Treatment of ventilator-associated pneumonia (VAP) due to Staphylococcus aureus (S aureus) in combination with standard of care (SOC) antibiotic therapy
Scientific Title of Study
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
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
AR-301-002, Ver 4.1 dated 26Nov2019
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Thanuja Naidu
Designation
Director, Clinical Operations-APAC & Country Manager-India
Affiliation
Pharm-Olam International (India) Pvt. Ltd
Address
Pharm-Olam International (India) Pvt. Ltd,
No. 15, KMJ Arcadia, I Floor,
Industrial Main Road,
Koramangala, 5th Block
Bangalore KARNATAKA 560 095 India
Phone
080-67182215
Fax
080-41105520
Email
Thanuja.Naidu@pharm-olam.com
Details of Contact Person Scientific Query
Name
Smita Deshmukh
Designation
Manager, Site Activation - APAC
Affiliation
Pharm-Olam International (India) Pvt. Ltd
Address
Pharm-Olam International (India) Pvt. Ltd,
No. 15, KMJ Arcadia, I Floor,
Industrial Main Road,
Koramangala, 5th Block
Bangalore KARNATAKA 560 095 India
Phone
080-67182215
Fax
080-41105520
Email
Smita.Deshmukh@pharm-olam.com
Details of Contact Person Public Query
Name
Thanuja Naidu
Designation
Director, Clinical Operations-APAC & Country Manager-India
Affiliation
Pharm-Olam International (India) Pvt. Ltd
Address
Pharm-Olam International (India) Pvt. Ltd,
No. 15, KMJ Arcadia, I Floor,
Industrial Main Road,
Koramangala, 5th Block
Bangalore KARNATAKA 560 095 India
Phone
080-67182215
Fax
080-41105520
Email
Thanuja.Naidu@pharm-olam.com
Source of Monetary or Material Support
Aridis Pharmaceuticals Inc
Primary Sponsor
Name
Aridis Pharmaceuticals Inc
Address
Aridis Pharmaceuticals, Inc
5941 Optical Court
San Jose, CA- 95138
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Republic of Korea Belarus Belgium Brazil China Czech Republic Estonia France Georgia India Israel Latvia Mexico Russian Federation Serbia South Africa Taiwan Turkey Ukraine United States of America
Apollo Research and Innovation, Auditorium building, 1st floor, Apollo Medical College, Jubilee Hills Hyderabad TELANGANA
9866415551
indialungdoc@gmail.com
Dr Vivek Gupta
Dayanand Medical College and Hospital
Unit Hero DMC Heart Institute, Tagore Nagar Ludhiana PUNJAB
9815398993
dr_vivekg@yahoo.com
Dr Yogesh Agrawal
Dr.Yogesh Agrawal
Consultant Pulmonologist, Dept. of Pulmonology, Aditya Birla
Memorial Hospita
Aditya Birla Marg Thergoan
Chichwadgoan. Pune 411033 Pune MAHARASHTRA
8149400043
dryogesh1980@gmail.com
Dr Prajapati Vipulkumar Bachubhai
GCS Medical College Hospital &Research Centre
GCS Medical College Hospital & Research Centre
Opposite DRM office, Naroda Road
Ahmedabad, 380025,
Gujarat, India
Ahmadabad GUJARAT
9909912551
prajapativipul1983@gmail.com
Dr Rojith Balakrishna
Government Medical College
Institute of Chest Diseases, Department of Pulmonary Medicine, Government Medical College, Kozhikode Kozhikode KERALA
9746006050
drrojith@gmail.com
Dr Archana Aher
Government Medical College and Hospital
Dept. of Medicine, Medical College Square Road
Nagpur MAHARASHTRA
9881556150
drarchnaaher@gmail.com
Dr Prachee Sathe
Grant Medical Foundations Ruby Hall Clinic
40, Sassoon Road
Urology OPD 1st Floor Pune MAHARASHTRA
09822059789
prachee.sathe@gmail.com
Dr Sarbari Swaika
Institute of Post graduate Medical Education & Research, SSKM Hospital
Department of Anesthesiology,
CCU-Anesthesiology
Level-I, Trauma care Center,
Institute of Post graduate Medical Education & Research,
SSKM Hospital,244, A.J.C Bose road, Kolkata-700020
Kolkata WEST BENGAL
9434021722
dr.s.swaika@gmail.com
Dr PA Mahesh
JSS Hospital
Dept. of Pulmonology, Mahatma Gnadhi Road Mysore KARNATAKA
9448044003
mahesh1971in@yahoo.com
Dr Jayaprakash Appajigol
KLES Dr. Prabhakar Kore Hospital and Medical Research Centre
General Medicine, OPD number 11, Ground floor,
Consultant Physician,
Nehru Nagar Belgaum KARNATAKA
AR-301 (KBSA301, tosatoxumab), is a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) specific for alpha-toxin of S. aureus. Single intravenous infusion of 20 mg of AR-301/kg of body weight (measured or estimated), up to a maximum dose of 2,500 mg (corresponding to 125 kg body weight), to be administered in approximately two hours
Comparator Agent
Placebo
Matching placebo. Single intravenous infusion of 20 mg of placebo/kg of body weight (measured or estimated), up to a maximum dose of 2,500 mg (corresponding to 125 kg body weight), to be administered in approximately two hours
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
1. Written Informed Consent given by the study patient, or, if not possible, by a legally acceptable representative and/or an independent physician/council of independent physicians (CIP), 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.
3. Treated in an ICU at the time of enrollment.
4. Endotracheal tube in place (tracheostomy is allowed).
5. The study patient is mechanically ventilated for at least 48 hours prior to the diagnosis of pneumonia.
6. Diagnosis of pneumonia based on the following criteria (a, b, and c, all must be met):
a. One definitive chest X-ray diagnostic of pneumonia within 48 hours.
b. Hypoxemia based on at least one of the following measurements/criteria:
i. Worsening in PaO2/FiO2 < 250 mmHg (at sea level or equivalent for significant elevations above sea level) while intubated and mechanically ventilated, as one or more measures within ï‚£ 48 hours prior to randomization, or
ii. Worsening in PaO2 < 60 mmHg (at sea level or equivalent for significant elevations above sea level) while intubated and mechanically ventilated, as one or more measures within ï‚£ 48 hours prior to randomization.
c. 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 S. aureus obtained by BAL, mini-BAL, or ETA (collectively ‘airway specimen’). For the study randomization, S. aureus must be identified as the primary pneumonia causing pathogen requiring S. aureus targeted antibiotic therapy (a list of antibiotics effective against S. aureus is provided in Appendix D), using a or b below. More than one pathogen is allowed if S. aureus is regarded as the primary pneumonia causing pathogen.
a. A rapid diagnostic test such as BioFire’s FA, Cepheid’s GX, mass spectrometry, PCR, and/or a semi quantitative Gram stain may be used for confirmation of S. aureus prior to randomization. In such case, the same sample must ALSO be used for standard microbiological culture test by the local laboratory (including organism identification, quantitative or semi-quantitative culture and susceptibility testing). In addition, the airway specimen will be sent to central laboratory for bioavailability testing. The corresponding culture results are NOT required prior to randomization, however, a positive microbiological culture for S. aureus is required to be part of micro-ITT population.
OR
b. A standard microbiological culture test for S. aureus that is obtained less than 72 hours prior to randomization. This sample will be used for baseline standard microbiological culture by the local laboratory (including organism identification, quantitative or semi quantitative culture and susceptibility testing). In addition, the airway specimen will be sent to central laboratory for bioavailability testing.
For further clarification and guidance on microbiological eligibility, refer to Figure 6 2 and Appendix F.
8. Approval by a CCC member must be obtained prior to randomization.
ExclusionCriteria
Details
1. The study patient is unlikely to survive for the study duration (i.e., for at least 28 days) despite delivery of adequate antibiotics and supportive care for treatment of the S. aureus VAP.
2. Effective antibacterial drug therapy for the index pneumonia administered continuously for more than 72 hours prior to initiation of study treatment. Effective antibiotics include intravenous (IV) and/or oral medications typically used to treat S. aureus. A list of antibiotics effective against S. aureus is provided in Appendix D.
3. Plasmapheresis (ongoing or planned), extracorporeal membrane oxygenation (ECMO) or any procedure that would remove/filter out the mAb/study drug.
4. Immunocompromised patients due to, but not limited to, the following:
a. HIV / AIDS who are not stable under medication and/or most recent CD4 < 200
b. Expected neutropenia due to chemotherapy
c. Absolute neutrophil count less than 500/µL (mm3)
d. Organ transplant requiring systemic immunosuppressive therapy within the past 6 months.
e. Chronic administration of systemic corticosteroids, defined as > 40 mg of prednisone or equivalent per day administered within 14 days prior to the first dose of study drug.
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). Chronic obstructive pulmonary disease (COPD) is not an exclusion criterion.
8. Study patient has received 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. Serum pregnancy screening for WOCBP would be preferable, where possible. Non pregnant with confirmation via local laboratory testing is required. Lactating women are also excluded. Women who are post-menopausal as evidenced by the absence of menstruation for at least 1 year are eligible; the date of last menstruation is to be recorded in the study files unless post menopausal status is obvious due to age.
10. Any sexually active study patient who is unwilling to use acceptable methods of contraception for 120 days after dosing. WOCBP must agree to use an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, barrier methods, abstinence) or male partner sterilization alone for the duration of the study and for at least 120 days after dosing. Males with female partners of reproductive potential must agree to practice abstinence or to use a condom (male) plus an additional barrier method (female partner) of contraception for the duration of the study and for at least 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 study 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 acceptable representative of the study patient or independent physician/CIP, as authorized by the competent EC or IRB and local regulations.
13. Participation as a study patient 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 study patient. Patients who are not receiving/have not received interventional active study drug (e.g., placebo) or medications/procedures except for SOC within the timeframe described above are eligible for this protocol. Patients who participate in observational or epidemiological studies are also eligible provided this does not interfere with their capacity or the capacity of the study staff to comply with all study requirements.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
To assess the difference in Clinical Cure rates between SOC alone and SOC with AR-301 at Day 21
Day 21
Secondary Outcome
Outcome
TimePoints
Clinical Cure rates at Day 7, 14 and 28, using the same criteria as for the primary efficacy objective at Day 21, Time to Clinical Cure, All-cause mortality, Pneumonia-related mortality, Respiratory functional assessment, Overall clinical status: Changes in Sequential Organ Failure Assessment (SOFA) score
Day 7, 14 and 28
Target Sample Size
Total Sample Size="240" Sample Size from India="20" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
This study is an international, multicenter, prospective, randomized, double blind, placebo’controlled, parallel design, Phase 3 protocol in patients with VAP caused by S. aureus. It will be performed at multiple ICUs. Study patients with a documented diagnosis of pneumonia due to S. aureus, as the primary pneumonia causing pathogen, requiring 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. Patients meeting eligibility requirements will be assessed for S. aureus, as the primary pneumonia causing pathogen, using an acceptable fresh airway specimen (ETA or BAL/mini’BAL). Approval by a Clinical Coordinating Committee (CCC) member must be obtained prior to randomization.
In total, approximately 240 study patients will be randomized 1:1 to be treated with placebo plus SOC or AR-301 (20 mg/kg) plus SOC in this Phase 3 study.
Study patients will receive a single study drug 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 route of administration is via IV infusion. The infusion will be administered over approximately two hours. “Clinical Cure†rates will be analyzed on Day 7, 14, 21 (primary efficacy endpoint) and 28.
Clinical safety assessments will be performed on an ongoing basis while predefined laboratory assessments will be performed at baseline, and thereafter at Day 4, 7, 14, 21, and 28.
The primary clinical efficacy endpoint is the proportion of study patients with Clinical Cure
The secondary clinical efficacy endpoint is Clinical Cure rates at Day 7, 14 and 28, using the same criteria as for the primary efficacy objective at Day 21,Time to Clinical Cure, All-cause mortality, Pneumonia-related mortality, Respiratory functional assessment and Overall clinical status: Changes in Sequential Organ Failure Assessment (SOFA) score.