delafloxacin
* Drug: Linezolid
* Drug: Vancomycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult (≥ 18 years of age) men or women Sexually active women and men with partners of childbearing potential must agree to use an acceptable form of contraception as determined by the investigator during participation in the study and for 30 days after the final dose of study drug Female partners of male subjects should also use an additional reliable method of contraception during study and for 30 days after the final dose of study drug Subjects must have a diagnosis of ABSSSI - one or more of the following 4 infection types: cellulitis/erysipelas, wound infection, major cutaneous abscess, or burn infection Subjects must have lymph node enlargement due to the present infection or at least one of the following symptoms of systemic infection: fever ≥ 38°C, lymphangitis, WBC (white blood cell) count ≥ 15,000 cells/μL, elevated C-reactive protein (> 5.0mg/L) In the opinion of the investigator, the subject must require and be a suitable candidate for IV antibiotic therapy Exclusion Criteria: A medical history of significant hypersensitivity or allergic reaction to quinolones, linezolid, vancomycin, or vancomycin derivatives Women who are pregnant or lactating Any chronic or underlying skin condition at the site of infection that may complicate the assessment of response Subjects with any of the following: infection involving prosthetic materials or foreign bodies, infection associated with a human or animal bite, osteomyelitis, decubitus ulcer, diabetic foot ulcer, septic arthritis, mediastinitis, necrotizing fasciitis, anaerobic cellulitis, or synergistic necrotizing cellulitis, myositis, tendinitis, endocarditis, toxic shock syndrome, gangrene, burns covering ≥ 10% of body surface area, severely impaired arterial blood supply, current evidence of deep vein thrombosis or superficial thrombophlebitis Minor abscesses, unless present with one of the ABSSSI types Any infection expected to require other antimicrobial agents in addition to study drug Receipt of > 24 hours of systemic antibiotic therapy in the 14 days before enrollment unless one of the following is documented: the subject received a single dose of a short-acting antibacterial drug 3 or more days before clinical trial enrollment for surgical prophylaxis or recently completed treatment with an antibacterial drug for an infection other than ABSSSI and the drug does not have antibacterial activity against bacterial pathogens that cause ABSSSI Receipt of more than 1 dose of a potentially effective antibacterial agent for treatment of the ABSSSI under study prior to enrollment Receipt of chronic anti-inflammatory therapy for longer than 14 days before enrollment Severely compromised immune systems Subjects taking any medicinal product which inhibits monoamine oxidases A or B or within 2 weeks of Screening Hypertension as defined by a systolic blood pressure of ≥ 180 mmHg or a diastolic blood pressure of ≥110 mmHg with confirmed re-check within 20 minutes of initial reading Subjects with pheochromocytoma, thyrotoxicosis and/or subjects taking any of the following types of medications: sympathomimetic agents, vasopressive agents, dopaminergic agents, or other agents with the potential for serotonergic interactions Subjects with carcinoid syndrome and/or subjects taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 (serotonin receptor) receptor agonists, meperidine, or buspirone Known history of liver disease History of severe renal impairment Life expectancy of < 3 months Any underlying disease that, in the opinion of the investigator, could interfere with the subject's ability to participate in the study Subjects previously randomized in this study or in who have received a dose of an investigational drug within 30 days of randomization Subjects > 140 kg in body weight

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Delafloxacin<br>300 mg IV (intravenous) every 12 hours for 5-14 days | Drug: Delafloxacin<br>* 300mg IV every 12 hours for 5-14 days<br>* Other names: RX-3341;|
| Active Comparator: Vancomycin<br>15 mg/kg, up to 1250 mg, IV every 12 hours for 5-14 dyas | Drug: Vancomycin<br>* 15mg/kg, up to 1250 mg, IV every 12 hours for 5-14 days<br>* Other names: Vancocin;|
| Active Comparator: Linezolid<br>600 mg IV every 12 hours for 5-14 days | Drug: Linezolid<br>* 600mg IV every 12 hours for 5-14 days<br>* Other names: Zyvox;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator's Assessment of Clinical Response in the ITT (Intent-to-treat) Population at Follow-up | The primary efficacy endpoint was the success rate, defined as (cure)/(cure + failure), and expressed as a percentage. Cure was defined as the complete resolution of all baseline signs and symptoms of ABSSSI and follow-up and late follow-up. If erythema was the only sign of infection present at follow-up and it was then absent at late follow-up, the case was classified as a Cure. | Follow-up (Day 14 ± 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Erythema Clinical Success | The number of ITT subjects who had cessation of erythema within 48-72 hours, based on digital measurements, as well as resolution/absence of fever. Cessation was defined as a percentage change from baseline in total area of erythema/induration that is less than or equal to 0%. | 48 - 72 hours | 
| Pharmacokinetic (PK) Parameter, Area Under Curve, (AUCinf, ug*h/mL), in Subjects Administered Delafloxacin, Vancomycin, and Linezolid | Blood samples for pharmacokinetic analyses were drawn from all subjects on Day 3 (± 1 day) of treatment within 2 hours before the first study drug infusion and at 1, 2, 3, 5, and 12 hours (ie, immediately before the second dose) after the start of the first study drug infusion. An analytical, validated method was used to analyze samples and determine human plasma concentrations. The primary pharmacokinetic parameter calculated was area under the plasma concentration - time curve from time 0 extrapolated to infinity (AUCinf, ug*h/mL). | Through Day 3 (± 1 day) | 
| The Levels of Inflammation Were Examined by Measuring a Surrogate, C-Reactive Protein (CRP) | CRP Levels (g/m3) were analyzed from blood samples collected from subjects at Baseline and various time points throughout the study. Change in baseline values were analyzed using an analysis of covariance (ANCOVA) model with treatment, infection category, and prior antimicrobial therapy as fixed effects and the baseline measure as the covariate. | Baseline, Days 1, 5, Follow-up (FU), and late Follow-up (LFU) | 
| Microbiological Response Rate in All Subjects (Microbiological Evaluable Population) | Based on the results of the baseline and follow up cultures and susceptibility testing, together with the clinical response assigned by the investigator, the sponsor determined a microbiological response for subjects in the ME population. | Follow-up (Day 14 ± 1) | 
| Microbiological Response Rate in Subjects With MRSA (Methicillin Resistant Staphylococcus Aureus) in Microbiological Evaluable (ME) Population | Based on the results of the baseline and follow up cultures and susceptibility testing, together with the clinical response assigned by the investigator, the sponsor determined a microbiological response for subjects in the ME population. | Follow-up (Day 14 ± 1) | 
| Clinical Response in Subjects With Infections Caused by MRSA - Microbiological ITT (MITT) Population | The success rate, defined as (cure)/(cure + failure), and expressed as a percentage. Cure was defined as the complete resolution of all baseline signs and symptoms of ABSSSI and follow-up and late follow-up. If erythema was the only sign of infection present at follow-up and it was then absent at late follow-up, the case was classified as a Cure. | Follow-up (Day 14 ± 1) |