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Trial registered on ANZCTR

Registration number
Ethics application status
Date submitted
Date registered
Date last updated
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of aerosol Amikacin and Fosfomycin delivered via a new nebulizer system in mechanically ventilated patients.
Scientific title
A randomised, double blind, placebo controlled, dose escalation study of aerosolized Amikacin and Fosfomycin delivered via the PARI investigational eFlow inline nebulizer system in mechanically ventilated patients.
Secondary ID [1] 280082 0
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ventilator Associated Pneumonia (VAP) 285990 0
Ventilator Associated Tracheobronchitis (VAT) 285991 0
Condition category
Condition code
Respiratory 286179 286179 0 0
Other respiratory disorders / diseases

Study type
Description of intervention(s) / exposure
Aerosolized Amikacin and Fosfomycin delivered via the PARI Investigational eFlow Nebulizer System.

Amikacin/Fosfomycin (50mg/ml amikacin and 20mg/ml fosfomycin) will be supplied as a solution.
Single dose escalating study with 3 doses adminitered over 3 days every 24hrs. Administration will take approx 15-30mins.
Patients will sequentially fill 4 cohorts. Cohort 1 (no=3) will recive 2ml, 4ml and 6ml doses on days 1 2 and 3 respectively
Cohort 2 (no =3) will recive 4ml, 6ml and 8ml doses on days 1 2 and 3 respectively
Cohort 3 (no =3) will recive 6ml, 8ml and 10ml doses on days 1 2 and 3 respectively
Cohort 4 (no=6) will recive 8ml, 10ml and 12ml doses on days 1 2 and 3 respectively.

The eflow nebulizer system is based on eFlow technolgy. The eFlow is a single patient multiuse nebulizer that uses a vibrating perforated membrane to generate the aerosol. It will be positioned in the inspiratory tubing approx 15 cm from the Y-piece (between the Puritan Bennett 840 ventiator and the patient). Once in place the nebulizer will remain in line until all study drug doses have been delivered.
Intervention code [1] 284404 0
Treatment: Drugs
Intervention code [2] 284405 0
Treatment: Devices
Comparator / control treatment
The Placebo is 0.9% saline. On day 3 only, each patient will recieve a volume matched dose of placebo in addition to the investigation drug delivered via the Pari eFlow nebulizer ie all patients will recieve investigational drug on days 1 and 2 at the required dosage but on day 3 patients will receive investigation drug and placebo (2hrs apart). The day 3 dose of the investigation drug will be the same volume amount as for the intervention group on day 3 but will be given 2hrs apart
Control group

Primary outcome [1] 286647 0
Plasma PK amikacin/fosfomycin concentrations following 2ml, 4ml, 6ml, 8ml, 10ml and 12ml dosing of nebulised amikacin/fosfomycin
Timepoint [1] 286647 0
blood samples at pre dose, 10mins, 1hr, 2hr, 4hr, 6hr and 24hr post dose
Primary outcome [2] 286648 0
Tracheal aspirate amikacin/fosfomycin concentrations following 2ml, 4ml, 6ml, 8ml, 10ml and 12ml dosing of nebulised amikacin/fosfomycin
Timepoint [2] 286648 0
Tracheal aspirate samples at pre dose, 15mins, 1hr, 2hr, 4hr, 6hr and 24hr post dose
Secondary outcome [1] 296372 0
To evaluate the safety and tolerability of nebulised amikacin/fosfomycin
Timepoint [1] 296372 0
ongoing through study until 24 hrs post dose 3.

The following will be ultilised- physical exam, vital signs (incl Heart rate, rsp rate, Blood pressure and temp) Heamatology, serum biochemistry, Urinalysis, Oximetry and peak and plateau airway pressures.

Adverse events and SAEs will also be monitored by the PI from screening visit until 24 hours post dose 3. As this is a phase 1 study, adverse events and SAEs are unknown but will be recorded if/as they occur.
Secondary outcome [2] 296373 0
To evaluate doses of amikacin/fosfomycin for future studies
Timepoint [2] 296373 0
Ongoing through study until 24 hrs post dose 3. Final evaluation will not occur until all data is collected and analysed for Clinical Study Report.

