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Trial registered on ANZCTR


Registration number
ACTRN12609000145202
Ethics application status
Approved
Date submitted
14/11/2008
Date registered
11/03/2009
Date last updated
30/08/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
Inhaled mannitol improves sputum clearance in intubated patients
Scientific title
Safety and efficacy of dry powder mannitol inhalation by intubated patients with sputum retention
Secondary ID [1] 281121 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sputum retention in intubated patients 3984 0
Condition category
Condition code
Respiratory 4667 4667 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dry powder mannitol is administered by aerosol to stable intubated patients using a standard technique of manual hyperinflation.
Mannitol is a naturally occurring sugar alcohol and osmotic agent that has been shown to improve sputum clearance and health status when delivered as a dry powder aerosol to patients with bronchiectasis and cystic fibrosis. The mechanisms of action include cough stimulation, improving innate mucociliary clearance by optimizing cilia efficiency and altering sputum rheology. it is postulated that if mannitol can be effectively delivered to the airways of intubated patients in intensive care, clearance of secretions can be optimized.
The technology to generate the powder aerosol using an inline device, incorporated into the ventilation circuit is not yet available but we have demonstrated that the powder can be delivered to the end of the endotracheal tube in vitro using a hand held bag, valve and delivery device.
Delivering an aerosol by bag and valve to ventilated patients is a standard technique for the administration of nebulised aerosols. This is a similar technique to manual hyperinflation with a bag and valve, a standard technique of hand ventilating intubated patients which has been shown to improve oxygenation and sputum clearance. This study uses this technique to disperse and deliver the mannitol to the airways via an endotracheal or tracheostomy tube.
Manual Hyperinflation (as per hospital Manual Hyperinflation procedure)- using a Mayo disposable bag with safety pressure release valve. A two handed deflation of bag, in synchrony with inspiratory effort.
Using flow curves obtained while performing normal manual hyperinflation and reproducing the technique in vitro has demonstrated that the dose delivered to the distal end of the endotracheal tube is up to 62% of the nominal dose and to the end of the tracheostomy tube is up to 73%. This is comparable to the estimated dose delivered to the airway of unventilated patients (300mg) nominal dose to bronchiectasis patients and 40% is respirable.
Dry powder mannitol 160mg (4 X 40mg capsules) dose to approximate 120mg to the airways. If no clinical effect is seen at the time of interim analysis (after 10 patients) the dose will be increased to 4 X 80mg capsules (approx. 200mg delivered to the airways). Patients will receive one dose per day for 4 consecutive days - study drug on alternate days and placebo on the other days. It takes less than 15 minutes to deliver the total dose.
Eligible and consented patient will be randomised to group A and receive active agent (dry powder mannitol) on Day 1 , or group B and receive placebo (empty capsules ) on Day 1.
The patient will be monitored during and after the aerosol delivery procedure in Intensive Care Unit for 1 hour by the patients nurse, criticlal care consultant, experienced Intensive Care nurse or physiotherapist delivering the aerosol. After that hour, there will be the standard one Intensive Care nurse to one patient allocation while in Intensive Care Unit. Then monitored by health professionals while in hospital.
The duration of the wash-out period is 75 minutes.
Intervention code [1] 3704 0
Treatment: Drugs
Comparator / control treatment
Empty capsuls are delivered with manual hyperinflation to intubated patients and each patient is a control and crossed over.
Patients will receive one dose of 160mg placebo inhalation (4 empty capsules) using the aerosol delivery with manual hyperinflation via the endotracheal or tracheostomy tube to the patients airways. This is administered once a day on alternate days to the mannitol delivery. The followup is the same every day for the four days of trial aerosol administration.
Control group
Placebo

Outcomes
Primary outcome [1] 5071 0
Efficacy - A clinical effect will have occurred if there is a clear difference in weight of sputum expectorated over the 6 and 24 hours post aerosol delivery. The sputum is suctioned from the patients airways with a suction catheter down the endotracheal or tracheostomy tube. The suction catheter is connected to a pre-weighed sputum trap. This sputum trap is then weighed on scales and assessed at 6 hours and at 24 hours following inhaled study agent.
Timepoint [1] 5071 0
weight of sputum aspirated over the 6 hour and 24 hour period after inhaled study agent. The samples will be collected in pre-weighed sputum collection traps and re-weighed.
Primary outcome [2] 5235 0
Safety. The study medication/aerosol will be considered safe if there are no serious side effects or serious adverse events compared with the placebo group.
The patient is continuously monitored by experienced health professionals (Intensive Care consultant, nurse and experienced nurse or physiotherapist in the Intensive Care Unit when the inhaled agent is administered and at least 1 hour following administration. Then patient will continue to be monitored as per Intensive Care standard - one nurse to one patient.
The procedure will be terminated if, due to cough or otherwise, the patient has:
-high respiratory rate(>35) for a sustained period of 3 minutes.
-desaturation(<90% or >20% below baseline)
-hypotension (MAP<65 for sustained period for 3 minutes)
-patient shows signs of distress or change in level of consciousness.
Timepoint [2] 5235 0
Hourly standard observations for 24 hours post study day 4. Patients will be followed up for 28 days post test to assess for adverse events - reportable under adverse event log and repeat sputum
Secondary outcome [1] 8821 0
Clinical effect - cough stimulation. Spontaneous cough frequency is recorded immediately after dose delivered (number of coughs over a 5 minute period, documented as coughs per minute and repeated at 30 and 60 minutes post dose) this will be measured by a single investigator.
Timepoint [1] 8821 0
The number of coughs over a 5 minute period, documented as coughs per minute and repeated at 30 and 60 minutes post dose.

Eligibility
Key inclusion criteria
Intubated patients with moderate or heavy sputum production or thick sputum,
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
<18 years, Asthma, pregnancy, neuromuscular blocker therapy, unstable haemodynamics, unstable respiratory function, contraindication to bronchodilators, contraindication to manual hyperinflation, endotracheal or tracheostomy tube <7.5 or >8.5, expected to be intubated <4 days, contraindication ot endotracheal suction, clinical condition where cough and suction are contraindicated, death is imminent, unable to obtain consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
randomized, placebo controlled double crossover study.
Patients will be recruited from general Intensive Care Unit (ICU), general High Dependency Unit (HDU), neurosurgical ICU and cardiothoracic ICU. They will be identified by the ICU medical , nursing or allied health staff under the inclusion criteria. They will be assessed by the principal or associate investigators, enrolled if they meet the inclusion/exclusion criteria and informed consent obtained. The patients will then be allocated the next sequential study number.
The pharmacist will make up patient packs numbered 1-25 and allocated each patient pack as per computerised sequence for Group A or Group B.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised sequence generation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
The people receiving the treatment and the people administering the treatment will be blinded up to the point of randomisation and those delivering the treatment may become unblinded as the treatment is given
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1295 0
2050

Funding & Sponsors
Funding source category [1] 4172 0
Hospital
Name [1] 4172 0
Royal Prince Alfred Hospital- Intensive Care Services
Country [1] 4172 0
Australia
Funding source category [2] 4173 0
University
Name [2] 4173 0
University of Sydney-Department of Pharmacy
Country [2] 4173 0
Australia
Funding source category [3] 285902 0
Commercial sector/Industry
Name [3] 285902 0
Pharmaxis PtyLtd
Country [3] 285902 0
Australia
Primary sponsor type
Individual
Name
A/Prof Paul Phipps
Address
Intensive Care Services
level 3, Building 89
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN
NSW 2050
Country
Australia
Secondary sponsor category [1] 3747 0
Individual
Name [1] 3747 0
Dorrilyn Rajbhandari
Address [1] 3747 0
Intensive Care Services
level 3 Building 89
Royal Prince Alfred Hospital
Missenden Road
Camperdown
NSW 2050
Country [1] 3747 0
Australia
Other collaborator category [1] 477 0
Individual
Name [1] 477 0
Prof Hak-Kim Chan
Address [1] 477 0
University of Sydney
Faculty of Pharmacy
Sydney
NSW 2006
Country [1] 477 0
Australia
Other collaborator category [2] 478 0
Individual
Name [2] 478 0
Dr Patricia Tang
Address [2] 478 0
Faculty of Pharmacy
University of Sydney
Sydney
NSW 2006
Country [2] 478 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6641 0
SSWAHS Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 6641 0
Ethics committee country [1] 6641 0
Australia
Date submitted for ethics approval [1] 6641 0
Approval date [1] 6641 0
12/12/2008
Ethics approval number [1] 6641 0
08/RPAH/495

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29134 0
Address 29134 0
Country 29134 0
Phone 29134 0
Fax 29134 0
Email 29134 0
Contact person for public queries
Name 12291 0
A/Prof Paul Phipps
Address 12291 0
Intensive Care Services
level 3, building 89
Royal Prince Alfred Hospital
Missenden Road
Camperdown
NSW 2050
Country 12291 0
Australia
Phone 12291 0
+61 2 9515 7668
Fax 12291 0
Email 12291 0
[email protected]
Contact person for scientific queries
Name 3219 0
A/Prof Paul Phipps
Address 3219 0
Intensive Care services
Level 3, building 89
Royal Prince Alfred Hospital
Camperdown
NSW 2050
Country 3219 0
Australia
Phone 3219 0
+61 2 9515 7668
Fax 3219 0
+61 2 9515 5040
Email 3219 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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