Study of the Efficacy and Safety of MEDI4893

Study Overview
=================
Brief Summary
-----------------
Clinical trial looking at safety and efficacy of MEDI4893 in prevention of pneumonia caused by Staphylococcus aureus in high-risk patients

Official Title
-----------------
A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study of the Efficacy and Safety of MEDI4893, a Human Monoclonal Antibody Against Staphylococcus Aureus Alpha Toxin in Mechanically Ventilated Adult Subjects.

Conditions
-----------------
Staphylococcus Aureus Pneumonia

Intervention / Treatment
-----------------
* Drug: MEDI4893
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MEDI4893 5000 mg<br>Participants will receive a single intravenous (IV) dose of MEDI4893 5000 milligrams (mg) on Day 1 of the study. | Drug: MEDI4893<br>* Participants will receive a single IV dose of MEDI4893 2000 or 5000 mg on Day 1 of the study.<br>|
| Placebo Comparator: Placebo<br>Participants will receive a single IV dose of placebo matched to MEDI4893 on Day 1 of the study. | Other: Placebo<br>* Participants will receive a single IV dose of placebo matched to MEDI4893 on Day 1 of the study.<br>|
| Active Comparator: MEDI4893 2000 mg<br>Participants will receive a single IV dose of MEDI4893 2000 mg on Day 1 of the study. | Drug: MEDI4893<br>* Participants will receive a single IV dose of MEDI4893 2000 or 5000 mg on Day 1 of the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 1 through Day 31 | 
| 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. | Day 1 through Day 31 | 
| 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. | Day 1 through Day 91 | 
| 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. | Day 1 through Day 191 | 
| 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. | Day 1 through Day 191 | 
| 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. | Day 1 through Day 191 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of MEDI4893 | Maximum observed serum concentration (Cmax) of MEDI4893 is reported. | 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 | Area under the serum concentration time curve from time zero to last measurable concentration (AUC[0 - Last]) of MEDI4893 is reported. | 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 | 
| 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). | 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 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). | 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 | 
| 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. | Pre-dose on Day 1 (Baseline); and on Days 31, 61, and 91 |