Safety & Efficacy of True Human Antibody, 514G3, in Staphylococcus Aureus Bacteremia Hospitalized Subjects.

XBiotech, Inc.52 enrolled

Overview

This study is a Phase I/II, double-blind, placebo-controlled trial investigating the True Human monoclonal antibody 514G3 in subjects hospitalized with Staphylococcus aureus bacteremia. Phase I involves dose escalation to evaluate potential toxicity and establish the recommended phase 2 dosage of 514G3. In Phase II (dose expansion), eligible subjects will be randomized at a ratio of 2:1 to receive either a single dose of 514G3 with standard IV antibiotic therapy or a single dose of placebo with standard IV antibiotic therapy, aiming to assess safety and tolerability. The trial aims to determine the safety, efficacy, and optimal dosage regimen of 514G3 in these hospitalized subjects.

The Phase I/II trial aims to assess the safety and efficacy of True Human monoclonal antibody 514G3 in hospitalized subjects with Staphylococcus aureus bacteremia. Phase I entails dose escalation, with subjects randomized (3:1) at three dose levels of the study drug (2 mg/kg, 10 mg/kg, and 40 mg/kg) and placebo, utilizing central randomization. Dose-limiting toxicities (DLTs), defined as Grade 3 or greater adverse events related to 514G3 during follow-up, guide escalation. The Maximum Tolerated Dose (MTD) is determined based on DLT occurrence. Phase II, focusing on preliminary efficacy, randomizes eligible subjects (2:1) to receive 514G3 or placebo with standard IV antibiotic therapy. Safety and efficacy assessments are conducted for both phases, encompassing pooled data from both the study drug and placebo groups.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. One or more blood cultures positive for staphylococcus aureus within 2 days of initiating treatment with 514G3. 2. Temperature ≥ 38.0°C 3. Age ≥18, male or female subjects. 4. Adequate renal function, defined by serum creatinine ≤ 2 times the upper limit of normal (ULN). 5. Adequate hepatic function 6. Adequate bone marrow function 7. For women of childbearing potential (WOCBP), a negative serum pregnancy test result at Screening. 8. Signed and dated institutional review board (IRB)/ Ethics Committee (EC)-approved informed consent before any protocol-specific screening procedures are performed. 9. Expected survival of at least 2 months. Exclusion Criteria: 1. Polymicrobial bacteremia. 2. Known or suspected osteomyelitis or meningitis. 3. 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. 4. 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. 5. Definite or possible left-sided endocarditis, by Modified Duke Criteria, based on screening echocardiogram. Subjects with suspected right-sided endocarditis are permitted. 6. Need for emergent valve surgery at the time of screening, and/or the presence of decompensated heart failure or cardiogenic shock. 7. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent. 8. Infection with human immunodeficiency virus (HIV) and a CD4 count \<200 cells/mm3. 9. Subjects with history of hypersensitivity to compounds of similar chemical or biologic composition to 514G3 or any component of its formulations. 10. Women who are pregnant or breastfeeding.

Outcomes

Primary Outcomes

Number of Participants Who Experienced Dose-limiting Toxicities

Dose limiting Toxicity are defined as any Grade 3 or greater AE which is probably or definitely related to 514G3 occurring during the FU period after dosing. This measure determines and assesses the maximum tolerated dose (MTD) through participants who experienced DLT at different dose levels.

Time frame: Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum

Number of Participants Who Experienced the Adverse Events

A summary of SAEs and other non-serious AEs, regardless of causality

Time frame: Adverse events occurring between day 0 and day 30 or hospital discharge whichever is shorter

Secondary Outcomes

Time to Clearance of Bacteremia (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.

Time frame: Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum

Steady State Maximum Concentration of 514G3

Blood samples were collected from participants who received study drug 514G3 for the determination of plasma concentration (Cmax).

Time frame: Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum

Length of Hospitalization (Duration of Hospitalization Stay After Randomization)

This outcome measure assesses the impact of the treatment on the time that participants spend in the hospital. The duration of hospitalization is expressed as the average number of days hospitalized for all participants in their respective cohorts.

Time frame: Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum

Difference in Opsonophagocytosis Activity Between Arms (Pharmacodynamics)

Serum samples from patients will be assessed with an in-vitro Opsonophagocytosis assay which measures the ability of the serum to mediate uptake of staphylococcus aureus by white blood cells. Differences in the levels of activity will be compared between treatment and placebo. This outcome measure assesses the dose-dependent functional antibody response to 514G3, providing insights into its potential efficacy across different dosage levels compared to placebo. Higher titers in the drug-treated groups indicate better opsonophagocytic activity and thus better efficacy of the drug. Opsonophagocytosis activity (OPA) score quantifies the functional antibody response to the investigational drug 514G3. For Phase II, this score is determined using an Opsonophagocytosis assay and is calculated as follows: Relative Opsonophagocytosis activity = %Phagocytosis 30 minutes after treatment adjusted by baseline / %Phagocytosis of 500 ug/mL spike standard.

Time frame: 14 days

Safety & Efficacy of True Human Antibody, 514G3, in Staphylococcus Aureus Bacteremia Hospitalized Subjects.

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes