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.
Brief Title
Safety & Efficacy of True Human Antibody, 514G3, in Staphylococcus Aureus Bacteremia 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.
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.
Completion Date
Completion Date Type
Actual
Conditions
Staphylococcus Aureus Bacteremia
Eligibility Criteria
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.
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.
Inclusion Criteria
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.
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.
Gender
All
Gender Based
false
Keywords
Staphylococcus Aureus, Bacteremia, Hospitalization, Antibody
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02357966
Org Class
Industry
Org Full Name
XBiotech, Inc.
Org Study Id
2014-PT029
Overall Status
Completed
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
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
Primary Outcomes
Outcome Description
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.
Outcome Measure
Number of Participants Who Experienced Dose-limiting Toxicities
Outcome 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
Outcome Description
A summary of SAEs and other non-serious AEs, regardless of causality
Outcome Measure
Number of Participants Who Experienced the Adverse Events
Outcome Time Frame
Adverse events occurring between day 0 and day 30 or hospital discharge whichever is shorter
Secondary Outcomes
Outcome Description
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.
Outcome 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
Outcome Measure
Time to Clearance of Bacteremia (Time to Sterile Culture From Date of Randomization)
Outcome Description
Blood samples were collected from participants who received study drug 514G3 for the determination of plasma concentration (Cmax).
Outcome 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
Outcome Measure
Steady State Maximum Concentration of 514G3
Outcome Description
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.
Outcome 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
Outcome Measure
Length of Hospitalization (Duration of Hospitalization Stay After Randomization)
Outcome Description
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.
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.
Outcome Time Frame
14 days
Outcome Measure
Difference in Opsonophagocytosis Activity Between Arms (Pharmacodynamics)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Paul Riska
Investigator Email
priska@montefiore.org
Investigator Phone
718-020-6494