| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Staphylococcus aureus pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pneumonia caused by bacteria Staphylococcus aureus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035734 |
| E.1.2 | Term | Pneumonia staphylococcal |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Efficacy:
To assess the difference in Clinical Cure rates between SOC alone and SOC with AR-301 at Day 21. Stringent Clinical Cure criteria have been defined in collaboration with clinical experts in the field.
Safety:
To assess the clinical safety and tolerability of AR-301 in the study population. |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy:
assess the difference the following clinical outcomes between SOC alone and SOC with AR-301:
-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
_Health economics outcomes: 1. Duration of intubation with ventilation or duration of mechanical ventilation if tracheostomy is in place. 2. Duration of stay in the ICU. 3. Duration of hospitalization. 4. Duration of antibiotic utilization.
_Pharmacokinetics
Safety:
To assess the immunogenicity of AR-301.
Microbiological Efficacy:
To assess the difference in eradication of index S. aureus at Day 21 and Day 28. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Two PK analyses will be performed to assess the PK profile of AR-301 in the target patient population. The pharmacokinetics (PK) of AR-301 will be assessed using a population PK (compartmental modeling) approach as well as a non-compartmental analysis approach. A PK sub-study ("Full PK") will be included, wherein more extensive sampling will be performed in a small number of subjects (from select sites) who provide consent (i.e., 16 subjects to obtain approximately 8 patients on active treatment). In the remaining patients, a sparse sampling strategy will be implemented with only a few samples obtained from each subject at varying time points (“Sparse PK”).
A compartmental population PK model will be developed using the PK data collected from the sub-study and the sparse samples. PK parameters will be estimated as well as between-subject or inter-individual variability (IIV) and residual variability (RV). The effects of select factors describing the characteristics of sub-populations of interest (e.g. high or low bacterial load, cause of admission [trauma or non-trauma]) on the PK of AR-301 will be assessed via covariate analysis. In addition to the population PK evaluation, non-compartmental analysis of the PK sub-study data will be performed. |
|
| E.3 | Principal inclusion criteria |
1. Written Informed Consent given by the study patient, or, if not possible, by a legally acceptable representative of the study patient 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.
For 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 ≤ 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 ≤ 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, 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 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 FilmArray (FA), Cepheid’s GeneXpert (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
8. Approval by a Clinical Coordinating Committee (CCC) member must be obtained prior to randomization. |
|
| E.4 | Principal exclusion criteria |
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 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.
3. Plasmapheresis (ongoing or planned), extracorporeal membrane oxygenation (ECMO) or any procedure that would remove/filter out the monoclonal antibody (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. Nonpregnant 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 Principal Investigator’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 and/or independent physician/CIP as authorized by 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 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Clinical Efficacy endpoints:
The proportion of patients with Clinical Cure at Day 21.
Microbiological Endpoints:
1. Microbiological outcome of the index S. aureus pneumonia based on the data provided by the local microbiology laboratory.
2. Eradication of S. aureus at Day 21 and Day 28.
Safety Endpoints:
1. Assessment of clinical adverse events,
2. Assessment of clinical laboratory safety tests,
3. Assessment of immunogenicity to AR-301. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinical Cure of pneumonia will be assessed daily by the investigator. “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. |
|
| E.5.2 | Secondary end point(s) |
Secondary Clinical Efficacy Endpoints:
1. Proportion of patients with Clinical Cure at Day 14
2. Proportion of patients with Clinical Cure at Day 28
3. All-cause mortality
4. Pneumonia-related mortality
5. Proportion of patients with Clinical Cure at Day 7
6. Change from baseline in respiratory functional assessment.
7. Mean change from baseline in overall clinical status measured by SOFA scores
8. Health economics outcomes |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary efficacy and health economics endpoints will be assessed in a similar manner during the 28-day period, daily when possible (e.g., time on mechanical ventilation, including if tracheostomy is in place; time on supplemental oxygenation; measures of respiratory health such as changes in PaO2/FiO2, using arterial blood gases (ABG) and/or pulse oximetry measurements), or upon occurrence (e.g., duration of intubation with ventilation, or duration of mechanical ventilation if tracheostomy is in place, duration of stay in the ICU, duration of hospitalization, antibiotic utilization). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| China |
| India |
| Israel |
| Mexico |
| Philippines |
| South Africa |
| Taiwan |
| United States |
| Estonia |
| France |
| Latvia |
| Belarus |
| Belgium |
| Georgia |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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