Efficacy and Safety Study of Brilacidin to Treat Serious Skin Infections

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of three different dosing regimens of brilacidin compared to daptomycin for the treatment of serious skin infections. This study will aid in selecting the appropriate dose of brilacidin for later stage studies.

Detailed Description
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This is a randomized, multi-center, double-blind study to evaluate the efficacy and safety of three regimens of brilacidin compared to an active control, daptomycin, in subjects with ABSSSI. Subjects must have infections that warrant intravenous therapy but may be treated as either inpatients or outpatients. Eligible subjects will be randomized to one of 4 treatment groups in a 1:1:1:1 ratio. Subjects randomized to brilacidin will receive either a single intravenous infusion (0.6 mg/kg or 0.8 mg/kg) followed by six days of once daily placebo, or a three day regimen (0.6 mg/kg on Day 1 followed by 0.3 mg/kg on Days 2 and 3) followed by 4 days of once daily placebo. Subjects randomized to daptomycin will receive 7 days of treatment. Subjects will be assessed for both clinical and microbiologic efficacy 48-72 hours after the first dose of study drug. After an assessment at Day 7-8, subjects will be again be evaluated for efficacy at Day 10-14 and via a phone contact at Day 21-28. Approximately 200 subjects randomized in a 1:1:1:1 ratio to receive one of the three brilacidin regimens or daptomycin will be evaluable. The primary efficacy outcome, early clinical response 48-72 hours after the first dose of study drug, will be determined in the Intent-to treat (ITT) population. Additional efficacy and safety analyses will be performed.

Official Title
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A Randomized, Double-Blind Study Comparing Three Dosing Regimens of Brilacidin to Daptomycin in the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Conditions
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Skin Infection, Bacterial Infection

Intervention / Treatment
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* Drug: Daptomycin
* Drug: Brilacidin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent Be ≥ 18 and ≤ 85 years of age Have one of the following types of ABSSSI: A post-traumatic or post-surgical wound infection, occurring within 30 days of the trauma or surgery, characterized by purulent or seropurulent drainage from the wound and surrounding erythema, edema and/or induration of a minimum surface area of 75 cm2. A major cutaneous abscess, characterized by a collection of pus within the dermis or deeper tissues, accompanied by erythema, edema, and/or induration of a minimum surface area of 75 cm2. Note: patients with major cutaneous abscess will be limited to 30% of total enrollment Cellulitis/erysipelas, characterized by spreading areas of erythema, edema, and/or induration of a minimum surface area of 75 cm2. Have two or more of the following signs: Purulent or seropurulent drainage or discharge Erythema Fluctuance Heat or localized warmth Pain or tenderness to palpation Have one or more of the following systemic signs: Temperature (oral or tympanic) ≥ 38⁰ C/100.4 F, as measured by the subject/caregiver or investigator up to 24 hours prior to baseline WBC count > 10,000/mm3 Greater than 10% bands or other immature neutrophils (total), irrespective of WBC count Elevated C-reactive protein (CRP) (> 40 mg/L), if tested Presence of lymphadenitis or lymphadenopathy proximal to the infected area Must not have received more than a single dose of a short-acting systemic antibiotic for the current ABSSSI within 72 hours prior to randomization, unless either of the following situations apply: Clinical evidence of treatment failure following at least 48 hours of prior systemic antimicrobial therapy; or The subject recently completed a course of antibiotic treatment for an infection other than ABSSSI and that drug is not active against the bacterial pathogens that typically cause ABSSSI. Exclusion Criteria: Female subjects who are pregnant, lactating (breast milk feeding), or planning a pregnancy during the course of the study. Skin or skin structure infection with any of the following characteristics: Presence of an uncomplicated skin or skin structure infection, such as folliculitis, furunculosis, or minor abscess likely to respond to incision and drainage alone Suspected or confirmed osteomyelitis Suspected or confirmed septic arthritis Suspected or confirmed infection caused exclusively by Gram-negative pathogens or by any anaerobes Known hypersensitivity to daptomycin Known creatinine clearance <50 mL/min (based on the Cockcroft-Gault formula using ideal body weight) Immunosuppression, defined as chronic corticosteroid use (20 mg prednisone/day or equivalent), solid organ or bone marrow transplantation, current cytotoxic chemotherapy, neutropenia (absolute neutrophil count < 500/mm3), or known HIV infection with CD4+ count < 200/mm3 Platelet count <50 x 103/L Exhibits signs of sepsis: Shock or profound hypotension, defined as systolic blood pressure <90 mm Hg or a decrease of >40 mm Hg from baseline that is not responsive to fluid challenge; Hypothermia (core temperature <35.6°C or <96.1°F); Disseminated intravascular coagulation as evidenced by prothrombin time (PT) or activated partial thromboplastin time (aPTT) 2 times the upper limit of normal; Inability or unwillingness to adhere to the study-specified procedures and restrictions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Single Dose Brilacidin<br>0.6mg/kg Brilacidin IV (single dose) | Drug: Brilacidin<br>* Experimental Drug<br>* Other names: PMX63;|
| Experimental: High Single Dose Brilacidin<br>0.8mg/kg Brilacidin IV (single dose) | Drug: Brilacidin<br>* Experimental Drug<br>* Other names: PMX63;|
| Experimental: 3-Day Regimen Brilacidin<br>0.6mg/kg Brilacidin IV on Day 1, followed by 0.3mg/kg Brilacidin IV on Days 2 & 3 | Drug: Brilacidin<br>* Experimental Drug<br>* Other names: PMX63;|
| Active Comparator: Standard dosing regimen Daptomycin<br>4mg/kg Daptomycin IV daily for 7 Days | Drug: Daptomycin<br>* Active Comparator<br>* Other names: Cubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early clinical response | The primary efficacy outcome, early clinical response 48-72 hours after the first dose of study drug, will be determined in the ITT population. A subject will be considered a Clinical Success if 1) the lesion area has decreased by ≥20% compared to baseline and 2) no additional systemic antibacterials that are potentially effective against gram positive organisms have been administered. | 48-72 hours after first dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | For Days 7/8 and 10-14, a response of Clinical Success will be assigned if all signs and symptoms of infection present at baseline have improved and/or resolved and no additional antibiotics are considered necessary. Subjects who have a response of Clinical Success at Day 10-14 will be assessed for sustained efficacy at Day 21-28. A response of Sustained Clinical Success will be assigned if all signs and symptoms remain resolved and no additional antibiotics are considered necessary. If signs and symptoms of infection recurred at the original site of infection and require additional antibiotic therapy, a response of Relapse will be assigned. | Day 7-8; Day 10-14; Day 21-28 | 
| Microbiological response | Microbiological responses for those subjects who had a relevant skin pathogen isolated at baseline (MITT and ME populations) | 48-72 hours; Day 7-8; Day 10-14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skin Infection, Staph aureus, MRSA, MSSA, Cellulitis/Erysipelas, Wound Infection, Abscess