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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03816956
Recruitment Status : Recruiting
First Posted : January 25, 2019
Last Update Posted : January 7, 2020
Sponsor:
Information provided by (Responsible Party):
Aridis Pharmaceuticals, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Lung Infection Pneumonia, Ventilator-Associated Infection, Bacterial Staphylococcus Aureus Drug: AR-301 Other: Placebo Phase 3

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 treatment 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : May 3, 2019
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Study treatment
Investigational/ Interventional Product group: AR-301 (tosatoxumab) 20 mg/kg administered once intravenously the day of enrolment.
Drug: AR-301
AR-301 (tosatoxumab) 20 mg/kg administered once intravenously the day of enrolment.
Other Name: Salvecin

Placebo Comparator: Placebo treatment
Control group: Placebo administered intravenously the day of enrolment.
Other: Placebo
Placebo comparator




Primary Outcome Measures :
  1. A comparison of Clinical Cure Rates of standard of care (SOC) alone and SOC with AR-301 [ Time Frame: 21 days ]
    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.

  2. Safety of AR-301 by treatment-emergent adverse events assessed by changes between treatment and placebo as assessed by the Principal Investigator [ Time Frame: 21 Days ]
    Safety of AR-301 of treatment-emergent adverse events as assessed by changes assessed by the PI between treatment and placebo

  3. Tolerability of AR-301 measured by the number of participants with treatment-emergent adverse events classified using CTCAE v 5.0 [ Time Frame: 21 Days ]
    Tolerability of AR-301 will be measured and evaluated by the severity of treatment-emergent adverse events using the CTCAE v 5.0.


Secondary Outcome Measures :
  1. 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 [ Time Frame: 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.

  2. The difference in mortality between Standard of Care alone or with AR-301 at Days 7,14,28 [ Time Frame: Day 7, 14, and 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

  3. The difference in PaO2/FiO2 between Standard of Care alone or with AR-301 at Days 7,14,28 [ Time Frame: Day 7, 14, and 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)

  4. The difference in time on supplemental oxygen assessment between Standard of Care alone or with AR-301 at Days 7,14,28 [ Time Frame: Day 7, 14, and 28 ]
    Difference in respiratory function between SOC alone or with AR-301 at Days 7,14, and 28 as time on supplemental oxygen

  5. Changes in baseline in SOFA score between Standard of Care alone or with AR301 at Days 7,14,28 [ Time Frame: Day 7, 14, and 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.


  6. Duration of intubation with ventilation [ Time Frame: 28 days ]
    Number of days with intubation with ventilation

  7. Duration mechanical ventilation if tracheostomy in place [ Time Frame: 28 days ]
    Number of days of intubation with mechanical ventilation if tracheostomy in place

  8. Duration of stay in ICU [ Time Frame: 28 days ]
    Number of days of stay in ICU

  9. Duration hospitalization [ Time Frame: 28 days ]
    Number of days of hospitalization

  10. Duration antibiotic use. [ Time Frame: 28 days ]
    Number of days on antibiotics

  11. Pharmacokinetic Analysis - (Cmax) [ Time Frame: 28 days ]
    Pharmacokinetic analysis measuring Maximum Serum Concentration (Cmax)

  12. Pharmacokinetic Analysis - (AUC) [ Time Frame: 28 Days ]
    Pharmacokinetic analysis measuring Area Under the Curve (AUC)

  13. Pharmacokinetic Analysis - (T1/2) [ Time Frame: 28 Days ]
    Pharmacokinetic analysis measuring time for half of the initial dose of study drug to be eliminated from the body (T1/2)

  14. Pharmacokinetic Analysis - (Tmax) [ Time Frame: 28 Days ]
    Pharmacokinetic analysis measuring time at which Cmax is obtained (Tmax)

  15. Pharmacokinetic Analysis (Blood levels of AR-301) [ Time Frame: 28 Days ]
    Blood levels of AR-301 in the patient over time during the study period.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03816956


Contacts
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Contact: Lynne M Deans, MT 925-200-3089 ext 9252003089 deansl@aridispharma.com
Contact: Ouadah M Hadjebi +33 777 86 06 99 ext 9252003089 deansl@aridispharma.com

Locations
Show Show 100 study locations
Sponsors and Collaborators
Aridis Pharmaceuticals, Inc.
Investigators
Layout table for investigator information
Study Director: Lynne M Deans, MT Aridis Pharmaceuticals

Additional Information:
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Responsible Party: Aridis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03816956    
Other Study ID Numbers: AR-301-002
First Posted: January 25, 2019    Key Record Dates
Last Update Posted: January 7, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Aridis Pharmaceuticals, Inc.:
Staphylococcus aureus
S. aureus
monoclonal antibody
Aridis
VAP
ventilator acquired pneumonia
infection
pneumonia
AR301
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Pneumonia, Ventilator-Associated
Bacterial Infections
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Cross Infection
Anti-Bacterial Agents
Anti-Infective Agents