Adjunctive Therapy to Antibiotics in the Treatment of S. Aureus Ventilator-Associated Pneumonia With AR-301 (AR-301-002)

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

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.

Study Overview

• Status: Completed
• Conditions: Staphylococcus Aureus; Pneumonia, Ventilator-Associated; Infection, Bacterial; Lung Infection
• Intervention / Treatment: Other: Placebo; Drug: AR-301

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Lynne M Deans, MT; Phone Number: 9252003089 925-200-3089; Email: deansl@aridispharma.com

Study Locations

• Belarus
  • Gomel, Belarus, 246029
    • BLR-04
  • Grodno, Belarus, 230017
    • BLR-06
  • Minsk, Belarus, 223041
    • BLR-01
• Belgium
  • Lodelinsart, Belgium, 6042
    • BEL-01
  • Ottignies, Belgium, 1340
    • BEL-05
• Brazil
  • Curitiba, Brazil, 80810-050
    • BRA-08
  • Curitiba, Brazil, 82050-350
    • BRA-04
• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510180
      • CHN-09
• Estonia
  • Tallinn, Estonia, 13419
    • EST-01
• France
  • Brive-la-Gaillarde, France, 19312
    • FRA-18
  • Bron, France, 69677
    • FRA-10
  • La Roche-sur-Yon, France, 85925
    • FRA-05
  • Limoges, France, 87042
    • FRA-04
  • Nantes, France, 44093
    • FRA-01
  • Orléans, France, 45067
    • FRA-16
  • Rennes, France, 35033
    • FRA-11
  • Trevenans, France, 90400
    • FRA-13
  • Cedex
    • Strasbourg, Cedex, France, 67091
      • FRA-02
• Georgia
  • Gori, Georgia, 1400
    • GEO-06
  • Kutaisi, Georgia, 4600
    • GEO-01
  • Kutaisi, Georgia, 4600
    • GEO-03
  • Kutaisi, Georgia, 4600
    • GEO-04
  • Kutaisi, Georgia, 4600
    • GEO-10
  • Tbilisi, Georgia, 0141
    • GEO-02
  • Tbilisi, Georgia, 0159
    • GEO-09
  • Tbilisi, Georgia, 0160
    • GEO-07
• Israel
  • Haifa, Israel, 31096
    • ISR-04
  • Ramat Gan, Israel, 5262100
    • ISR-01
• Latvia
  • Riga, Latvia, LV-1006
    • LVA-02
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • MEX-07
• Russian Federation
  • Arkhangelsk, Russian Federation, 163002
    • RUS-18
  • Chelyabinsk, Russian Federation, 454000
    • RUS-11
  • Krasnoyarsk, Russian Federation, 660022
    • RUS-01
  • Novosibirsk, Russian Federation, 630051
    • RUS-04
  • Saint Petersburg, Russian Federation, 192242
    • RUS-02
  • Smolensk, Russian Federation, 214018
    • RUS-10
  • Zhukovskiy, Russian Federation, 140180
    • RUS-16
• South Africa
  • Johannesburg, South Africa, 2193
    • ZAF-09
• Spain
  • Madrid, Spain, 28040
    • ESP-01
• Turkey
  • Istanbul, Turkey, 34214
    • TUR-06
  • Trabzon, Turkey, 61080
    • TUR-01
• Ukraine
  • Chernivtsi, Ukraine, 58000
    • UKR-05
  • Ivano-Frankivsk, Ukraine, 76008
    • UKR-03
  • Kharkiv, Ukraine, 61103
    • UKR-02
  • Kharkiv, Ukraine, 61103
    • UKR-09

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. 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.
3. Treated in an ICU at the time of enrollment.
4. Endotracheal tube in place (tracheostomy is allowed).
5. The patient is mechanically ventilated for at least 48 hours.

6. Diagnosis of pneumonia based on the following criteria (a, b, and c, all must be met):

   1. One definitive chest X-ray diagnostic of pneumonia within 48 hours,
   2. Hypoxemia based on PaO2/FiO2.
   3. 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.

7. Documented pulmonary infection with Staphylococcus aureus obtained by bronchoalveolar lavage (BAL), mini-BAL, protected endotracheal aspiration/aspirate (ETA) (collectively 'airway specimen').

Exclusion Criteria

1. The subject is unlikely to survive for the study duration despite delivery of adequate antibiotics and supportive care for treatment of S. aureus pneumonia.
2. 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.
3. Plasmapheresis (ongoing or planned), extracorporeal membrane oxygenation (ECMO) or any procedure that would remove/filter out the monoclonal antibody/study drug.
4. Immunocompromised patients.
5. Known hereditary complement deficiency.
6. 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]).
7. 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).
8. Patient has received intravenous (IV) immunoglobulin therapy within 3 months prior to the Screening Visit.
9. 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.
10. Any sexually active subject who is unwilling to use acceptable methods of contraception for 120 days after dosing.
11. 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.
12. 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.
13. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Aridis Pharmaceuticals, Inc.
• Investigators: Study Director: Hasan S Jafri, MD, FAAP, Aridis Pharmaceuticals

Publications and helpful links

Helpful Links

• Website of the Sponsor

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2019
• Primary Completion (Actual): October 28, 2022
• Study Completion (Actual): October 28, 2022

Study Registration Dates

• First Submitted: December 21, 2018
• First Submitted That Met QC Criteria: January 24, 2019
• First Posted (Actual): January 25, 2019

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 4, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: monoclonal antibody; infection; pneumonia; Staphylococcus aureus; S. aureus; VAP; Aridis; ventilator acquired pneumonia; AR301
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Bacterial Infections and Mycoses; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Infections; Communicable Diseases; Pneumonia; Bacterial Infections; Pneumonia, Ventilator-Associated
• Other Study ID Numbers: AR-301-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes