A study to investigate the efficacy, safety tolerability, and pharmacokinetics of treatment with the drug murepavadin combined with one anti-pseudomonal antibiotic versus two anti-pseudomonal antibiotics in adult subjects with ventilator-associated bacterial pneumonia (type of lung infection that occurs in people who are on mechanical ventilation breathing machines in hospitals) suspected or confirmed to be due to a bacteria called Pseudomonas aeruginosa.

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2017-003933-27-HU
• Date of registration: 07/12/2017
• Prospective Registration: Yes
• Primary sponsor: Polyphor Ltd.
• Public title: A study to investigate the efficacy, safety tolerability, and pharmacokinetics of treatment with the drug murepavadin combined with one anti-pseudomonal antibiotic versus two anti-pseudomonal antibiotics in adult subjects with ventilator-associated bacterial pneumonia (type of lung infection that occurs in people who are on mechanical ventilation breathing machines in hospitals) suspected or confirmed to be due to a bacteria called Pseudomonas aeruginosa.
• Scientific title: A multicenter, open-label, randomized, active-controlled, parallel group, pivotal study to investigate the efficacy, safety and tolerability, and pharmacokinetics of murepavadin combined with one anti-pseudomonal antibiotic versus two anti-pseudomonal antibiotics in adult subjects with ventilator-associated bacterial pneumonia suspected or confirmed to be due to Pseudomonas aeruginosa.
• Date of first enrolment: 29/01/2018
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003933-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Croatia, Estonia, France, Greece, Hungary, Ireland, Israel, Mexico, South Africa, Spain, Thailand, United States

Contacts

• Name: Chief Medical & Development Officer
• Affiliation: Polyphor Ltd.

• Name: Chief Medical & Development Officer
• Affiliation: Polyphor Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Provide written informed consent prior to any study-related procedure not part of normal medical care. Surrogate consent/use of a legally-authorized representative may be provided, if permitted by local country and institution-specific guidelines. If a subject regains consciousness while still in the study and, per the investigator’s judgment, the subject is able to read, assess, understand, and make his/her own decision to participate in the trial, the subject can agree to continue study participation and the subject should be re-consented, if required by local country and institution-specific guidelines
2. Male or female subjects, =18 years of age
3. Hospitalized for = 48 hours, intubated (via endo- or nasotracheal tube, including tracheostomy subjects) and receiving mechanical ventilation for = 48 hours at the time of randomization, and with acute changes made in the ventilator support system to enhance oxygenation
4. Chest radiograph shows the presence of new or progressive infiltrate(s) characteristic of bacterial pneumonia (based on Investigator’s evaluation). A chest computerized tomography (CT) scan may be used in place of a chest X-ray.
5. Clinical findings to support diagnosis of VABP. At least one of the following must be present within 24 hours prior to randomization:
• Documented fever (oral = 38.0°C [100.4°F] or a tympanic, temporal, rectal or core temperature = 38.3°C [101°F]), or an axillary or forehead scanner = 37.5°C [99.5°F] OR
• Hypothermia (rectal / core body temperature = 35°C [95.2°F]), OR
• Total peripheral white blood cell count (WBC) = 10,000 cells/mm3, OR
• Leukopenia with WBC = 4500 cells/mm3
6. Acute Physiology and Chronic Health Evaluation (APACHE II) score between 8 and 30 inclusive, within 24 hours prior to randomization
7. High probability of pneumonia caused by P. aeruginosa, defined as follows:
• A rapid diagnostic test (RDT), performed within 36 hours prior to randomization, using an acceptable respiratory sample (broncho-alveolar lavage [BAL], mini-BAL endotracheal aspirate [ETA], or sample from an exudative pleural effusion) positive for P. aeruginosa, OR
• A surveillance culture from a respiratory sample positive for P. aeruginosa.
Only if the above methods cannot be used, enrollment can be based on:
• A Gram stain performed within 36 hours prior to randomization using an acceptable respiratory sample (protected brush specimen [PBS], BAL, mini-BAL, ETA (= 25 PMNs/LPF and = 10 squamous epithelial cells/LPF), or sample from an exudative pleural effusion) showing Gram-negative rods (with or without Gram-positive bacteria). The Gram stain will be performed in all subjects, even if the enrollment is based on a RDT.
Note:if BAL, mini-BAL, or PBS is available at the site, these modalities are recommended rather than an ETA for obtaining the baseline lower respiratory tract specimen.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 75
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 75

Exclusion criteria:
1. Known or suspected community-acquired bacterial, viral, fungal orparasitic pneumonia
2. Any of the following health conditions:
• Confirmed legionella infection (Legionella pneumophila
pneumonia), Aspergillus spp. pneumonia (testing is not required)
• Cystic fibrosis
• Known or suspected Pneumocystitis jiroveci pneumonia
• Known or suspected active tuberculosis
• Lung abscess
• Solid organ transplant within 6 months prior to randomization
• Pleural empyema
• Evidence of deep-seated infection, e.g., endocarditis, osteomyelitis
3. Bronchial obstruction or a hisotry of post-obstructive pneumoniathis does not exclude subjects with pneumonia who have an underlying chronic obstructive pulmonary disease)
4. Expected survival < 72 hours or a Do-Not-Resuscitate Order
5. Burns > 40% of total body surface area
6. Current or anticipated neutropenia with absolute neutrophil count (ANC) < 500 cells/mm3
7. Severe renal disease defined as an eGFR-MDRD-6 < 30 mL/min/1.73m2, or requirement for peritoneal dialysis, hemodialysis, hemofiltration, or a urine output < 20 mL/hour over a 24-hour period.
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 5 times upper limit of normal or Child-Pugh B and C in subjects with chronic liver function impairment
9. Received systemic or inhaled antibiotic therapy potentially effective against P. aeruginosa within 72 hours prior to randomization as follows:
- > 8 i.v. doses of an antibiotic administered q.i.d. (e.g., piperacillin-tazobactam)
- > 6 i.v. doses of an antibiotic administered t.i.d. (e.g., meropenem)
EXCEPTIONS:
• Progression of disease on the prior antibacterial regimen for this episode of pneumonia after > 72 hours of treatment OR
• Subject developed symptoms of pneumonia and a new infiltrate while receiving the prior antibacterial regimen for reasons other than the current pneumonia; if the pneumonia occurred while the subject was receiving antibiotics as prophylaxis or for treatment of an unrelated infection, the antibacterial therapy will be considered ineffective irrespective of the susceptibility profile of the study qualifying pathogen, OR
• Subject received systemic antibacterial therapy that does not cover P. aeruginosa, OR
• Prior therapy with a non-absorbed antibiotic therapy used for gut decontamination or to eradicate Clostridium difficile.
10. Investigator’s opinion of clinically significant ECG finding such as ischemia, infarct, or ventricular arrhythmia with immediate potential for a fatal outcome, or, prior to the current infection, a history of New York Heart Association (NYHA) (Appendix X) Class IV cardiac failure
11. Stroke (ischemic or intracerebral hemorrhage) within 5 days prior to randomization
12. Women who are pregnant or nursing, or who are of childbearing potential and unwilling to use an acceptable method of birth control (e.g., 2 methods of contraception, one of which with a failure rate <1% per year, vasectomized male partner, or true abstinence (excluding women

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Ventilator-associated bacterial pneumonia (VABP)
MedDRA version: 20.1 Level: LLT Classification code 10065153 Term: Ventilator associated pneumonia System Organ Class: 100000004862

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Product Name: Murepavadin
Product Code: POL7080
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: MUREPAVADIN
CAS Number: 944252-63-5
Current Sponsor code: POL7080 Acetate
Other descriptive name: POL7080; formerly RO7033877
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 8-

Product Name: Piperacillin Tazobactam
Pharmaceutical Form:
INN or Proposed INN: PIPERACILLIN
Other descriptive name: PIPERACILLIN SODIUM
INN or Proposed INN: TAZOBACTAM
Other descriptive name: TAZOBACTAM SODIUM

Product Name: Ceftazidime
Pharmaceutical Form:
INN or Proposed INN: CEFTAZIDIME
CAS Number: 72558-82-8

Product Name: Cefepime
Pharmaceutical Form:
INN or Proposed INN: CEFEPIME
CAS Number: 88040-23-7

Product Name: Meropenem
Pharmaceutical Form:
INN or Proposed INN: MEROPENEM
CAS Number: 96036-03-2
Other descriptive name: MEROPENEM

Product Name: Amikacin
Pharmaceutical Form:
INN or Proposed INN: AMIKACIN
CAS Number: 37517-28-5

Product Name: Ciprofloxacin
Pharmaceutical Form:
INN or Proposed INN: CIPROFLOXACIN
Other descriptive name: CIPROFLOXACIN

Product Name: Levofloxacin
Pharmaceutical Form:
INN or Proposed INN: LEVOFLOXACIN
CAS Number: 100986-85-4

Product Name: i.v./inh. CMS
Pharmaceutical Form:
INN or Propose

Primary Outcome(s)

Secondary Objective: • To assess the all-cause mortality (ACM) rates at 14 and 28 days after randomization in different analysis sets
• To assess the clinical cure rates at different timepoints and in different analysis sets

Timepoint(s) of evaluation of this end point: Please refer to Apendix I : Schedule of Assessment of Prototcol: POL7080-011

Main Objective: To assess the clinical cure rates of intravenous (i.v.) murepavadin + one anti-pseudomonal antibiotic compared to two anti-pseudomonal antibiotics in the microbiological intention-to-treat (micro-ITT) analysis set in subjects with VABP due to P. aeruginosa at the Test-of-Cure (ToC) visit.

Primary end point(s): The primary efficacy endpoint variable is the clinical cure rates determined by the CEC at the ToC visit in the micro-ITT analysis set. Clinical outcomes are defined as follows:
• Clinical cure:
o Complete resolution or marked improvement of all signs and symptoms (e.g., changes in fever, oxygenation, purulence of respiratory specimen, absence of respiratory secretions) of pneumonia (unless there is (i) an alternative reason other than pneumonia, (ii) occurrence/persistence of a non-pseudomonal pneumonia, that explains the persistence of certain symptoms, (iii) or presence of residual signs and symptoms of pneumonia that do not require further anti-pseudomonal antibiotic treatment), AND
o None of the clinical failure criteria (see below) are fulfilled
• Clinical failure:
o Worsening or no improvement in clinical signs and symptoms,
o Treatment-limiting AE leading to discontinuation of study drugs antibiotic, when subject requires alternative antimicrobial therapy to treat the pneumonia
o Death
The authorized anti-pseudomonal antibiotic(s) can be changed in either treatment arm. The decision to modify the authorized anti-pseudomonal treatment should be based on the absence of clinical improvement as per the investigator’s evaluation (i.e., infection due to a non-susceptible strain does not necessarily require a modification of treatment if the subject is improving). Changing therapy based on non-susceptibility alone is not considered treatment failure unless accompanied by lack of clinical improvement at the ToC visit.
• Indeterminate:
o Lack of clinical cure or clinical failure, insufficient information to determine cure or failure

Secondary Outcome(s)

Secondary end point(s): All-Cause Mortality (ACM)
• ACM rate 28 days after randomization in the micro-ITT analysis set
• ACM rate 14 days after randomization in the micro-ITT analysis set
• ACM 28 days after randomization in the ITT, micro-MITT, IIAT/IAAT
and PP analysis sets
• ACM 14 days after randomization in the ITT, micro-MITT, IIAT/IAAT
and PP analysis sets
Clinical Response
• Clinical cure rates at the ToC visit in the ITT, micro-MITT, IIAT/IAAT
and PP analysis sets
• Clinical cure rates at Day 3, 5, 7 10, the EoT visit in the ITT, micro-
ITT, micro-MITT, IIAT/IAAT, and PP analysis sets

Timepoint(s) of evaluation of this end point: Please refer to Apendix I : Schedule of Assessment of Prototcol: POL7080-011

Secondary ID(s)

120996

POL7080-011

Source(s) of Monetary Support

Polyphor Ltd.

Ethics review

Status: Approved
Approval date:
Contact: