Staphylococcus Aureus Bacteremia
Conditions
Keywords
Staphylococcus Aureus, Bacteremia, Hospitalization, Antibody
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.
Interventions
BIOLOGICAL514G3 (2 mg/kg) plus standard IV antibiotic treatment
BIOLOGICAL514G3 (10 mg/kg) plus standard IV antibiotic treatment
BIOLOGICAL514G3 (40 mg/kg) plus standard IV antibiotic treatment
OTHERPlacebo plus standard IV antibiotic treatment
Sterile isotonic formulation buffered at pH 6.2 - 6.5 plus standard IV antibiotic treatment
BIOLOGICAL514G3 (40 mg/kg) plus standard IV antibiotic treatment: Phase II
A single dose of 514G3 plus standard IV antibiotic therapy
OTHERPlacebo plus standard IV antibiotic treatment: Phase II
A single dose of placebo plus standard IV antibiotic therapy
Sponsors
XBiotech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
This is a Phase I/II, double blind placebo controlled trial of the True Human monoclonal antibody 514G3 in subjects hospitalized with Staphylococcus Aureus bacteremia. 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 of the study drug (514G3). Eligible subjects will be randomized (3:1) to receive single dose of 514G3 (Either 2, 10, 40 mg/kg) plus standard IV antibiotic therapy or single dose of placebo plus standard IV antibiotic therapy. A phase 2 of the trial is designed to assess the preliminary efficacy through randomization of subjects in two arm groups i.e. a single dose of 514G3 administered at the RP2D with standard IV treatment or placebo plus standard IV treatment. Eligible subjects will be randomized (2:1) to receive either a single dose of 514G3 plus standard IV antibiotic therapy versus a single dose of placebo plus standard IV antibiotic treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
STUDY_CHAIRMark Rupp, M.D.
University of Nebraska
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Treatment The participant received 514G3 (2 mg/kg) plus standard IV antibiotic treatment | 3 |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Treatment The participant received 514G3 (10 mg/kg) plus standard IV antibiotic treatment | 3 |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Treatment The participant received 514G3 (40 mg/kg) plus standard IV antibiotic treatment | 6 |
| Placebo Plus Standard IV Antibiotic Treatment The participant received placebo (sterile isotonic formulation buffered at pH 6.2 - 6.5) plus standard IV antibiotic treatment | 4 |
| Phase II: 514G3 (40 mg/kg) Plus Standard IV Antibiotic Treatment The participant received a single dose of 514G3 (40 mg/kg) plus standard IV antibiotic therapy | 24 |
| Phase II: Placebo Plus Standard IV Antibiotic Treatment The participant received a single dose of placebo plus standard IV antibiotic therapy. | 12 |
| Total | 52 |
Baseline characteristics
| Characteristic | 514G3 (2 mg/kg) Plus Standard IV Antibiotic Treatment | Total | Phase II: Placebo Plus Standard IV Antibiotic Treatment | Phase II: 514G3 (40 mg/kg) Plus Standard IV Antibiotic Treatment | Placebo Plus Standard IV Antibiotic Treatment | 514G3 (40 mg/kg) Plus Standard IV Antibiotic Treatment | 514G3 (10 mg/kg) Plus Standard IV Antibiotic Treatment |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 13 Participants | 2 Participants | 7 Participants | 1 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 39 Participants | 10 Participants | 17 Participants | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 13 Participants | 2 Participants | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 33 Participants | 9 Participants | 14 Participants | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 17 Participants | 3 Participants | 8 Participants | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 35 Participants | 9 Participants | 16 Participants | 3 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 4 | 0 / 24 | 0 / 12 |
| other Total, other adverse events | 2 / 3 | 3 / 3 | 5 / 6 | 4 / 4 | 19 / 24 | 9 / 12 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 1 / 6 | 2 / 4 | 6 / 24 | 5 / 12 |
Outcome results
Primary
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
Population: Participants in Phase 1 who received a single IV dose of 514G3 (2mg/kg, 10mg/kg, and 40mg/kg) is a sequential manner
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced Dose-limiting Toxicities | 0 participants |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced Dose-limiting Toxicities | 0 participants |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced Dose-limiting Toxicities | 0 participants |
| Placebo Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced Dose-limiting Toxicities | 0 participants |
Primary
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
Population: This measure assesses all adverse events from all randomized participants who received at least 1 dose of study drug according to the assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Serious adverse events | 1 participants |
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Non-serious adverse events | 2 participants |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Serious adverse events | 1 participants |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Non-serious adverse events | 3 participants |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Serious adverse events | 1 participants |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Non-serious adverse events | 6 participants |
