Adjunctive Therapy to Antibiotics in the Treatment of S. Aureus Ventilator-Associated Pneumonia With AR-301

Study Overview
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Brief Summary
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AR-301 is being evaluated as an adjunctive treatment of ventilator-associated pneumonia (VAP) due to Staphylococcus aureus (S. aureus) in combination with standard of care (SOC) antibiotic therapy in patients with confirmed S. aureus infection.

Detailed Description
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This study is an international, multicenter, prospective, randomized, double blind, placebo controlled, parallel design protocol in patients with Ventilator-Associated Pneumonia (VAP) caused by S. aureus. Patients with a documented diagnosis of pneumonia due to S. aureus, and require ICU care, who have been intubated (or have a tracheostomy tube in place) and mechanically ventilated for at least 48 hours are eligible for screening. In total, approximately 240 subjects will be randomized 1-1 to be treated with placebo plus standard of care (SOC) or AR-301 (20 mg/kg) plus SOC in this Phase 3 study. Study subjects will receive a single dose at Day 0 in addition to SOC antibiotic treatment, and then enter a safety, efficacy and PK study period for a total study duration of 28 days. The selection of SOC antibiotics is made in accordance with local best practices at the discretion of the investigator.

Official Title
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A Randomized Double-blind Placebo-controlled Multicenter Phase 3 Study of Efficacy and Safety of AR-301 as Adjunct Therapy to Antibiotics in the Treatment of Ventilator-Associated Pneumonia (VAP) Caused by S. Aureus

Conditions
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Lung Infection, Pneumonia, Ventilator-Associated, Infection, Bacterial, Staphylococcus Aureus

Intervention / Treatment
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* Drug: AR-301
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written Informed Consent given by the patient or, if not possible, by a legally acceptable representative and/or an independent physician as authorized by the competent ethics committee (EC) or independent review board (IRB) and local regulations. To be at least 18 years of age. Taiwan only: To be at least 20 years of age. South Korea only: To be at least 19 years of age. Treated in an ICU at the time of enrollment. Endotracheal tube in place (tracheostomy is allowed). The patient is mechanically ventilated for at least 48 hours. Diagnosis of pneumonia based on the following criteria (a, b, and c, all must be met): One definitive chest X-ray diagnostic of pneumonia within 48 hours, Hypoxemia based on PaO2/FiO2. At least one of the following signs: i. Documented fever (e.g., body temperature greater than or equal to 38º Celsius). ii. Hypothermia (e.g., core body temperature less than or equal to 35º Celsius). iii. Total peripheral white blood cell (WBC) count greater than or equal to 10,000 cells/µL (or mm3). iv. Leukopenia with total WBC less than or equal to 4,500 cells/µL (mm3). v. Greater than 15 percent immature neutrophils (bands) noted on peripheral blood smear. Documented pulmonary infection with Staphylococcus aureus obtained by bronchoalveolar lavage (BAL), mini-BAL, protected endotracheal aspiration/aspirate (ETA) (collectively 'airway specimen'). Exclusion Criteria The subject is unlikely to survive for the study duration despite delivery of adequate antibiotics and supportive care for treatment of S. aureus pneumonia. Effective antibacterial drug therapy for the index pneumonia administered continuously for 48 hours or more prior to initiation of study treatment. Effective antibiotics would include those typically used to treat S. aureus. Plasmapheresis (ongoing or planned), extracorporeal membrane oxygenation (ECMO) or any procedure that would remove/filter out the monoclonal antibody/study drug. Immunocompromised patients. Known hereditary complement deficiency. Liver dysfunction with a Child Pugh C score > 9 (Child Pugh score of A or B are acceptable at discretion of the Principal Investigator [PI]). Pulmonary disease that precludes evaluation of a therapeutic response (such as lung cancer resulting in bronchial obstruction or on the same side as the pneumonia, active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary infection, lung abscess, pleural empyema or post obstructive pneumonia). Patient has received intravenous (IV) immunoglobulin therapy within 3 months prior to the Screening Visit. Any woman of child-bearing potential (WOCBP) who does not have a negative pregnancy test result at Screening using SERUM or URINE testing based on Beta-subunit human chorionic gonadotropin (HCG) standard tests and methods from the local laboratory. Any sexually active subject who is unwilling to use acceptable methods of contraception for 120 days after dosing. Known lack of treatment compliance from prior studies or ongoing medical care based on medical records and PI's judgment and/or the capacity of the patient to comply with all study requirements. Any medical, psychological, cognitive, social or legal conditions that would interfere in the ability to give an Informed Consent OR the absence of a legally valid representative of the patient or independent physician allowed and able to give consent on his/her behalf. Participation as a subject in another interventional study within 30 days prior to the first dose of study treatment, or planned participation in such a study during the study or within 30 days of its completion by the patient.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment<br>Investigational/ Interventional Product group: AR-301 (tosatoxumab) 20 mg/kg administered once intravenously on the day of randomization. | Drug: AR-301<br>* AR-301 (tosatoxumab) 20 mg/kg administered once intravenously the day of enrolment.<br>* Other names: AR-301 (tosatoxumab);|
| Placebo Comparator: Placebo treatment<br>Control group: Placebo administered intravenously on the day of randomization. | Other: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A comparison of Clinical Cure Rates of standard of care (SOC) alone and SOC with AR-301 | Clinical cure rates of standard of care (SOC) alone and (SOC) with AR-301 at Day 21 as measured by all-cause mortality, need for mechanical ventilation and signs and symptoms of pneumonia. | 21 days | 
| Safety of AR-301 by treatment-emergent adverse events assessed by changes between treatment and placebo as assessed by the Principal Investigator | Safety of AR-301 of treatment-emergent adverse events as assessed by changes assessed by the PI between treatment and placebo | 21 Days | 
| Tolerability of AR-301 measured by the number of participants with treatment-emergent adverse events classified using CTCAE v 5.0 | Tolerability of AR-301 will be measured and evaluated by the severity of treatment-emergent adverse events using the CTCAE v 5.0. | 21 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference in clinical cure rates between Standard of Care alone or with AR301 as time to clinical cure at Day 7, 14 and 28 | Difference in Clinical Cure rates between SOC alone or with AR-301 defined by time to clinical cure (number of days) using the same criteria as for the primary efficacy objective at Day 21. | Day 7, 14, and 28 | 
| The difference in mortality between Standard of Care alone or with AR-301 at Days 7,14,28 | Difference in mortality defined as cause of death (all-cause mortality and pneumonia-related mortality)between SOC alone or with AR-301 at Days 7,14, and 28 | Day 7, 14, and 28 | 
| The difference in PaO2/FiO2 between Standard of Care alone or with AR-301 at Days 7,14,28 | Difference in respiratory function between SOC alone or with AR-301 at Days 7,14, and 28 as changes in PaO2/FiO2 ratio (e.g. by arterial blood gases), if available and whenever possible OR changes in non-invasive measures of oxygenation (e.g. by pulse oximetry) | Day 7, 14, and 28 | 
| The difference in time on supplemental oxygen assessment between Standard of Care alone or with AR-301 at Days 7,14,28 | Difference in respiratory function between SOC alone or with AR-301 at Days 7,14, and 28 as time on supplemental oxygen | Day 7, 14, and 28 | 
| Changes in baseline in SOFA score between Standard of Care alone or with AR301 at Days 7,14,28 | Difference in Clinical Cure rates between SOC alone or with AR-301 at Days 7,14, and 28 in the following clinical outcomes: Changes from Baseline in sequential organ failure assessment (SOFA) score using the following scale: Maximum SOFA score 0-6, <10% Mortality, 7-9 15-20% mortality, 10-12 40-50% mortality, 13-14 50-60% mortality, 15 >80% mortality, 15-24 >90% mortality. Lower numbers are considered to be better outcome of mortality and higher scores worse outcome of mortality. | Day 7, 14, and 28 | 
| Duration of intubation with ventilation | Number of days with intubation with ventilation | 28 days | 
| Duration mechanical ventilation if tracheostomy in place | Number of days of intubation with mechanical ventilation if tracheostomy in place | 28 days | 
| Duration of stay in ICU | Number of days of stay in ICU | 28 days | 
| Duration hospitalization | Number of days of hospitalization | 28 days | 
| Duration antibiotic use. | Number of days on antibiotics | 28 days | 
| Pharmacokinetic Analysis - (Cmax) | Pharmacokinetic analysis measuring Maximum Serum Concentration (Cmax) | 28 days | 
| Pharmacokinetic Analysis - (AUC) | Pharmacokinetic analysis measuring Area Under the Curve (AUC) | 28 Days | 
| Pharmacokinetic Analysis - (T1/2) | Pharmacokinetic analysis measuring time for half of the initial dose of study drug to be eliminated from the body (T1/2) | 28 Days | 
| Pharmacokinetic Analysis - (Tmax) | Pharmacokinetic analysis measuring time at which Cmax is obtained (Tmax) | 28 Days | 
| Pharmacokinetic Analysis (Blood levels of AR-301) | Blood levels of AR-301 in the patient over time during the study period. | 28 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Staphylococcus aureus, S. aureus, monoclonal antibody, Aridis, VAP, ventilator acquired pneumonia, infection, pneumonia, AR301