A Study of the Safety and Efficacy of 514G3 in Subjects Hospitalized With Bacteremia Due to Staphylococcus Aureus

Study Overview
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Brief Summary
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This study will evaluate the maximum safe dose of the true human monoclonal antibody, 514G3, in the treatment of patients with Staphylococcus Aureus bacteremia. Preliminary evidence of efficacy will be evaluated as well. Patients will receive 514G3 plus antibiotics or placebo plus antibiotics in approximately a 3 to 1 ratio.

Official Title
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A Phase I-II Study of the Safety and Efficacy of a True Human Antibody, 514G3, in Subjects Hospitalized With Bacteremia Due to Staphylococcus Aureus

Conditions
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Staphylococcus Aureus Bacteremia

Intervention / Treatment
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* Biological: 514G3
* Drug: Placebo
* Drug: Standard IV antibiotic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: One or more blood cultures positive for staphylococcus aureus within 2 days of initiating treatment with 514G3. Temperature ≥ 38.0°C Age ≥18, male or female subjects. Adequate renal function, defined by serum creatinine ≤ 2 times the upper limit of normal (ULN). Adequate hepatic function Adequate bone marrow function For women of childbearing potential (WOCBP), a negative serum pregnancy test result at Screening. Signed and dated institutional review board (IRB)/ Ethics Committee (EC)-approved informed consent before any protocol-specific screening procedures are performed. Expected survival of at least 2 months. Exclusion Criteria: Polymicrobial bacteremia. Known or suspected osteomyelitis or meningitis. Patients that are being mechanically ventilated as a result of a pulmonary infection at the time of screening. Mechanical ventilation for other reasons, such as trauma, is acceptable. Presence of any removable infection source (e.g., intravascular line, abscess, or prosthesis) that will not be removed or debrided within 3 days after randomization. Definite or possible left-sided endocarditis, by Modified Duke Criteria, based on screening echocardiogram. Subjects with suspected right-sided endocarditis are permitted. Need for emergent valve surgery at the time of screening, and/or the presence of decompensated heart failure or cardiogenic shock. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent. Infection with human immunodeficiency virus (HIV) and a CD4 count <200 cells/mm3. Subjects with history of hypersensitivity to compounds of similar chemical or biologic composition to 514G3 or any component of its formulations. Women who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 514G3<br>Phase I of the study will include a single dose of 514G3 at three different dose levels. Phase II utilizes a single dose of 514G3 at the highest dose level. Standard antibiotic therapies will be used in both phases. | Biological: 514G3<br>* True Human Monoclonal Antibody<br>Drug: Standard IV antibiotic therapy<br>* standard antibiotic therapy will be determined by the attending physician and will be guided by the results of cultures with sensitivities.<br>|
| Placebo Comparator: Placebo<br>Both Phase I and II will include a single dose of placebo in addition to standard antibiotic therapies. | Drug: Placebo<br>* Buffered saline solution<br>Drug: Standard IV antibiotic therapy<br>* standard antibiotic therapy will be determined by the attending physician and will be guided by the results of cultures with sensitivities.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Determination of the Maximum Tolerated Dose | The highest dose administered with no more than one dose limiting toxicity | 14 Days | 
| Phase II: Safety and tolerability | The incidence of adverse events, serious adverse events, and laboratory abnormalities will be compared between the 514G3 arm and the placebo arm. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the serum half-life of 514G3 | Serum levels of 514G3 will be measured at protocol specified timepoints to determine the half-life, and to ensure clearance of the antibody during the follow up period after dosing. | 28 days | 
| Duration of Fever |  | 28 days | 
| Length of hospitalization |  | 28 days | 
| Time to sterile culture from date of randomization | The time to sterile culture is the interval in days from the first dose of study drug until 2 consecutive days of negative blood cultures has occurred. The difference in this interval will be compared between patients randomized to placebo and those who received the highest dose of 514G3 | 28 Days | 
| Incidence of Serious Adverse Events | Differences in the incidence of SAEs between the 514G3 and placebo arms will be compared. | 28 days | 
| Opsonophagocytosis Assay | Serum samples from patients will be assessed with an in vitro opsonophagocytosis assay which measures the ability of the serum to mediate uptake of staph aureus by white blood cells. Differences in the levels of activity will be compared between treatment and placebo | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibody, Staph