E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Pneumonia caused by bacteria P. 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 | 19.1 |
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
antibiotic regimen, in terms of clinical cure at day 14, i.e., resolution of the P. aeruginosa
pneumonia event diagnosed at enrollment, as compared to standard antibiotic therapy alone.
2. To assess the clinical safety and tolerability of Aerucin® in the study population. |
|
E.2.2 | Secondary objectives of the trial |
-Clinical Efficacy Objectives:
1.Clinical cure: Clinical cure rate at day 4,7,21,28,using the same criteria as for the
primary efficacy objective.Time to clinical cure
2.Mortality: All-cause mortality.Pneumonia-related mortality post-treatment as adjudicated
by an independent, blinded committee
3.Respiratory function assessment:Changes in PaO2/FiO2.Need for mechanical ventilator
support
4.Overall clinical status:Changes in SOFA score
5.Health economics and well-being:antibiotic utilization, duration of: stay in the ICU,hospitalization, mechanical ventilation,intubation
-Pharmacokinetics:PK Profile over the study follow-up period
-Safety Objectives:To assess the immunogenicity of Aerucin®
-Microbiological Efficacy Objectives
1.Eradication of index P.aeruginosa at 4,7,14, 21, 28 days post-treatment
2.Relapse defined as a reoccurrence of pneumonia due to P. aeruginosa within the 28-day follow-up period
3.Reduction in bacterial load related 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. Diagnosis of pneumonia based on the following criteria:
a. A sequence of at least 2 chest X-rays showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia or 1 definitive chest X-ray diagnostic of pneumonia
b. Hypoxemia based on at least one of the following criteria:
i. PaO2/FiO2 <250
ii. PaO2 <60 mmHg
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.
3. To be at least 18 years of age.
4. To be treated in an ICU at the time of enrollment.
5. Endotracheal tube in place (tracheostomy is allowed),
6. The patient is mechanically ventilated.
7. Documented pulmonary infection with P. aeruginosa obtained by BAL, mini-BAL, protected endotracheal tube aspiration (ETA). For the purpose of randomization, P. aeruginosa must be identified either by:
a. On the basis of available results from a culture positive by any method for P. aeruginosa of a sample obtained less than 72 hours prior to randomization. In such case, a fresh sample must be obtained prior to treatment initiation for standard microbial culture by the local laboratory (including organism identification, quantitative culture and susceptibility testing); the corresponding culture results are not required prior to randomization.
OR
b. On the basis of a rapid diagnostic test (see section 14.3 for allowed methods). In such case, the same sample must be used for standard microbial culture by the local laboratory (including organism identification, quantitative culture and susceptibility testing). The corresponding culture results are not required prior to randomization.
8. APACHE II score ≥ 10 and ≤ 35 within 24 hours of enrollment |
|
E.4 | Principal exclusion criteria |
1. The subject is moribund.
2. Effective antibacterial drug therapy for the index pneumonia administered continuously for 48 hours or more prior to initiation of study treatment.
3. Plasmapheresis (ongoing or planned)
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 function deficiency associated with chronic conditions (e.g., liver cirrhosis Child- Pugh C).
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. Administration of anti-infective monoclonal antibody within 3 months prior to enrollment.
9. Women of childbearing potential who are sexually active and have not been using a medically acceptable method contraception for at least 12 months and in whom a pregnancy test is either not available or positive at the time of enrollment. Women who are surgically sterile or sterile for any other reason are eligible provided medical evidence is provided and maintained in the study file. Women who are post-menopausal as evidenced by the absence of menstruation for at least 1 year are eligible; the date of the last menstruation is to be recorded in the study file unless postmenopausal status is obvious due to age.
10. 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.
11. 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.
12. Participation as 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) |
Clinical cure, relapse ( pneumonia due to P. aeruginosa), or reinfection (pneumonia due to a pathogen other than P. aeruginosa) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinical cure, i.e., resolution of the pneumonia event diagnosed at enrollment. “Clinical cure” is resolution of pneumonia as determined by an independent adjudication committee based on objective criteria. Clinical cure at day 14 will be used as primary clinical efficacy parameter. |
|
E.5.2 | Secondary end point(s) |
Secondary Clinical Efficacy Parameters
1. Clinical cure:
- Clinical cure rate at day 4, 7, 21 and 28.
- Time to clinical cure.
2. Mortality:
- All-cause mortality
- Pneumonia-related mortality
- Time to death over the 28-day follow-up period.
3. Respiratory function assessment: PaO2/FiO2
4. Overall clinical status: SOFA
5. Health economics and well-being: antibiotic utilization, duration of stay in the ICU,
duration of hospitalization, ventilator-free days.
Microbiological Endpoints |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The clinical course of pneumonia will be assessed daily by the investigator.
Secondary endpoints will be assessed for analytical purposes on day 4, 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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 7 |
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 |
Belgium |
Czech Republic |
France |
Germany |
Greece |
Hungary |
Italy |
Korea, Republic of |
Poland |
Russian Federation |
Spain |
Taiwan |
United Kingdom |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |