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

Infection, Bacterial Clinical Trial

— AR-301-002  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03816956
• Other study ID #: AR-301-002
• Status: Completed
• Phase: Phase 3
• Start date: May 3, 2019
• Est. completion date: October 28, 2022

Study information

• Verified date: July 2023
• Source: Aridis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 174
• Est. completion date: October 28, 2022
• Est. primary completion date: October 28, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bacterial Infections
• Communicable Diseases
• Infection, Bacterial
• Infections
• Lung Infection
• Pneumonia
• Pneumonia, Ventilator-Associated
• Staphylococcus Aureus

Intervention

Drug:
• AR-301
AR-301 (tosatoxumab) 20 mg/kg administered once intravenously the day of enrolment.

Other:
• Placebo
Placebo comparator

Locations

Country	Name	City	State
Belarus	BLR-04	Gomel
Belarus	BLR-06	Grodno
Belarus	BLR-01	Minsk
Belgium	BEL-01	Lodelinsart
Belgium	BEL-05	Ottignies
Brazil	BRA-04	Curitiba
Brazil	BRA-08	Curitiba
China	CHN-09	Guangzhou	Guangdong
Estonia	EST-01	Tallinn
France	FRA-18	Brive-la-Gaillarde
France	FRA-10	Bron
France	FRA-05	La Roche-sur-Yon
France	FRA-04	Limoges
France	FRA-01	Nantes
France	FRA-16	Orléans
France	FRA-11	Rennes
France	FRA-02	Strasbourg	Cedex
France	FRA-13	Trevenans
Georgia	GEO-06	Gori
Georgia	GEO-01	Kutaisi
Georgia	GEO-03	Kutaisi
Georgia	GEO-04	Kutaisi
Georgia	GEO-10	Kutaisi
Georgia	GEO-02	Tbilisi
Georgia	GEO-07	Tbilisi
Georgia	GEO-09	Tbilisi
Israel	ISR-04	Haifa
Israel	ISR-01	Ramat Gan
Latvia	LVA-02	Riga
Mexico	MEX-07	Guadalajara	Jalisco
Russian Federation	RUS-18	Arkhangelsk
Russian Federation	RUS-11	Chelyabinsk
Russian Federation	RUS-01	Krasnoyarsk
Russian Federation	RUS-04	Novosibirsk
Russian Federation	RUS-02	Saint Petersburg
Russian Federation	RUS-10	Smolensk
Russian Federation	RUS-16	Zhukovskiy
South Africa	ZAF-09	Johannesburg
Spain	ESP-01	Madrid
Turkey	TUR-06	Istanbul
Turkey	TUR-01	Trabzon
Ukraine	UKR-05	Chernivtsi
Ukraine	UKR-03	Ivano-Frankivsk
Ukraine	UKR-02	Kharkiv
Ukraine	UKR-09	Kharkiv

Sponsors (1)

Lead Sponsor	Collaborator
Aridis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

Belarus,  Belgium,  Brazil,  China,  Estonia,  France,  Georgia,  Israel,  Latvia,  Mexico,  Russian Federation,  South Africa,  Spain,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Duration of intubation with ventilation	Number of days with intubation with ventilation	28 days
Secondary	Duration mechanical ventilation if tracheostomy in place	Number of days of intubation with mechanical ventilation if tracheostomy in place	28 days
Secondary	Duration of stay in ICU	Number of days of stay in ICU	28 days
Secondary	Duration hospitalization	Number of days of hospitalization	28 days
Secondary	Duration antibiotic use.	Number of days on antibiotics	28 days
Secondary	Pharmacokinetic Analysis - (Cmax)	Pharmacokinetic analysis measuring Maximum Serum Concentration (Cmax)	28 days
Secondary	Pharmacokinetic Analysis - (AUC)	Pharmacokinetic analysis measuring Area Under the Curve (AUC)	28 Days
Secondary	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
Secondary	Pharmacokinetic Analysis - (Tmax)	Pharmacokinetic analysis measuring time at which Cmax is obtained (Tmax)	28 Days
Secondary	Pharmacokinetic Analysis (Blood levels of AR-301)	Blood levels of AR-301 in the patient over time during the study period.	28 Days

External Links

•   Website of the Sponsor