To evaluate the efficacy (superiority) and safety of BAY 41-6551 as measured by the comparison of the clinical cure rate of aerosolized BAY 41-6551, administered via the PDDS Clinical, versus placebo (normal saline) at the Test-of-Cure (TOC0 visit…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy variables:
The primary efficacy variable will be the clinical response at the Test-of-Cure
(TOC) visit in the modified Intent-to-Treat (mITT; ie, ITT population plus a
pre-therapy culture positive for a Gram negative respiratory tract pathogen and
an APACHE II score of * 10) population. The mITT population will be the
primary analysis group.
Safety variables:
All patients who have received at least one dose of the study drug(s) will be
evaluated for safety in a descriptive manner. The safety analysis will include
tabulation of the type (using Medical Dictionary for Regulatory Activities
[MedDRA] glossary) and frequency of all AEs. Drug-related AEs, serious AEs
(SAEs), and premature discontinuations due to AEs will also be summarized, as
well as AEs by severity, outcome, and action taken.
Incidence tables will be presented for all AEs up to seven days after the end
of treatment and for SAEs up to Day 28 visit.
All laboratory data will be analyzed using descriptive statistics including
identification of laboratory data outside normal ranges.
Rates of organ failure will also be summarized by patient as well as by
specific organ type.
Mortality during the treatment period, Day 15 and Day 28 visit will be
summarized.
Secondary outcome
The secondary objectives are to evaluate the efficacy of BAY 41-6551 (versus
placebo) as measured by:
* The number of days on mechanical ventilation
* The number of ICU days at Day 28
* The total number of days of Gram-negative intravenous (IV) antibiotics per
patient
* CPIS changes through TOC
* The clinical relapse rates at Day 28
* The all all-cause mortality rate during therapy, at Day 15, and at Day 28
* The number of hospital days at Day 28
Secondary microbiological objectives will include comparisons (aerosolized BAY
41-6551 versus placebo) of the:
* per pathogen microbiological response rates at the TOC visit
* per patient microbiological response rate at the TOC visit
* microbiological recurrence rates at the TOC and Day 28 visit
* emergence of new respiratory pathogens during the treatment period
* emergence of resistance among baseline pathogens in those patients with
persistent infection or colonization
Background summary
Amikacin is a semi-synthetic aminoglycoside antibiotic derived from kanamycin A
with demonstrated in vitro activity against aerobic Gram-negative bacteria,
particularly those with increased resistance associated with hospital-acquired
infections. It is used intravenously
(IV) or intramuscularly (IM) for the treatment of infections caused by
Gram-negative microorganisms.
Aerosolized delivery of amikacin inhalation solution offers an attractive
adjunctive therapeutic option to systemic to IV or IM treatment of lower
respiratory tract infections because it minimizes systemic exposure while
delivering amikacin directly to the site of infection.
Aerosolized antibiotics have been administered as adjunctive therapy
tomechanically-ventilated patients with deep lung infections, specifically
including hospital-acquired pneumonia (HAP), ventilator-associated pneumonia
(VAP), and ventilator-associated tracheobronchitis. Efforts to improve
therapies of inhalation antibiotics have been hampered by the low efficiency of
pulmonary drug delivery with conventional nebulizers connected to ventilator
circuits.
Study objective
To evaluate the efficacy (superiority) and safety of BAY 41-6551 as measured by
the comparison of the clinical cure rate of aerosolized BAY 41-6551,
administered via the PDDS Clinical, versus placebo (normal saline) at the
Test-of-Cure (TOC0 visit in patients with microbiologically confirmed Gram
negative pneumonia.
Study design
This is a prospective, randomized, double-blind, placebo-controlled,
multicenter study to evaluate the safety and efficacy of 10 calendar day (20
doses) course of aerosolized BAY 41-6551 400 mg (amikacin as free base) every
12 hours versus placebo (normal saline) as adjunctive therapy in intubated and
mechanically-ventilated patients with Gram negative pneumonia. All patients
will receive parenteral antibiotics according to the 2005 ATS/IDSA guidelines
for the management of HAP, VAP, or HCAP for 10 days. Patients who are extubated
before completing the full course (10 calendar days if the first dose is
administered in the AM or 11 calendar days if the first dose is administered in
the PM [20 doses]) of aerosol therapy will be continued on aerosolized therapy
with the handheld adaptor.
Seven to ten days after completing 10 days of aerosolized treatment, patients
will be evaluated for clinical response, which will be assessed based on the
results of chest x-rays, CPIS scores, use of antibiotic therapy, and survival.
Intervention
Aerosolized BAY 41-6551/placebo is given via the Pulmonary Drug Delivery System
[PDDS Clinical] to Intubated and Mechanically Ventilated Patients with Gram
Negative Pneumonia as Adjunctive Therapy to the Standard of care antimicrobial
treatment as per the 2005 American Thoracic Society (ATS) / Infectious Diseases
Society of America (IDSA) Guidelines for the Management of Hospital-Acquired
Pneumonia (HAP), Ventilator-Associated Pneumonia (VAP), or
Healthcare-Associated Pneumonia (HCAP)
Study burden and risks
Following examinations will be performed:
- Brief Physical Exam/Vitals: 10x Treatment Visit (i.e. Day1 until Day 10)
temperatuur), lengte en gewicht: 10x Treatment Visit (i.e. Dag 1 tot Dag 10)
- Assessment of clinical signs and symptoms of pneumonia: 1X at Screening, 10x
Treatment Visit (i.e. Day1 until Day 10), 1X Premature Discontinuation Visit,
1X Test of Cure (TOC) Visit, 1X Late FU Visit
- Chest X-Ray: 1X at Screening, 1X Day 1, 1X Day 3, 1X Day 5, 1X Day 7, 1X Day
10 (End of Treatment Visit), 1X Premature Discontinuation Visit, 1X Test of
Cure Visit, 1X Late FU Visit
With chest x-rays, there is no discomfort, but the patient will be exposed to a
very low level of radiation with risks as seen for routine practice.
- Urine or Serum pregnancy test: 1X at Screening
- Hematology / Serum Chemistry / Urinalysis: 1X at Screening, 1X Day 1, 1X Day
3, 1X Day 5, 1X Day 7, 1X Day 10 (End of Treatment Visit), 1X Premature
Discontinuation Visit, 1X Test of Cure (TOC) Visit, 1X Late FU Visit
- Aerobic blood culture: 1X at Screening (if the result is positive, to be
repeated as needed , Days 1, 3, 5, 7, 10, Test of Cure Visit, Late FU Visit,
until negative)
- Arterial blood gases/pulse oximetry: 1X at Screening, 1X Day 1, 1X Day 3, 1X
Day 5, 1X Day 7, 1X Day 10 (End of Treatment Visit), 1X Premature
Discontinuation Visit, 1X Test of Cure (TOC) Visit, 1X Late FU Visit
- Serum creatinine: 10x Treatment Visit (i.e. Day1 until Day 10)
- Serum amikacin trough level: 10x Treatment Visit (i.e. Day1 until Day 10)
Possible side effects for collection of blood: discomfort, pain, bleeding,
burning, dizziness, fainting or bruising at the site where blood is drawn.
There is also a slight risk of local infection. The total amount of blood that
will be taken on any study day is about 25 mL. The maximum amount of blood that
will be taken over the entire study is about 220-230 mL.
- Collect respiratory specimen for Gram stain and culture: 1X at Screening, 1X
Day 1, 1X Day 3, 1X Day 5, 1X Day 7, 1X Day 10 (End of Treatment Visit), 1X
Premature Discontinuation Visit, 1X Test of Cure (TOC) Visit, 1X Late FU Visit
- Pleural fluid culture: 1X at Screening (if the result is positive, to be
repeated as needed , Days 1, 3, 5, 7, 10, Test of Cure Visit, Late FU Visit,
until negative)
- Study Medication: 10x Treatment Visit (i.e. Day1 until Day 10), doses every
12 hours, therefore 20 doses in total
Very little is known about the risks of amikacin as an aerosol as amikacin has
not been given to patients very often in this way. What is known are the type
of side effects that amikacin may have when given in the usual way, intravenous
or intramuscular.
When given through a needle into a patient*s muscle or vein, amikacin has
caused side effects that may include rash, fever, headache, tingling, tremor,
nausea, vomiting, eosinophilia, joint aches, anemia, and low blood pressure.
In addition, serious side effects that may occur include nephrotoxicity and
ototoxicity, and neurotoxicity, paresthesias and dysesthesias. Hearing
problems may occur after the treatment with amikacin has stopped. In the case
of hearing loss, this side effect could be permanent. Systemic administration
of amikacin can also lead to neuromuscular blockade and respiratory paralysis
in rare cases. Neuromuscular blockade causes paralysis of the skeletal
muscles. It is more likely in patients who also receive anesthetics and
neuromuscular blocking agents. The concurrent use of amikacin with potent
diuretics: ethacrynic acid or furosemide should be avoided since diuretics by
themselves may cause ototoxicity. In addition, when administered
intravenously, diuretics may increase ototoxicity of amikacin.
Over 100 patients and healthy volunteers have had the inhaled form of amikacin
via the PDDS Clinical delivery system in 4 clinical trials. The inhaled
amikacin was well tolerated in these individuals and the risks associated were
low. Possible reactions to this method of giving the drug is bronchospasm and
worsening of kidney function.
As with any medication, there is always a risk, however small, of severe
allergic reaction, which may occur within 24 hours of taking the medication and
can include severe itching, difficulty breathing, and respiratory failure that
can result in death. When a medication is given directly into the lung, there
is a chance that it could lead to irritation of the upper airways and the lung,
with coughing or wheezing and/or breathing problems as a result.
- Late Follow-up Questionnaire: 1X Late FU Visit
Please note that the questionnaire as described in the Protocol section 15.6 is
reported in the CRF and questions are going to be completed directly into the
CRF by the investigator during the Late Follow-Up face to face or phone call
with the patient. This questionnaire is a guidance for the Investigator to help
the him/her on collecting all the relevant data from the patient during the
Late Follow-Up visit/call. The patient will not complete this questionnaire
directly.
Kaiser-Wilhelm-Allee 51368
Leverkussen 51368
DE
Kaiser-Wilhelm-Allee 51368
Leverkussen 51368
DE
Listed location countries
Age
Inclusion criteria
Patients of age 18 and older, who are hospitalized, have pneumonia suspected or confirmed to be caused by Gram-negative organisms, and who are intubated and mechanically-ventilated will be selected for this study. In all patients where the pathogen is suspected of being Gram-negative, it should be confirmed as soon as culture results are available. Patients with microbiologically-confirmed pneumonia are those who have a Gram-negative organism cultured from an appropriate respiratory tract specimen collected prior to enrollment. The main inclusion criteria are:
*
Males and non-pregnant, non-lactating females, 18 years of age or older
Intubated and mechanically-ventilated
Diagnosis of pneumonia defined as presence of a new or progressive infiltrate(s) on chest radiograph
Presence of Gram-negative organism(s) indicated by Gramstain, or culture of pre-therapy respiratory specimen, or suspected Gram-negative pathogen
Impaired oxygenation
Clinical Pulmonary Infection Score (CPIS) * 6
The presence of a MDR organism in a pre-therapy respiratory
specimen OR at least two risk factors for MDR organisms
Exclusion criteria
The main exclusion criteria are:
* A history of hypersensitivity to amikacin, or other
aminoglycosides,
* 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.
Exception: 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.
* 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: Please note that patients with complete resection of non-small cell lung carcinoma are eligible for the study.
* Known or suspected active tuberculosis, cystic fibrosis, human immunodeficiency virus (HIV) infection with CD 4 count
200 cell/mm3, or invasive fungal infection of the lung, lung abscess, or empyema
* Known or suspected bacteremia secondary to Staphylococcus
aureus
* Known or suspected neuromuscular disorders such as myasthenia gravis or parkinsonism
* Has had a stroke within five days
* A positive urine and/or serum beta-human chorionic gonadotropin (*-hCG) pregnancy test
* Burns greater than 40% of total body surface area
* Patients with a serum creatinine * 2 mg/dL (177 *mol/L)
Exception: Patients with a serum creatinine * 2 mg/dL (177 *mol/L) and being treated with continuous renal replacement therapy (continuous veno-venous hemofiltration [CVVH] and continuous veno-venous hemofiltration with dialysis[CVVH-D]) or daily hemodialysis will receive the
aerosol study drug treatment (Section 8.4.6.1)
* Neutropenia (Screening absolute neutrophil count [ANC] * 103 neutrophils/mm3)
* Has been on mechanical ventilation for * 28 days
* Is participating in or has participated in other investigational interventional studies within the last 28 days prior to study treatment
* 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
* Stem cell transplantation
* Patients with documented Legionella infection (eg, Legionella pneumonia)
* Has an Acute Physiology and Chronic Health Evaluation II (APACHE II) score < 10
* Patients receiving veno-venous extracorporeal circulation membrane oxygenation (V-V ECMO)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-000906-35-NL |
| CCMO | NL43977.091.13 |