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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01952470
Registration number
NCT01952470
Ethics application status
Date submitted
31/08/2013
Date registered
30/09/2013
Date last updated
28/08/2019
Titles & IDs
Public title
Preliminary Study of Dornase Alfa to Treat Chest Infections Post Lung Transplant.
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Scientific title
Investigating the Role of Nebulised Mucolytic Therapy During Lower Respiratory Tract Infections Post Lung Transplantation.
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Secondary ID [1]
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DOI:10.1111/tri.13400
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Secondary ID [2]
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342/13
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Lung Transplant Infection
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Lower Respiratory Tract Infection
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Condition category
Condition code
Infection
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Studies of infection and infectious agents
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Infection
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Other infectious diseases
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Infection
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Sexually transmitted infections
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Respiratory
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Other respiratory disorders / diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Dornase Alfa
Treatment: Drugs - Isotonic Saline.
Experimental: Dornase Alfa - Once daily, 2.5ml inhaled dornase alfa.
Active Comparator: Isotonic Saline - Once daily, 5ml inhaled 0.9% normal saline.
Treatment: Drugs: Dornase Alfa
Once daily, 2.5ml inhaled dornase alfa (evening if able) with inhalational breathing routine (IBR). IBR consists of 4 slow deep breaths followed by 6 relaxed breaths, repeated until nebuliser is complete, coughing when the patient feels the need to expectorate. The patient will be instructed to sit in an upright position with upper limb support as able.
Treatment: Drugs: Isotonic Saline.
Once daily, 5ml inhaled 0.9% normal saline (evening if able) with inhalational breathing routine (IBR). IBR consists of 4 slow deep breaths followed by 6 relaxed breaths, repeated until nebuliser is complete, coughing when the patient feels the need to expectorate. The patient will be instructed to sit in an upright position with upper limb support as able.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Lung Clearance Index 2% (LCI2%)
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Assessment method [1]
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A measure of ventilation inhomogeneity as measured during multiple breath washout (MBW) of inert tracer gases. It has been shown that this test is a potentially more sensitive measure of peripheral airway obstruction than regular spirometry in short term (4 week) mucolytic interventional studies in pediatric Cystic Fibrosis (CF)(17-18). This test would be performed within the respiratory physiology lung function laboratory on site at all assessment points, by an assessor who is blinded to group allocation for follow up data collection.
Conventionally used primary endpoints in this population, such as regular spirometry(3), may be unable to detect between group differences without large sample sizes and long treatment durations. Based on current evidence from non-lung transplant populations, LCI has been able to show short-term change, whereas regular spirometry has not shown change(17-18).
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Timepoint [1]
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1 month, 3 months
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Secondary outcome [1]
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Multiple Breath Washout (MBW)
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Assessment method [1]
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Multiple breath washout is a sensitive measure of respiratory function performed with the subject in a seated position, breathing a fixed tidal volume (1L) of inert gas (nitrogen) from functional residual capacity (FRC) via mouthpiece.
Two common outcomes of MBW are Sacin, a measure of gas mixing at the diffusion front, or acinar entrance in the airways, and Scond, in the proximal, conductive zones. An increase in either Sacin or Scond represents an increase in ventilation heterogeneity (deterioration). Both increase with age, normal values are non-zero between 0-0.25(Sacin) and 0-0.1(Scond).
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Timepoint [1]
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1 month, 3 months
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Secondary outcome [2]
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Functional Residual Capacity (FRC)
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Assessment method [2]
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Volume of air remaining in the lungs after normal expiration.
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Timepoint [2]
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1 month, 3 months
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Secondary outcome [3]
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Forced Expiratory Volume in 1 Second (FEV1) Liters
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Assessment method [3]
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FEV1 is the maximal amount of air you can forcefully exhale in one second.
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Timepoint [3]
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1 month, 3 months.
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Secondary outcome [4]
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Forced Expiratory Volume in 1 Second (FEV1) Percent.
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Assessment method [4]
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FEV1 is the maximal amount of air you can forcefully exhale in one second.
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Timepoint [4]
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1 month, 3 months
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Secondary outcome [5]
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Forced Vital Capacity (FVC) Liters
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Assessment method [5]
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Forced vital Capacity (FVC) is a measure of the amount of air someone can forcibly expel out of the lungs after taking a breath to fill the lungs as much as possible.
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Timepoint [5]
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1 month, 3 months
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Secondary outcome [6]
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Forced Vital Capacity (FVC) Percent
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Assessment method [6]
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Forced vital Capacity (FVC) is a measure of the amount of air someone can forcibly expel out of the lungs after taking a breath to fill the lungs as much as possible.
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Timepoint [6]
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1 month, 3 months
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Secondary outcome [7]
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Forced Expiratory Ratio (FER)
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Assessment method [7]
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FER represents the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).
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Timepoint [7]
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1 month, 3 months
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Secondary outcome [8]
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Leicester Cough Questionnaire (LCQ) - Change
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Assessment method [8]
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Cough specific quality of life questionnaire. The LCQ is a 19-question tool, validated in chronic lung disease other than lung transplant(19). Scale 1-7 for physical, psychological, social. Combined score of 3-21 for total. Lower=worse.
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Timepoint [8]
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1 month, 3 months.
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Secondary outcome [9]
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St. George's Respiratory Questionnaire (SGRQ) - Change
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Assessment method [9]
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The SGRQ is a 2-part questionnaire, validated in chronic lung disease other than lung transplant(20).
50 items, 76 weighted responses. Scores range 0-100, higher=worse.
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Timepoint [9]
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1 month, 3 months.
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Secondary outcome [10]
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Inpatient Days
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Assessment method [10]
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Number of days spent in the acute inpatient setting.
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Timepoint [10]
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Across study period (3 months).
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Secondary outcome [11]
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Oral, Inhaled or Intravenous Antibiotic (IVAB) Days.
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Assessment method [11]
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Antibiotic use for the treatment of lower respiratory tract infections (LRTI) only.
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Timepoint [11]
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Over study period (3 months).
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Secondary outcome [12]
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Number of Hospitalizations
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Assessment method [12]
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Number of admissions to the acute setting.
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Timepoint [12]
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Over study period (3 months).
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Secondary outcome [13]
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C-reactive Protein (CRP)
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Assessment method [13]
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An inflammatory marker measured with routine blood tests on admission with LRTI. Taken during inpatient (IP) stay and routinely on outpatient (OP) follow-up. Existing / available data only will be used - no extra routine bloods will be taken on account of study inclusion.
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Timepoint [13]
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1 month, 3 months.
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Secondary outcome [14]
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Breathlessness, Cough and Sputum Scale (BCSS) - Exacerbations
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Assessment method [14]
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Self-reported symptom severity, used as a daily patient diary. The BCSS is a 12 point self-reported symptom severity score, consisting of 3 sections concerning how much difficulty the subject is having with breathing; subjective cough symptoms and trouble caused by sputum, each scoring between 0-4, combining to a total score of 0-12 (higher=worse). This scale is validated for daily use in Chronic Obstructive Pulmonary Disease (COPD)(21).
An exacerbation was defined as an increase in BCSS>1 with =5 days preceding stability.
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Timepoint [14]
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Daily up to 3 months.
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Secondary outcome [15]
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BronkoTest (Sputum Colour) - Purulent Sputum Days
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Assessment method [15]
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Sputum colour chart. Sputum colour has been shown to correlate with physiological infection in other chronic lung disease groups(22).
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Timepoint [15]
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Daily up to 3 months.
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Eligibility
Key inclusion criteria
- Post bilateral sequential lung transplant
- Capable of performing airway clearance techniques / nebulisers
- Pulmonary exacerbation as defined by Fuchs et al
- Must be productive of sputum
- Able to provide informed consent within 48 hours of presentation.
*Fuchs Scale(8): Treatment with / without parenteral antibiotics for 4/12 signs and
symptoms:
- Change in sputum
- New or increased haemoptysis
- Increased cough
- Increased dyspnoea
- Malaise, fever or lethargy
- Temp above 38
- Anorexia or weight loss
- Sinus pain or tenderness
- Change in sinus discharge
- Change in physical examination of the chest
- Radiographic changes indicative of pulmonary infection
- Decrease in pulmonary function by 10 % or more
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Paediatric transplant <18yrs
- Single lung transplant - native lung physiology may confound outcome measures
- Interstate - unable to complete follow up
- Unable to perform lung function testing
- Unable to complete subjective outcome measures- unable to read English fluently
- Critically unwell / intensive care unit / ventilator dependent
- Within 2 months of transplant date *Cystic Fibrosis will be stratified
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people assessing the outcomes
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
31/10/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
23/08/2017
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Sample size
Target
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Accrual to date
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Final
32
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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The Alfred - Melbourne
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Recruitment postcode(s) [1]
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3000 - Melbourne
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Funding & Sponsors
Primary sponsor type
Other
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Name
The Alfred
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Address
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Country
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Other collaborator category [1]
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Other
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Name [1]
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The Alfred Research Trusts Small Project Grant.
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Address [1]
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Country [1]
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Other collaborator category [2]
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Other
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Name [2]
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Dr Carey Denholm and Laura Denholm
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Address [2]
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Country [2]
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Ethics approval
Ethics application status
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Summary
Brief summary
Patients who have undergone lung transplantation are at an increased risk of developing chest
infections due to long-term medication suppressing the immune response. In other chronic lung
diseases such as cystic fibrosis (CF) and bronchiectasis, inhaled, nebulised mucolytic
medication such as dornase alfa and isotonic saline are often used as part of the management
of lung disease characterized by increased or retained secretions. These agents act by making
it easier to clear airway secretions, and are currently being used on a case-by-case basis
post lung transplantation.
To the investigators knowledge, these agents have not been evaluated via robust scientific
investigation when used post lung transplant, yet are widely used in routine practice.
Patients post lung transplant must be investigated separately as they exhibit differences in
physiology that make the clearance of sputum potentially more difficult when compared to
other lung diseases. Lower respiratory tract infections are a leading cause of hospital
re-admission post lung transplant. Therefore, this highlights the need for a randomized
controlled trial. The aim of this study is to assess the efficacy of dornase alfa, compared
to isotonic saline, in the management of lower respiratory tract infections post lung
transplant. Investigators hypothesize that dornase alfa will be more effective than isotonic
saline.
The effect of a daily dose of dornase alfa and isotonic saline will be compared over a
treatment period of 1 month. Patients admitted to hospital suffering from chest infections
characterized by sputum production post lung transplant will be eligible for study inclusion.
Patients will be followed up through to 3 months in total to analyze short-medium term
lasting effect. Investigators wish to monitor physiological change within the lung
non-invasively via lung function analysis whilst assessing patient perceived benefit via
cough specific quality of life questionnaires. These measures will be taken at study
inclusion and repeated after 1 month and 3 months. Day to day monitoring will be performed
via patient symptom diaries, incorporating hospital length of stay and exacerbation rate. The
outcomes of this study have the potential to guide clinical decision-making and highlight
safe and efficacious therapies.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01952470
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Trial related presentations / publications
Hertz MI. The Registry of the International Society for Heart and Lung Transplantation--Introduction to the 2012 annual reports: new leadership, same vision. J Heart Lung Transplant. 2012 Oct;31(10):1045-51. doi: 10.1016/j.healun.2012.08.003. No abstract available. Erratum In: J Heart Lung Transplant. 2013 Feb;32(2):275.
Herve P, Silbert D, Cerrina J, Simonneau G, Dartevelle P. Impairment of bronchial mucociliary clearance in long-term survivors of heart/lung and double-lung transplantation. The Paris-Sud Lung Transplant Group. Chest. 1993 Jan;103(1):59-63. doi: 10.1378/chest.103.1.59.
Munro PE, Button BM, Bailey M, Whitford H, Ellis SJ, Snell GI. Should lung transplant recipients routinely perform airway clearance techniques? A randomized trial. Respirology. 2008 Nov;13(7):1053-60. doi: 10.1111/j.1440-1843.2008.01386.x. Epub 2008 Aug 18.
Veale D, Glasper PN, Gascoigne A, Dark JH, Gibson GJ, Corris PA. Ciliary beat frequency in transplanted lungs. Thorax. 1993 Jun;48(6):629-31. doi: 10.1136/thx.48.6.629.
Humplik BI, Sandrock D, Aurisch R, Richter WS, Ewert R, Munz DL. Scintigraphic results in patients with lung transplants: a prospective comparative study. Nuklearmedizin. 2005 Apr;44(2):62-8. doi: 10.1267/nukl05020062.
Higenbottam T, Jackson M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis. 1989 Jul;140(1):58-61. doi: 10.1164/ajrccm/140.1.58.
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl ME. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994 Sep 8;331(10):637-42. doi: 10.1056/NEJM199409083311003.
Touleimat BA, Conoscenti CS, Fine JM. Recombinant human DNase in management of lobar atelectasis due to retained secretions. Thorax. 1995 Dec;50(12):1319-21; discussion 1323. doi: 10.1136/thx.50.12.1319.
Voelker KG, Chetty KG, Mahutte CK. Resolution of recurrent atelectasis in spinal cord injury patients with administration of recombinant human DNase. Intensive Care Med. 1996 Jun;22(6):582-4. doi: 10.1007/BF01708100.
Riethmueller J, Borth-Bruhns T, Kumpf M, Vonthein R, Wiskirchen J, Stern M, Hofbeck M, Baden W. Recombinant human deoxyribonuclease shortens ventilation time in young, mechanically ventilated children. Pediatr Pulmonol. 2006 Jan;41(1):61-6. doi: 10.1002/ppul.20298. Erratum In: Pediatr Pulmonol. 2006 Apr;41(4):388.
Crockett AJ, Cranston JM, Latimer KM, Alpers JH. Mucolytics for bronchiectasis. Cochrane Database Syst Rev. 2000;(2):CD001289. doi: 10.1002/14651858.CD001289.
Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD001506. doi: 10.1002/14651858.CD001506.pub3.
Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006 Jan 19;354(3):229-40. doi: 10.1056/NEJMoa043900.
Nicolson CH, Stirling RG, Borg BM, Button BM, Wilson JW, Holland AE. The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis. Respir Med. 2012 May;106(5):661-7. doi: 10.1016/j.rmed.2011.12.021. Epub 2012 Feb 19.
Safdar A, Shelburne SA, Evans SE, Dickey BF. Inhaled therapeutics for prevention and treatment of pneumonia. Expert Opin Drug Saf. 2009 Jul;8(4):435-49. doi: 10.1517/14740330903036083.
Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, Kerrigan S, Gustafsson P, Ratjen F. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J. 2011 Apr;37(4):806-12. doi: 10.1183/09031936.00072510. Epub 2010 Aug 6.
Amin R, Subbarao P, Jabar A, Balkovec S, Jensen R, Kerrigan S, Gustafsson P, Ratjen F. Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function. Thorax. 2010 May;65(5):379-83. doi: 10.1136/thx.2009.125831.
Raj AA, Pavord DI, Birring SS. Clinical cough IV:what is the minimal important difference for the Leicester Cough Questionnaire? Handb Exp Pharmacol. 2009;(187):311-20. doi: 10.1007/978-3-540-79842-2_16.
Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J. 2002 Mar;19(3):398-404. doi: 10.1183/09031936.02.00063702.
Leidy NK, Rennard SI, Schmier J, Jones MK, Goldman M. The breathlessness, cough, and sputum scale: the development of empirically based guidelines for interpretation. Chest. 2003 Dec;124(6):2182-91. doi: 10.1378/chest.124.6.2182.
Stockley RA, Bayley D, Hill SL, Hill AT, Crooks S, Campbell EJ. Assessment of airway neutrophils by sputum colour: correlation with airways inflammation. Thorax. 2001 May;56(5):366-72. doi: 10.1136/thorax.56.5.366.
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Public notes
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Contacts
Principal investigator
Name
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Benjamin J Tarrant, B.Physio
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Address
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The Alfred
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01952470
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