Staphylococcus Aureus Pneumonia
Conditions
Brief summary
Clinical trial looking at safety and efficacy of MEDI4893 in prevention of pneumonia caused by Staphylococcus aureus in high-risk patients
Interventions
DRUGMEDI4893
Participants will receive a single IV dose of MEDI4893 2000 or 5000 mg on Day 1 of the study.
OTHERPlacebo
Participants will receive a single IV dose of placebo matched to MEDI4893 on Day 1 of the study.
Sponsors
Innovative Medicines Initiative
Antibacterial Resistance Leadership Group
National Institute of Allergy and Infectious Diseases (NIAID)
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Colonized with Staphylococcus aureus, expected to require prolonged intubation and mechanical ventilation, without any evidence of active pneumonia.
Exclusion criteria
* Staphylococcal disease at randomisation; lung injury score consistent with pneumonia; current lung disease; chronic tracheostomy patients; currently receiving systemic anti-staphylococcal antibiotics; moribund patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With New Onset Chronic Diseases (NOCDs) | Day 1 through Day 191 | An NOCD defined as a newly diagnosed medical condition that is of a chronic, ongoing nature. It is observed after receiving the study drug and is assessed by the investigator as medically significant. |
| Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus Aureus (S Aureus) Pneumonia | Day 1 through Day 31 | The EAC S aureus pneumonia was based on clinical, radiographic, and microbiologic criteria. Clinical criteria: 1 major criteria (PaO2/FiO2 ratio \< 240 mmHg maintained for at least 4 hours or decrease in PaO2/FiO2 by \>= 50 mmHg maintained for at least 4 hrs or a need to initiate non-invasive mechanical ventilation or re-initiate invasive mechanical ventilation because of respiratory failure or worsening of respiratory status); and at least 2 of minor criteria (systemic signs of infection, production of purulent sputum/endotracheal secretions, new onset of cough, physical examination findings consistent with pneumonia/pulmonary consolidation, dyspnea, and/or tachypnea). Radiographic criteria: new or worsening infiltrate consistent with pneumonia on chest X-ray obtained within 24 hrs of event. Microbiologic criteria: at least 1 culture positive for S aureus (respiratory specimen, or blood, or pleural fluid aspirate or lung tissue culture during episode of pneumonia). |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days | Day 1 through Day 31 | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. |
| Number of Participants With TEAEs Through 91 Days | Day 1 through Day 91 | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. |
| Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) | Day 1 through Day 191 | A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. |
| Number of Participants With Adverse Events of Special Interest (AESIs) | Day 1 through Day 191 | An AESI is one of scientific and medical interest specific to understanding of the study drug and may have required close monitoring and rapid communication by the investigator to the sponsor. An AESI may have been serious or non-serious. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0-Last]) of MEDI4893 | Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 91 | Area under the serum concentration time curve from time zero to last measurable concentration (AUC\[0 - Last\]) of MEDI4893 is reported. |
| Observed Serum Concentration of MEDI4893 Through 30 Days Post Dose (C30) | Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, and 30 | Observed serum concentration of MEDI4893 through 30 days post dose (C30) is reported. Serum concentration of MEDI4893 through 30 days post dose accounted the overall concentration of MEDI4893 measured on specified time points (Days 1, 4, 8, 15, 22, and 30). |
| Observed Serum Concentration of MEDI4893 Through 90 Days Post Dose (C90) | Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 90 | Observed serum concentration of MEDI4893 through 90 days post dose (C90) is reported. Serum concentration of MEDI4893 through 90 days post dose accounted the overall concentration of MEDI4893 measured on specified time points (Days 1, 4, 8, 15, 22, 31, 61, and 91). |
| Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Pre-dose on Day 1 (Baseline); and on Days 31, 61, and 91 | Participants with ADA-positive at any of Day 31, Day 61, or Day 91 post-baseline assessments were always counted as positive at post-baseline. |
| Maximum Observed Serum Concentration (Cmax) of MEDI4893 | Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 91 | Maximum observed serum concentration (Cmax) of MEDI4893 is reported. |
Countries
Belgium, Czechia, France, Germany, Greece, Hungary, Portugal, Spain, Switzerland, United States
Participant flow
Recruitment details
The study was conducted between 10Oct2014 and 02Oct2018.
Pre-assignment details
A total of 767 participants consented to participate in the study, of which 554 were screen failures. A total of 213 participants were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received a single IV dose of placebo matched to MEDI4893 on Day 1 of the study. | 100 |
| MEDI4893 2000 mg Participants received a single IV dose of MEDI4893 2000 mg on Day 1 of the study. | 15 |
| MEDI4893 5000 mg Participants received a single IV dose of MEDI4893 5000 mg on Day 1 of the study. | 96 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 24 | 3 | 27 |
| Overall Study | Lost to Follow-up | 5 | 2 | 7 |
| Overall Study | Not - specified | 0 | 0 | 1 |
| Overall Study | Not treated | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | MEDI4893 2000 mg | MEDI4893 5000 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 55.7 Years STANDARD_DEVIATION 16.6 | 52.5 Years STANDARD_DEVIATION 14.6 | 57.7 Years STANDARD_DEVIATION 15.7 | 56.4 Years STANDARD_DEVIATION 16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants | 15 Participants | 92 Participants | 203 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 97 Participants | 13 Participants | 94 Participants | 204 Participants |
| Sex: Female, Male Female | 45 Participants | 5 Participants | 37 Participants | 87 Participants |
| Sex: Female, Male Male | 55 Participants | 10 Participants | 59 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 24 / 100 | 3 / 15 | 27 / 96 |
| other Total, other adverse events | 90 / 100 | 15 / 15 | 85 / 96 |
| serious Total, serious adverse events | 40 / 100 | 7 / 15 | 50 / 96 |
Outcome results
Primary
Number of Participants With Adverse Events of Special Interest (AESIs)
An AESI is one of scientific and medical interest specific to understanding of the study drug and may have required close monitoring and rapid communication by the investigator to the sponsor. An AESI may have been serious or non-serious.
Time frame: Day 1 through Day 191
Population: As-treated population included all participants, who received any dose of study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | 0 Participants |
| MEDI4893 2000 mg | Number of Participants With Adverse Events of Special Interest (AESIs) | 4 Participants |
| MEDI4893 5000 mg | Number of Participants With Adverse Events of Special Interest (AESIs) | 3 Participants |
Primary
Number of Participants With New Onset Chronic Diseases (NOCDs)
An NOCD defined as a newly diagnosed medical condition that is of a chronic, ongoing nature. It is observed after receiving the study drug and is assessed by the investigator as medically significant.
Time frame: Day 1 through Day 191
Population: As-treated population included all participants, who received any dose of study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With New Onset Chronic Diseases (NOCDs) | 2 Participants |
| MEDI4893 2000 mg | Number of Participants With New Onset Chronic Diseases (NOCDs) | 0 Participants |
| MEDI4893 5000 mg | Number of Participants With New Onset Chronic Diseases (NOCDs) | 3 Participants |
Primary
Number of Participants With TEAEs Through 91 Days
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time frame: Day 1 through Day 91
Population: As-treated population included all participants, who received any dose of study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With TEAEs Through 91 Days | 92 Participants |
| MEDI4893 2000 mg | Number of Participants With TEAEs Through 91 Days | 15 Participants |
| MEDI4893 5000 mg | Number of Participants With TEAEs Through 91 Days | 89 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time frame: Day 1 through Day 31
Population: As-treated population included all participants, who received any dose of study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days | 90 Participants |
| MEDI4893 2000 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days | 15 Participants |
| MEDI4893 5000 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days | 87 Participants |
Primary
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs)
A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time frame: Day 1 through Day 191
Population: As-treated population included all participants, who received any dose of study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) | 40 Participants |
| MEDI4893 2000 mg | Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) | 7 Participants |
| MEDI4893 5000 mg | Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) | 50 Participants |
Primary
Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus Aureus (S Aureus) Pneumonia
The EAC S aureus pneumonia was based on clinical, radiographic, and microbiologic criteria. Clinical criteria: 1 major criteria (PaO2/FiO2 ratio \< 240 mmHg maintained for at least 4 hours or decrease in PaO2/FiO2 by \>= 50 mmHg maintained for at least 4 hrs or a need to initiate non-invasive mechanical ventilation or re-initiate invasive mechanical ventilation because of respiratory failure or worsening of respiratory status); and at least 2 of minor criteria (systemic signs of infection, production of purulent sputum/endotracheal secretions, new onset of cough, physical examination findings consistent with pneumonia/pulmonary consolidation, dyspnea, and/or tachypnea). Radiographic criteria: new or worsening infiltrate consistent with pneumonia on chest X-ray obtained within 24 hrs of event. Microbiologic criteria: at least 1 culture positive for S aureus (respiratory specimen, or blood, or pleural fluid aspirate or lung tissue culture during episode of pneumonia).
Time frame: Day 1 through Day 31
Population: An mITT population included all participants, who received any dose of study drug and analyzed according to their randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus Aureus (S Aureus) Pneumonia | 26.0 Percentage of Participants |
| MEDI4893 2000 mg | Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus Aureus (S Aureus) Pneumonia | 20.0 Percentage of Participants |
| MEDI4893 5000 mg | Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus Aureus (S Aureus) Pneumonia | 17.7 Percentage of Participants |
Comparison: The key efficacy analyses were based on 5000 mg MEDI4893 and placebo. Participants who received 2000 mg MEDI4893 were summarized descriptively.p-value: 0.16690% CI: [-7.5, 56.8]Poisson regression with robust variance
Secondary
Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0-Last]) of MEDI4893
Area under the serum concentration time curve from time zero to last measurable concentration (AUC\[0 - Last\]) of MEDI4893 is reported.
Time frame: Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 91
Population: An ITT population included all randomized participants and were analyzed according to their randomized treatment group. Participants who had quantifiable PK samples were analyzed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0-Last]) of MEDI4893 | 9045.5 day*μg/mL | Standard Deviation 5383.1 |
| MEDI4893 2000 mg | Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0-Last]) of MEDI4893 | 20127.5 day*μg/mL | Standard Deviation 12852.2 |
Secondary
Maximum Observed Serum Concentration (Cmax) of MEDI4893
Maximum observed serum concentration (Cmax) of MEDI4893 is reported.
Time frame: Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 91
Population: An Intent-to-treat (ITT) population included all randomized participants and were analyzed according to their randomized treatment group. Participants who had quantifiable pharmacokinetic (PK) samples were analyzed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Observed Serum Concentration (Cmax) of MEDI4893 | 471.9 μg/mL | Standard Deviation 123 |
| MEDI4893 2000 mg | Maximum Observed Serum Concentration (Cmax) of MEDI4893 | 1143.7 μg/mL | Standard Deviation 375.6 |
Secondary
Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893
Participants with ADA-positive at any of Day 31, Day 61, or Day 91 post-baseline assessments were always counted as positive at post-baseline.
Time frame: Pre-dose on Day 1 (Baseline); and on Days 31, 61, and 91
Population: As-treated population included all participants, who received any dose of study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline | 3 Participants |
| Placebo | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive post-baseline | 5 Participants |
| Placebo | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Not detected at baseline; positive post-baseline | 3 Participants |
| Placebo | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline; not detected post-baseline | 0 Participants |
| Placebo | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline and post-baseline | 2 Participants |
| MEDI4893 2000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline and post-baseline | 0 Participants |
| MEDI4893 2000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline | 0 Participants |
| MEDI4893 2000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline; not detected post-baseline | 0 Participants |
| MEDI4893 2000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Not detected at baseline; positive post-baseline | 0 Participants |
| MEDI4893 2000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive post-baseline | 0 Participants |
| MEDI4893 5000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Not detected at baseline; positive post-baseline | 0 Participants |
| MEDI4893 5000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline and post-baseline | 0 Participants |
| MEDI4893 5000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive post-baseline | 0 Participants |
| MEDI4893 5000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline | 2 Participants |
| MEDI4893 5000 mg | Number of Participants With Positive Anti-Drug Antibodies (ADA) Titer to MEDI4893 | Positive at baseline; not detected post-baseline | 1 Participants |
Secondary
Observed Serum Concentration of MEDI4893 Through 30 Days Post Dose (C30)
Observed serum concentration of MEDI4893 through 30 days post dose (C30) is reported. Serum concentration of MEDI4893 through 30 days post dose accounted the overall concentration of MEDI4893 measured on specified time points (Days 1, 4, 8, 15, 22, and 30).
Time frame: Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, and 30
Population: An ITT population included all randomized participants and were analyzed according to their randomized treatment group. Participants who had quantifiable PK samples were analyzed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Observed Serum Concentration of MEDI4893 Through 30 Days Post Dose (C30) | 122.0 μg/mL | Standard Deviation 65 |
| MEDI4893 2000 mg | Observed Serum Concentration of MEDI4893 Through 30 Days Post Dose (C30) | 295.9 μg/mL | Standard Deviation 130.6 |
Secondary
Observed Serum Concentration of MEDI4893 Through 90 Days Post Dose (C90)
Observed serum concentration of MEDI4893 through 90 days post dose (C90) is reported. Serum concentration of MEDI4893 through 90 days post dose accounted the overall concentration of MEDI4893 measured on specified time points (Days 1, 4, 8, 15, 22, 31, 61, and 91).
Time frame: Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 90
Population: An ITT population included all randomized participants and were analyzed according to their randomized treatment group. Participants who had quantifiable PK samples were analyzed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Observed Serum Concentration of MEDI4893 Through 90 Days Post Dose (C90) | 71.5 μg/mL | Standard Deviation 35.5 |
| MEDI4893 2000 mg | Observed Serum Concentration of MEDI4893 Through 90 Days Post Dose (C90) | 192.0 μg/mL | Standard Deviation 84 |