Key inclusion criteria
Clinical diagnosis of VAP or VAT and expected to be on mechanical ventilation for at least 3 days

Gram positive or gram negative stain of the tracheal aspirate

Able to produce 1ml of tracheal aspirate for PK analyses
Minimum age
18 Years
Maximum age
80 Years
Both males and females
Can healthy volunteers participate?
Key exclusion criteria
1. Severely compromised or suppressed immune system prior to hospital admission
2. Fraction of Inspired Oxygen (FIO2) > 0.8 at enrolment
3. Relative hypoxemia (O2 saturation of less than 93% on an FIO2 =0.8) at enrolment
4. PEEP > 15cm H2O at enrolment
5. Creatinine > 0.18 mmol/L
6. Positive pregnancy screening test or breast feeding (for female participants only)
7. Burns to greater than 40% of the body
8. Current treatment with systemic amikacin or fosfomycin within 48 hours of dosing
9. A history of previous allergy or sensitivity to amikacin or fosfomycin
10. Participation in a clinical study with administration of an investigational drug product within three months of Investigational Product administration.
11. Blood hemoglobin < 70 g/L at enrolment.
12. Any other condition which in the view of the Investigator is likely to interfere with the study or put the patient at risk.

Study design
Purpose of the study
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?

Intervention assignment
Other design features
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment status
Date of first participant enrolment
Date of last participant enrolment
Date of last data collection
Sample size
Accrual to date
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 6959 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 284833 0
Commercial sector/Industry
Name [1] 284833 0
Cardeas Pharma
Address [1] 284833 0
2025 First Avenue, Suite 1200 Seattle WA9121
Country [1] 284833 0
United States of America
Primary sponsor type
Commercial sector/Industry
Cardeas Pharma
2025 First Avenue, Suite 1200 Seattle WA9121
United States of America
Secondary sponsor category [1] 283711 0
Commercial sector/Industry
Name [1] 283711 0
Address [1] 283711 0
124 Lipson St Port Adelaide SA 5015
Country [1] 283711 0

Ethics approval
Ethics application status
Ethics committee name [1] 286823 0
Ethics committee address [1] 286823 0
Ethics committee country [1] 286823 0
Date submitted for ethics approval [1] 286823 0
Approval date [1] 286823 0
Ethics approval number [1] 286823 0

Brief summary
Ventilator Associated Tracheobronchitis (VAT) and Ventilator Associated Pneumonia (VAP) are common complications of mechanical ventilation, that may result in prolonging ICU stays and can also be fatal for critically ill patients. The standard treatment is currently intravenous antibiotics. The emergence of multidrug resistant bacteria and Gram negative pathogens makes this approach increasingly less effective. In order to improve treatment options, aerosol antibiotics have been investigated. They generally result in a higher sputum concentration compared to intravenous delivery, with reduced systemic exposure. Studies of aerosolized antibiotics to treat or to prevent VAP indicate benefits such as lower rates of VAP at the end of treatment, reduced usage of systemic antibiotics, and earlier weaning of patients from the ventilator, leading to shorter stays in the ICU. Since VAP may be caused by Gram negative and/or positive bacteria, an adequate antibiotic regimen needs to cover both, and also have coverage for MRSA. This study therefore plan to investigate the combination of amikacin and fosfomycin.
Trial website
Trial related presentations / publications
Public notes

Principal investigator
Name 33872 0
Dr Tim Leong
Address 33872 0
Alfred Hospital, ICU Dept, Commercial Rd, Melbourne 3004 VIC
Country 33872 0
Phone 33872 0
61 3 9076 2000
Fax 33872 0
Email 33872 0
Contact person for public queries
Name 17119 0
Ms Tammy Abuan
Address 17119 0
2025 First Avenue, Suite 1200 Seattle WA 98121
Country 17119 0
United States of America
Phone 17119 0
Fax 17119 0
Email 17119 0
Contact person for scientific queries
Name 8047 0
Ms Tammy Abuan
Address 8047 0
2025 First Avenue, Suite 1200 Seattle WA 98121
Country 8047 0
United States of America
Phone 8047 0
Fax 8047 0
Email 8047 0

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary