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

Phase 1

Completed

• Conditions: Staphylococcus Aureus Bacteremia
• Interventions: Biological: 514G3 (2 mg/kg) plus standard IV antibiotic treatment; Biological: 514G3 (10 mg/kg) plus standard IV antibiotic treatment; Biological: 514G3 (40 mg/kg) plus standard IV antibiotic treatment; Other: Placebo plus standard IV antibiotic treatment

• Registration Number: NCT02357966
• Lead Sponsor: XBiotech, Inc.

Brief Summary

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.

Detailed Description

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 Timeline

• Study First Submitted: 2015-01-29
• Study First Submitted QC: 2015-02-02
• Study First Posted: 2015-02-06
• Study Start: 2015-05
• Primary Completion: 2016-12
• Study Completion: 2016-12
• Results First Submitted: 2024-01-24
• Status Verified: 2024-10
• Results First Submitted QC: 2024-10-30
• Last Update Submitted: 2024-10-30
• Results First Posted: 2024-11-21
• Last Update Posted: 2024-11-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 52

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase I	514G3 (10 mg/kg) plus standard IV antibiotic treatment	A phase I of the trial is a dose escalation study intended to assess the possible toxicity and to determine the recommended phase 2 dose (RP2D) of the study drug (514G3). Randomized subjects were administered the study drug at 3 dose levels i.e. 2 mg/kg, 10 mg/kg, and 40 mg/kg or placebo.
Phase I	514G3 (2 mg/kg) plus standard IV antibiotic treatment	A phase I of the trial is a dose escalation study intended to assess the possible toxicity and to determine the recommended phase 2 dose (RP2D) of the study drug (514G3). Randomized subjects were administered the study drug at 3 dose levels i.e. 2 mg/kg, 10 mg/kg, and 40 mg/kg or placebo.
Phase I	514G3 (40 mg/kg) plus standard IV antibiotic treatment	A phase I of the trial is a dose escalation study intended to assess the possible toxicity and to determine the recommended phase 2 dose (RP2D) of the study drug (514G3). Randomized subjects were administered the study drug at 3 dose levels i.e. 2 mg/kg, 10 mg/kg, and 40 mg/kg or placebo.
Phase I	Placebo plus standard IV antibiotic treatment	A phase I of the trial is a dose escalation study intended to assess the possible toxicity and to determine the recommended phase 2 dose (RP2D) of the study drug (514G3). Randomized subjects were administered the study drug at 3 dose levels i.e. 2 mg/kg, 10 mg/kg, and 40 mg/kg or placebo.
Phase II	514G3 (40 mg/kg) plus standard IV antibiotic treatment	A phase 2 of the trial is a dose expansion study designed to assess the preliminary efficacy. Eligible subjects are randomized (2:1) and received a single dose of 40 mg/kg study drug (514G3) with standard IV treatment versus placebo with standard IV treatment.
Phase II	Placebo plus standard IV antibiotic treatment	A phase 2 of the trial is a dose expansion study designed to assess the preliminary efficacy. Eligible subjects are randomized (2:1) and received a single dose of 40 mg/kg study drug (514G3) with standard IV treatment versus placebo with standard IV treatment.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose-limiting Toxicities	Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum	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.
Number of Participants Who Experienced the Adverse Events	Adverse events occurring between day 0 and day 30 or hospital discharge whichever is shorter	A summary of SAEs and other non-serious AEs, regardless of causality

Secondary Outcome Measures

Name	Time	Method
Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization)	Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum	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.
Steady State Maximum Concentration of 514G3	Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum	Blood samples were collected from participants who received study drug 514G3 for the determination of plasma concentration (Cmax).
Length of Hospitalization (Duration of Hospitalization Stay After Randomization)	Pre-dose at Day 0 through Day 14. After day 14, samples are collected every other day including discharge, up to 30 days maximum	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.
Difference in Opsonophagocytosis Activity Between Arms (Pharmacodynamics)	14 days	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.

Trial Locations

Locations (1)

XBiotech Investigative Site; 🇺🇸 Charlotte, North Carolina, United States