A study to test the safety and effectiveness of Bay 41-6551 as additional therapy to standard of care antimicrobial treatment in patients who have Gram-Negative Pneumonia and are intubated and mechanially ventilated

• Register: EUCTR
• Last refreshed on: 11 December 2017
• Main ID: EUCTR2013-001048-73-CZ
• Date of registration: 20/05/2013
• Prospective Registration: Yes
• Primary sponsor: Bayer AG
• Public title: A study to test the safety and effectiveness of Bay 41-6551 as additional therapy to standard of care antimicrobial treatment in patients who have Gram-Negative Pneumonia and are intubated and mechanially ventilated
• Scientific title: A Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of BAY 41-6551 as Adjunctive Therapy in Intubated and Mechanically-Ventilated Patients with Gram-Negative Pneumonia
• Date of first enrolment: 25/07/2013
• Target sample size: 362
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-001048-73
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes 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

Argentina, Australia, Brazil, Canada, Colombia, Czech Republic, Korea, Republic of, Mexico, Philippines, Taiwan, Thailand, Turkey, United States

Contacts

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

Key inclusion & exclusion criteria

Inclusion criteria:
1. Males and non-pregnant, non-lactating females, 18 years of age or older. For females of child-bearing potential, one of the following medically acceptable contraceptive methods must be used: or they agree to abstain from heterosexual intercourse while participating in the study. One or more of these methods should be used during the study and continue for 30 days after completion of the antibiotic therapy.
a) Double-barrier methods of contraception (eg, condoms plus spermicidal foam)
b) Intrauterine contraceptive device
c) Approved pharmaceutical contraceptive product (eg, birth control pills or patches, long-term injectable or implantable hormonal contraceptive)

2. Intubated and mechanically-ventilated (patients who have had a tracheotomy may be considered as possible study participants as long as they are being mechanically ventilated)

3. Diagnosis of pneumonia defined as presence of a new or progressive infiltrate(s) on chest radiograph

4. Presence of Gram-negative organism(s) indicated by:
a) Gram-stain OR
b) Culture of pre-therapy respiratory specimen (eg, acceptable TA, BAL, mini-BAL, PSB) OR
c) Suspected Gram-negative pathogen based on local surveillance data and medical history. Local surveillance data reflects the local patterns of bacterial prevalence and antibiotic resistance. Consideration should be given to the recent incidence of infections with Gram-negative organisms in the hospital

5. Removed with amendment 5

6. Impaired oxygenation (within 48 hours prior to screening): a PaO2/FiO2 = 300 mmHg

7. CPIS greater than or equal to 6, (Section 15.3)

8. The presence of a MDR organism in a pre-therapy respiratory specimen OR at least two risk factors for MDR organisms (MDR organism: an organism resistant to representative agents in two or more of the following antibiotic classes - beta-lactams, including penicillins, cephalosporins, and monobactams; carbapenems; fluoroquinolones; and aminoglycosides):
a) Antimicrobial therapy in the preceding two weeks
b) Current hospitalization greater than or equal to 5 days
c) High frequency (> 10%) of antibiotic resistance in the community or in the specific hospital unit
d) Immunosuppressive disease and/or therapy
e) Presence of the risk factors for HCAP
• Hospitalization for two days or more in the preceding 90 days
• Residence in a nursing home or extended care facility
• Home infusion therapy (including antibiotics)
• Chronic dialysis within 30 days
• Home wound care
• Family member with multidrug-resistant pathogen

9. Be willing and able to give written informed consent. If the patient is unable to give written informed consent, the patient's authorized representative may may provide written consent as approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
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 278
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 84

Exclusion criteria:
1. A history of hypersensitivity to amikacin or other aminoglyosides,

2. Has received systemic Gram-negative antibiotic therapy for greater than 48 hours at the time of administration of first dose of study drug. There should be as minimal a time delay as possible between randomization and first dose of study drug but up to 48 hours will be acceptable.
Exceptions: Systemic antibiotic therapy for more than 48 hours for gram negative infection prior to administration of first dose of study drug is permitted if the infection is caused by pathogens that are resistant to the antimicrobial agent(s) used, or the patient's pneumonia is worsening.

3. Has primary lung cancer (including patients with small cell lung carcinoma/non-small cell lung carcinoma and patients with unknown histology) or another malignancy metastatic to the lungs or other known endobronchial obstructions. Exception: Note that patients with complete
resection of non-small cell lung carcinoma are eligible for the study.

4. Known or suspected active tuberculosis, cystic fibrosis, human immunodeficiency virus (HIV) infection with CD 4 count < 200 cell/mm3 (HIV testing is not required as part of this protocol), or invasive fungal infection of the lung, lung abscess, or empyema.

5. Known or suspected bacteremia secondary to Staphylococcus aureus

6. Known or suspected neuromuscular disorders such as myasthenia gravis or parkinsonism

7. Has had a stroke within five days. Additionally, patients with stroke in the acute or sub-acute phase should not be enrolled if at least one or both of the following apply:
a) There is an increased risk of fatal brain edema as indicated by a history of hypertension or heart failure, major early computed tomography (CT) hypodensity exceeding 50% of the middle cerebral artery territory, and/or involvement of additional vascular territories.
b) There is indication for deterioration based on comparison of patient's neurological condition within six hours of planned study drug dosing and patient's neurological condition two days before, judged by applying the National Institute of Health (NIH) Stoke Scale (Section 15.4).

8. A positive urine and /or serum beta-human chorionic gonadotropin (B-hCG) pregnancy test

9. Burns greater than 40% of total body surface area

10. Patients with a serum creatinine > 2 mg/dL (177 µmol/L) Exception: Patients with a serum creatinine > 2 mg/dL (177 µmol/L) and being treated with continuous renal replacement therapy (continuous venovenous hemofiltration [CVVH] and continuous venovenous hemofiltration with dialysis [CVVH-D]) or daily hemodialysis will receive the aerosol study drug treatment (Section 8.4.6.1).

11. Neutropenia (Screening absolute neutrophil count [ANC] < 103 neutrophils/mm3)

12. Has been on mechanical ventilation for > 28 days (ie, current event should not be more than 28 continuous days). A patient is not considered extubated if cessation of mechanical ventilation lasts less than 24 hours.

13. Is participating in or has participated in other investigational interventional studies within the previous 28 days

14. The risk of rapidly fatal illness and death within 72 hours, or any concomitant conditions not related to VAP that, in the opinion of the investigator, precludes completion of study evaluations and the course of therapy.

15. Stem cell transplantation

16. Patients with documented Legionella infection (Legionella pneumonia)

17. Has an APACHE II score <

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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Gram-negative pneumonia
MedDRA version: 19.0 Level: LLT Classification code 10035701 Term: Pneumonia gram-negative bacterial NOS System Organ Class: 100000004862

Intervention(s)

Product Name: Amikacin Sulfate 1:1.8 Solution for Inhalation
Product Code: BAY41-6551
Pharmaceutical Form: Nebuliser solution
INN or Proposed INN: Amikacin
Current Sponsor code: BAY41-6551
Other descriptive name: Amikacin sulfate 1:1.8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 125-
Pharmaceutical form of the placebo: Nebuliser solution
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Primary end point(s): The primary efficacy variable will be Clinical Success in the mITT population (ie, the ITT population who prove to be culture positive for a Gram-negative pathogen and have an APACHE II score = 10). Clinical Success is achieved when all of the following criteria are met:
1) Systemic antibiotics (IV or by mouth [PO]) for pneumonia must be stopped on or before the Test-of-Cure (TOC) visit (Day 17-19)
2) Systemic antibiotics (IV or PO) for pneumonia must not be restarted after the TOC visit
3) The patient must survive through the late follow-up (LFU) visit
4) The patient must not have a reported AE of lung abscess or empyema through the LFU visit and
5) The patient must have stable respiratory function measured at the TOC visit

Main Objective: To demonstrate that as adjunctive therapy to IV antibiotics, BAY 41-6551 400 mg (amikacin as free base) administered as an aerosol by the PDDS Clinical every 12 hours is safe and more effective than placebo (aerosolized normal saline) administered as an aerosol by the PDDS Clinical every 12 hours, in intubated and mechanically-ventilated patients with Gram-negative pneumonia.

Secondary Objective: - To evaluate the superiority of aerosolized BAY 41-6551 versus aerosolized placebo in pneumonia-related mortality to the LFU visit,
- To evaluate the Early Clinical Response at Day 10,
- To evaluate the days on ventilation through the LFU visit,
- To evaluate the days in the ICU at the LFU visit.

Timepoint(s) of evaluation of this end point: TOC visit

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Secondary efficacy endpoints:
1: days 1-28.
2: Days 1-10
3: Day 28-32
4: Day 28-32

Safety endpoints:
1, 2: throughout the study
3: days 15 and at Day 28

Secondary end point(s): Secondary efficacy endpoints:
1. Pneumonia-related mortality to the LFU visit
2. Early Clinical Response based on CPIS scores, the presence of empyema or lung abscess, and all-cause mortality through Day 10
3. The number of days on mechanical ventilation through the LFU visit
4. The number of ICU days assessed at the LFU visit

The safety endpoints are to compare (BAY 41-6551 vs aerosolized placebo, as adjunctive therapy to IV antibiotics in both arms) as measured by:
1. The frequency of AEs
2. The progression and incidence rates of organ failure
3. The all cause mortality rate during therapy, at Day 15 and at Day 28

Secondary ID(s)

BAY41-6551/13084

Source(s) of Monetary Support

Bayer AG