| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pseudomonas aeruginosa pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pneumonia caused by bacteria Pseudomonas aeruginosa |
|
| 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 | 10035664 |
| E.1.2 | Term | Pneumonia |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To assess the efficacy of Aerucin®, administered as a single dose in addition to standard of care (SOC) antibiotic regimen on Clinical Cure rates (resolution of pneumonia) between SOC alone and SOC with Aerucin® at Day 21.
2. To assess the clinical safety and tolerability of Aerucin® in the study population. |
|
| E.2.2 | Secondary objectives of the trial |
-Clin. Eff. Obj:
1.Clin.cure:Clin. cure rates at d.7,14,28 using the same crit. as for the
prim. eff. obj.Time to clin. cure
2.Mortality and pneumonia-related mort. post-treatment.
3.Respir. funct. assess.: Time on mech.ventil. (incl.if tracheostomy in place).Time on supplem.oxygen. Meas.of respir.health such as changes in PaO2/FiO2, using arterial blood gases and/or pulse oximetry meas.
4.Overall clin.status:Changes in sequential organ failure assessm(SOFA)score
5.Health econom.:antibiotic utiliz., duration of: stay in ICU,hospitaliz.,and intub. with ventil. or mech. ventil. if tracheostomy in place
-PK:To assess the PK Profile of Aerucin®
-Safety Obj:To assess the immunogenicity of Aerucin®
-Microb. Eff. Obj:
1.Eradic. of index P.aeruginosa at d. 21, 28 post-treatment
2.Re-infection/new infection def. as a reoccurrence of pneumonia due to P. aeruginosa within the 28-day f-up period
3.Reduction in bact. load rel. to the index P. aeruginosa |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written Informed Consent given by the patient or, if not possible, by a legally authorized 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.
3. To be treated in an ICU at the time of enrollment.
4. Endotracheal tube in place (tracheostomy is allowed).
5. The patient is mechanically ventilated.
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, or a sequence of at least 2 chest X-rays showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia.
b. Hypoxemia based on at least one of the following measurements/criteria:
i. 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 </= 24 hours prior to randomization, or
ii. 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 </= 24 hours prior to randomization, or
iii. Respiratory failure necessitating intubation and mechanical ventilation. If tracheostomy is in place, the need for mechanical ventilation.
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 P. aeruginosa obtained by BAL, mini-BAL, protected endotracheal tube aspiration (ETA) (collectively 'airway specimen'). For the study randomization, P. aeruginosa must be identified by one of the three methods below:
a. An airway specimen culture positive by any method for P. aeruginosa of specimen obtained less than 72 hours prior to randomization. A fresh airway specimen must be obtained prior to treatment initiation for baseline standard microbial culture by the local laboratory (including organism identification, quantitative/semi-quantitative culture and susceptibility testing); the corresponding culture results are not required prior to randomization.
OR
b. A rapid diagnostic test. In such case, the same sample must ALSO be used for standard microbial culture by the local laboratory (including organism identification, quantitative/semi-quantitative culture and susceptibility testing). The corresponding culture results are NOT required prior to randomization.
OR
c. A positive airway specimen culture by any method of P. aeruginosa from a specimen obtained at screening (quantitative, semi-quantitative).
8. APACHE II score ≥ 10 and ≤ 35 within 24 hours once subject has consented. |
|
| E.4 | Principal exclusion criteria |
1. The subject is moribund. Clinical judgment by the investigator that the subject is unlikely to survive the current illness/ICU-admission/treatment period despite delivery of adequate antibiotics for treatment of P.aeruginosa 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 P. aeruginosa.
3. Plasmapheresis (ongoing or planned) or any procedure that would remove/filter out the monoclonal antibody/study drug.
4. Immunocompromised and at risk of infection by opportunistic pathogens including, 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. Heart or lung transplant recipient within the past 6 months
5. Known hereditary complement deficiency.
6. Liver dysfunction with a Child Pugh C score (Child Pugh score of A or B are acceptable at discretion of the 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 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. Non-pregnant and non-lactating with confirmation via local laboratory testing is required. Woman 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 subject 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 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. Patients who participate in observational or epidemiological studies are 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) |
The proportion of patients with Clinical Cure at Day 21 in patients treated with Aerucin versus the placebo group as assessed by the investigator. The investigator's assessment will be the primary analysis of the primary endpoint.
Additionally, newly defined Clinical Cure criteria will be applied post hoc by an independent adjudication committee:
1. The subject must be alive through the index day visit
2. The patient must have improved respiratory function evaluated at the index day, because:
● The patient is now off the ventilator and extubated
or
● if the patient entered the study with mechanical ventilation due to reasons other than pneumonia and was assessed "likely ventilated beyond day 28" at screening, criteria #1 (survival) and #3 (no signs and symptoms of pneumonia) are sufficient to establish Clinical Cure (presumed not ventilated)
3. The subject must show no clinical signs and symptoms of bacterial pneumonia at the index day, which is determined by
●Not receiving any antibiotic therapy active against the initial P. aeruginosa strain or against persisting pulmonary bacterial infection for 48 hours (antibiotic therapy for documented extra-pulmonary infection permitted)
and
●Resolution of signs and symptoms of bacterial pneumonia, as determined by the PI based on their clinical assessment. Parameters to be considered may include:
-Fever>38°C or hypothermia (<35°C) attributable to the primary bacterial pneumonia
-Tachypnea or shortness of breath (> 22 respirations/min) if off the ventilator and/ or back to baseline respiratory rate
-Tachycardia (> 100 bpm) or bradycardia (< 60 bpm) and/ or back to baseline heart rate
-Improvement of hypoxemia (ABG or PaO2/FiO2 > 200 or pulse oximetry > 90%)
-If patient still produces sputum - negative P. aeruginosa culture from sputum, blood or pleural fluid |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The proportion of patients with Clinical Cure at Day 21 in patients treated with Aerucin versus the placebo group as assessed by the investigator. The investigator's assessment will be the primary analysis of the primary endpoint. Additionally, newly defined Clinical Cure criteria will be applied post hoc by an independent adjudication committee |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of patients with Clinical Cure at Day 28
2. Proportion of patients with Clinical Cure at Day 14
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: 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 and/or pulse oximetry measurements.
7. Mean change from baseline in overall clinical status measured by SOFA scores.
8. Health economics: antibiotic utilization, duration of stay in the ICU,
duration of hospitalization, duration of intubation with ventilation or duration of mechanical ventilation of tracheostomy in place.
Microbiological Endpoints
Microbiological outcome of the index P. aeruginosa pneumonia based on the data provided by the local microbiology laboratory and central microbiology laboratory.
Eradication of P. aeruginosa at Day 21 and 28. Eradication is considered as obtained when a specimen of respiratory secretions is obtained between the visit day and Day 28 and is negative. When no specimen is obtained within this time frame, microbiological outcome will be assessed as "Eradicated" only if the study subject is not receiving any antibiotic active against the initial strain after the study drug administration visit day and displays no signs and symptoms of pneumonia.
Change in bacterial load related to the index P. aeruginosa on the basis of quantitative or semi quantitative cultures by the local microbiological laboratory.
Pharmacokinetic Endpoints
Assessment of the PK parameters during the full PK sub-study.
Assessment of the PK parameters during sparse PK sub-study
Safety Endpoints:
1. Assessment of clinical adverse events
2. Assessment of clinical laboratory safety tests
3. Assessment of immunogenicity to Aerucin® |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be assessed for analytical purposes on day 7, 14, 21 and 28. |
|
| 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 | No |
| 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 | Yes |
| 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) | Yes |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Australia |
| Belarus |
| Belgium |
| Czech Republic |
| France |
| Georgia |
| Germany |
| Greece |
| Hungary |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Ukraine |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