| Placebo Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Non-serious adverse events | 4 participants |
| Placebo Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Serious adverse events | 2 participants |
| Phase II: 40 mg/kg Study Drug (514G3) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Non-serious adverse events | 23 participants |
| Phase II: 40 mg/kg Study Drug (514G3) Plus Standard IV Antibiotic Therapy | Number of Participants Who Experienced the Adverse Events | Serious adverse events | 5 participants |
| Phase II: Placebo Plus Standard Intravenous Therapy | Number of Participants Who Experienced the Adverse Events | Serious adverse events | 5 participants |
| Phase II: Placebo Plus Standard Intravenous Therapy | Number of Participants Who Experienced the Adverse Events | Non-serious adverse events | 9 participants |
Secondary
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
Population: Safety population is all randomized participants who received at least one dose of the study treatment and provided valid Opsonophagocytosis assay (OPA) results'. Intent-to-treat (ITT) population is same as the safety population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Difference in Opsonophagocytosis Activity Between Arms (Pharmacodynamics) | 129.7 percentage of phagocytosis activity | Standard Deviation 33.1 |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Difference in Opsonophagocytosis Activity Between Arms (Pharmacodynamics) | 1.1 percentage of phagocytosis activity | Standard Deviation 2.5 |
Secondary
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
Population: The analysis population for this study will include all eligible subjects who have been randomized and received at least one dose of the study drug or placebo in both phases of the protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Length of Hospitalization (Duration of Hospitalization Stay After Randomization) | 23.67 Days | Standard Deviation 21.36 |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Length of Hospitalization (Duration of Hospitalization Stay After Randomization) | 11.33 Days | Standard Deviation 3.06 |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Therapy | Length of Hospitalization (Duration of Hospitalization Stay After Randomization) | 11.67 Days | Standard Deviation 4.18 |
| Placebo Plus Standard IV Antibiotic Therapy | Length of Hospitalization (Duration of Hospitalization Stay After Randomization) | 20 Days | Standard Deviation 6.98 |
| Phase II: 40 mg/kg Study Drug (514G3) Plus Standard IV Antibiotic Therapy | Length of Hospitalization (Duration of Hospitalization Stay After Randomization) | 13.71 Days | Standard Deviation 9.07 |
| Phase II: Placebo Plus Standard Intravenous Therapy | Length of Hospitalization (Duration of Hospitalization Stay After Randomization) | 17 Days | Standard Deviation 11.09 |
Secondary
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
Population: The PK-evaluable population included participants in the treatment arm who received 514G3 who had no major protocol violations and had documented adherence to the dosing and PK regimens. Data was not collected from subjects assigned to the placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Steady State Maximum Concentration of 514G3 | 37.5 microgram/millilitre | Standard Deviation 22.4 |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Steady State Maximum Concentration of 514G3 | 198.0 microgram/millilitre | Standard Deviation 88.9 |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Therapy | Steady State Maximum Concentration of 514G3 | 684.7 microgram/millilitre | Standard Deviation 143.1 |
| Placebo Plus Standard IV Antibiotic Therapy | Steady State Maximum Concentration of 514G3 | 740.0 microgram/millilitre | Standard Deviation 202.4 |
Secondary
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
Population: All participants who had ≥1 positive blood cultures for staphylococcus Aureus within 2 days of randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 514G3 (2 mg/kg) Plus Standard IV Antibiotic Therapy | Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization) | 1.67 Days | Standard Deviation 0.58 |
| 514G3 (10 mg/kg) Plus Standard IV Antibiotic Therapy | Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization) | 3.67 Days | Standard Deviation 1.53 |
| 514G3 (40 mg/kg) Plus Standard IV Antibiotic Therapy | Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization) | 2.0 Days | Standard Deviation 0.89 |
| Placebo Plus Standard IV Antibiotic Therapy | Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization) | 3.5 Days | Standard Deviation 1.91 |
| Phase II: 40 mg/kg Study Drug (514G3) Plus Standard IV Antibiotic Therapy | Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization) | 2.54 Days | Standard Deviation 2.28 |
| Phase II: Placebo Plus Standard Intravenous Therapy | Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization) | 2.33 Days | Standard Deviation 1.5 |