Clinical trial NCT01952470
Conditions: Lung Transplant Infection Lower Respiratory Tract Infection
Keywords: Lung transplantation Respiratory Tract Infections Respiratory Therapy Isotonic Solutions Sodium Chloride Postoperative complications Postoperative care dornase alfa
Sponsor: The Alfred
Start date: 2013-10-31; Completion date: 2017-08-23
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:
According to the International Society for Heart and Lung Transplantation (ISHLT), the incidence of lung transplants per annum worldwide is rising annually, with over 3000 transplants completed according to the latest registry(1). The Alfred is a state-wide, internationally renowned lung transplant service, transplanting between 59 - 79 patients over the last two calendar years, with a wait-list of more than 40 potential recipients. This makes it one of only 7 centres worldwide completing this volume of transplants(1).

Patients who have undergone lung transplantation for end-stage lung disease are subject to life-long immunosuppression to prevent allograft rejection. These patients are at a heightened risk of acquiring opportunistic lower respiratory tract infections (LRTI)(2), often characterized by sputum retention and / or production, which can have a negative impact on both morbidity and mortality(3). Patients post lung transplant often find it difficult to clear secretions due to an alteration in normal physiology. Transplanted lung tissue is denervated upon resection from the donor, which has been shown to lead to slower cilial beat frequencies(4), impaired muco-ciliary clearance (MCC) rates(4-6) and an impaired cough reflex(7). Devascularisation to lung tissue post ischaemic surgical time in the acute period can lead to an alteration in mucosal properties and structural changes around anastomoses, which may further impair the ability to clear secretions(3).

Inhaled, nebulised mucolytic agents are commonly used in the management of other suppurative chronic lung diseases characterized by excessive production of secretions. Dornase alfa acts by digesting the extracellular deoxyribonucleic acid (DNA) released by inflammatory cells during infection(8). It has been shown to have positive long-term effects on lung function in cystic fibrosis (CF)(8) and short-term benefits treating atelectasis and mucous plugging in acute, non-CF adult and pediatric cases(9-11). Yet shown to be safe in normal subjects(8), it has been shown to have a detrimental effect on pulmonary function in non-CF bronchiectasis(12).

Inhaled saline acts by restoring the airway surface liquid layer of the mucosa, favorably altering mucous properties, accelerating MCC and stimulating cough(13-14). Positive evidence exists for hypertonic saline (6-7%) in CF(13-14) and both hypertonic and isotonic (0.9%) saline in non-CF bronchiectasis(15). There is discussion of clinical use of saline as a mucolytic in the post transplant patient(16) with no evidence by way of randomized controlled trial to demonstrate effect. There is no current evidence on the use of inhaled mucolytics post transplant.

Currently, both dornase alfa and saline (isotonic / hypertonic) are used in the inpatient and outpatient setting at this institution as a reactive treatment strategy for LRTI characterized by excessive sputum production and / or retention. The investigators believe this warrants a short-term, randomized trial to assess the efficacy of current practice, and to evaluate whether dornase alfa is more effective than 0.9% saline, a cheaper, more accessible alternative.

Aim

To evaluate the efficacy of inhaled dornase alfa compared to inhaled isotonic (0.9%) saline on:

* Quantitative and qualitative respiratory outcomes
* The need for antibiotics, length of stay and exacerbation / re-admission rates

Hypothesis Dornase alfa is more effective than isotonic saline in the post lung transplant population during LRTI.

Study design Phase 2, assessor blinded, prospective randomized controlled trial.

Intervention On admission to the ward as an inpatient, patients who give informed consent within 48 hours of initial presentation will be randomly assigned to one of two groups defined below. The randomization sequence will be concealed using opaque envelopes. Randomization will be stratified according to pre-transplant diagnosis (cystic fibrosis or not) as people with cystic fibrosis are expected to be younger and have a different underlying systemic disease process.

All participants will undertake treatment for one month according to their allocated group, with follow up to 3 months, (2 months off randomized intervention). Both groups will continue to do their regular prescribed physical exercise routine over the course of the study.

Timing of assessment All outcome measures will be performed at study baseline, 1 month and 3 months follow-up. Daily outcome measures used as a monitoring diary are an exception. There are no cough-specific quality of life questionnaires validated for use in the post lung transplant population.

Sample size and power calculation A total of 30 participants (15 in each group) will enter this study. The probability is 80 percent that the study will detect a treatment difference at a two-sided 0.05 significance level, if the true difference between treatments is 1.000 unit in lung clearance index (LCI).

This is a conservative estimate that is smaller than previous differences found in pediatric populations(17-18). This is based on the assumption that the standard deviation of the response variable is 0.94 units(17-18).

As a phase 2 study, this project is powered to detect differences in physiological outcomes, rather than quality of life or hospitalization. However, should the treatment prove to have physiological benefits, the secondary outcomes of this study will provide critical information for powering a future phase 3 trial.

Feasibility: Approximately 12 patients with pulmonary exacerbations are admitted under the lung transplant service each month (minimum estimate). Investigators estimate that 70% will meet the eligibility criteria for the study and 50% will consent to participate. It is therefore anticipated that it will be possible to recruit the numbers needed for this study in 8 months.

Statistical analysis An intention to treat analysis will be conducted, with inclusion of all randomized participants, regardless of study completion. Data for continuous outcomes including LCI will be analyzed using a linear mixed models analysis, which makes use of all available data at each time point and is less affected by incomplete data than analysis of variance. The likelihood of exacerbation or hospitalization during the follow-up period for the dornase alpha group will be expressed as a relative risk compared to the isotonic saline group.

Bias / Confounders There is potential for performance bias in this study due to the lack of ability to blind participants to their allocated treatment regimen. Investigators are unable to package medications in a way other than that currently produced. It is the aim to outline, as part of the participant information and consent form (PICF), that both inhaled medications have proven to be efficacious (and detrimental in certain circumstances) in disease processes other than post lung transplant LRTI. Detection bias will be controlled by the use of a blinded outcome assessor for all follow-up data collection points.

Potential confounders in this study include the diagnosis of bronchiolitis obliterans (BOS), or chronic lung rejection, during which LRTI occurs simultaneously. Patients with a diagnosis of BOS may in fact demonstrate differences in lung physiology and ease of sputum expectoration, which may have an effect on outcomes variables. We feel that excluding these patients may have a detrimental impact on the external validity of this study, therefore we will stratify patients according to a diagnosis of BOS on study inclusion.

Outcomes and Significance This will be the first randomized controlled trial to analyze inhaled dornase alfa and isotonic saline in the post lung transplant population.

The outcome of this trial will help to guide physiotherapy and pharmacological management of post lung transplant patients with LRTI in the future, both nationally and internationally.

Arms: arm 1: Once daily, 2.5ml inhaled dornase alfa. arm 2: Once daily, 5ml inhaled 0.9% normal saline.
Interventions: intervention 1: Dornase Alfa intervention 2: Isotonic Saline.
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
1 
Investigating the role of nebulised mucolytic therapy during lower respiratory 
tract infections post lung transplantation 
 
Clinical Protocol 
 
Background 
According to the International Society for Heart and Lung Transplantation 
(ISHLT), the incidence of lung transplants per annum worldwide is rising 
annually, with over 3000 transplants completed according to the latest registry10. 
The Alfred is a state-wide, internationally renowned lung transplant service, 
transplanting between 59 - 79 patients over the last two calendar years, with a 
waitlist of more than 40 potential recipients. This makes it one of only 7 centres 
worldwide completing this volume of transplants10.  
 
Patients who have undergone lung transplantation for end-stage lung disease are 
subject to life-long immunosuppression to prevent allograft rejection. These 
patients are at a heightened risk of acquiring opportunistic lower respiratory tract 
infections (LRTI)13, often characterised by sputum retention and / or production, 
which can have a negative impact on both morbidity and mortality11. Patients 
post lung transplant often find it difficult to clear secretions due to an alteration in 
normal physiology. Transplanted lung tissue is denervated upon resection from 
the donor, which has been shown to lead to slower cilial beat frequencies12, 
impaired muco-ciliary clearance (MCC) rates12-14 and an impaired cough reflex25. 
Devascularisation to lung tissue post ischaemic surgical time in the acute period 
can lead to an alteration in mucosal properties and structural changes around 
anastomoses, which may further impair the ability to clear secretions11. 
 
Inhaled, nebulised mucolytic agents are commonly used in the management of 
other suppurative chronic lung diseases characterised by excessive production of 
secretions. Dornase alfa acts by digesting the extracellular DNA released by 
inflammatory cells during infection8. It has been shown to have positive long-
term effects on lung function in cystic fibrosis (CF)8 and short-term benefits 
treating atelectasis and mucous plugging in acute, non-CF adult and paediatric 
cases3-5. Yet shown to be safe in normal subjects8, it has been shown to have a 
detrimental effect on pulmonary function in non-CF bronchiectasis17. 
 
Inhaled saline acts by restoring the airway surface liquid layer of the mucosa, 
favourably altering mucous properties, accelerating MCC and stimulating cough1-2. 
Positive evidence exists for hypertonic saline (6-7%) in CF1-2 and both hypertonic 
and isotonic (0.9%) saline in non-CF bronchiectasis6. There is discussion of 
clinical use of saline as a mucolytic in the post transplant patient9 with no 
evidence by way of randomised controlled trial to demonstrate effect. There is no 
current evidence on the use of inhaled mucolytics post transplant. 
 
Currently, both dornase alfa and saline (isotonic / hypertonic) are used in the 
inpatient and outpatient setting at this institution as a reactive treatment strategy 
for LRTI characterised by excessive sputum production and / or retention. We 
believe this warrants a short-term, randomised trial to assess the efficacy of 
current practice, and to evaluate whether dornase alpha is more effective than 
0.9% saline, a cheaper, more accessible alternative. 
 
Aim 
To evaluate the efficacy of inhaled dornase alfa compared to inhaled isotonic 
(0.9%) saline on: 
- 
Quantitative and qualitative respiratory outcomes 
- 
The need for antibiotics, length of stay and exacerbation / re-
admission rates  


Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
2 
Hypothesis 
Dornase alfa is more effective than isotonic saline in the post lung transplant 
population during LRTI. 
 
Study design 
Phase 2, assessor blinded, prospective randomised controlled trial. 
 
Study population 
Inclusion: 
• 
Post bilateral sequential lung transplant 
• 
Capable of performing airway clearance techniques / nebulisers 
• 
Pulmonary exacerbation as defined by Fuchs et al8 
• 
Must be productive of sputum 
*As part of the Fuchs criteria screening, existing plain film CXR or CT scans taken 
as part of standard care will be used based on availability and the fulfilment of 
other criteria points to assess patient suitability. 
Exclusion: 
• 
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 / ICU / ventilator dependent 
• 
Within 2 months of transplant date 
*Cystic Fibrosis will be stratified 
 
Intervention 
On admission to the ward as an inpatient, patients who give informed consent will 
be randomly assigned to one of two groups defined below. The randomisation 
sequence will be concealed using opaque envelopes. Randomisation will be 
stratified according to pre-transplant diagnosis (cystic fibrosis or not) as people 
with cystic fibrosis are expected to be younger and have a different underlying 
systemic disease process. 
 
Treatment group: 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. 
 
Control group: Once daily, 5ml inhaled 0.9% normal saline with IBR as above 
(evening if able). 
 
All participants will undertake treatment for one month according to their 
allocated group, with follow up to 3 months, (2 months off randomised 
intervention). Both groups will continue to do their regular prescribed physical 
exercise routine over the course of the study. 
 
Timing of assessment 
All outcome measures will be performed at study baseline, 1 month and 3 months 
follow-up. Daily outcome measures used as a monitoring diary are an exception. 
There are no cough-specific quality of life questionnaires validated for use in the 
post lung transplant population.   
 
 


Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
3 
Primary outcome 
Lung clearance index (LCI) is 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 paediatric CF18,19. 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 
spirometry11, 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 18,19.  
  
Secondary outcomes – to be completed at specified follow up times as 
above 
1. Regular spirometry (FEV1, FVC, FEF) 
2. Cough specific quality of life (QOL) 
- 
Leicester Cough Questionnaire (LCQ)24 
- 
St. George’s Respiratory Questionnaire (SGRQ)23 
The LCQ is a 19-question tool, the SGRQ a 2-part questionnaire, both are 
validated QOL questionnaires used in chronic lung disease other than lung 
transplant 
3. Inpatient days  
4. Oral, inhaled or IVAB days (for LRTI only) 
5. Number of hospitalisations  
6. Exacerbations over study period – as defined by:  
- 
Presentation to hospital and commencement of antibiotics (oral, inhaled or 
IV) 
- 
Worsening of symptom scores (BCSS >120), sputum colour score 
(BronkoTest colour 3-5) 
 
7. C-reactive protein (CRP). An inflammatory marker measured with routine blood 
tests on admission with LRTI. Taken during IP stay and routinely on OP follow-up. 
Exisiting / available data only will be used – no extra routine bloods will be taken 
on account of study inclusion. 
 
Secondary outcomes – to be completed daily 
8. Self-reported symptom severity, used as a daily patient diary 
- 
Breathlessness, Cough and Sputum Scale (BCSS)20 
The BCSS is a 12 point self-reported symptom severity score, validated for daily 
use in COPD 
- 
Sputum colour score22 – BronkoTest Ltd, London UK 
Sputum colour has been shown to correlate with physiological infection in other 
chronic lung disease groups. 
- 
Sputum quantity (nil, low, moderate, high) 
Self-reported symptom scores are to be completed at the same time each day, 
prior to going to bed. They will be collected at each assessment interval as above. 
Treatment compliance will be measured by return of used and un-used 
medication packaging at each assessment point. 
 
 
 
 
 


Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
4 
Sample size and power calculation 
A total of 30 participants (15 in each group) will enter this design study. The 
probability is 80 percent that the study will detect a treatment difference at a 
two-sided 0.05 significance level, if the true difference between treatments is 
1.000 unit in LCI.  
This is a conservative estimate that is smaller than previous differences found in 
paediatric populations18,19. This is based on the assumption that the standard 
deviation of the response variable is 0.94 units18,19. 
 
As a phase 2 study, this project is powered to detect differences in physiological 
outcomes, rather than quality of life or hospitalization. However, should the 
treatment prove to have physiological benefits, the secondary outcomes of this 
study will provide critical information for powering a future phase 3 trial. 
 
Feasibility: Approximately 12 patients with pulmonary exacerbations are admitted 
under the lung transplant service each month (minimum estimate). We estimate 
that 70% will meet the eligibility criteria for the study and 50% will consent to 
participate. We therefore anticipate that it will be possible to recruit the numbers 
needed for this study in 8 months. 
 
Statistical analysis 
An intention to treat analysis will be conducted, with inclusion of all randomised 
participants, regardless of study completion. Data for continuous outcomes 
including LCI will be analysed using a linear mixed models analysis, which makes 
use of all available data at each time point and is less affected by incomplete data 
than analysis of variance. The likelihood of exacerbation or hospitalisation during 
the follow-up period for the dornase alpha group will be expressed as a relative 
risk compared to the isotonic saline group. 
 
Bias / Confounders 
There is potential for performance bias in this study due to the lack of ability to 
blind participants to their allocated treatment regimen. We are unable to package 
medications in a way other than that currently produced. We aim to outline, as 
part of the PICF, that both inhaled medications have proven to be efficacious (and 
detrimental in certain circumstances) in disease processes other than post lung 
transplant LRTI. Detection bias will be controlled by the use of a blinded outcome 
assessor for all follow-up data collection points. 
 
Potential confounders in this study include the diagnosis of bronchiolitis obliterans 
(BOS), or chronic lung rejection, during which LRTI occurs simultaneously. 
Patients with a diagnosis of BOS may in fact demonstrate differences in lung 
physiology and ease of sputum expectoration, which may have an effect on 
outcomes variables. We feel that excluding these patients may have a detrimental 
impact on the external validity of this study, therefore we will stratify patients 
according to a diagnosis of BOS on study inclusion.    
 
Outcomes and significance 
This will be the first randomised controlled trial to analyse inhaled dornase alfa 
and isotonic saline in the post lung transplant population. 
The outcome of this trial will help to guide physiotherapy and pharmacological 
management of post lung transplant patients with LRTI in the future, both 
nationally and internationally. 
 
 
 
 
 


Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
5 
References  
 
1. Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. 
Cochrane Database of Systematic Reviews 2009; Issue 2, Art. No.: 
CD001506. DOI: 10.1002/14651858.CD001506.pub3. 
2. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, 
Belousova EG, Xuan W, Bye PTP. A controlled trial of long-term inhaled 
nebulised hypertonic saline in patients with cystic fibrosis. N Eng J Med 
2006; 354:229-40.     
3. Touleimat BA, Conoscenti CS, Fine JM. Recombinant human DNase in 
management of lobar atelectasis due to retained secretions. Thorax 
1995;50:1319-1321. 
4. Voelker KG, Chetty KG, Mahutte CK. Resolution of recurrent atelectasis in 
spinal cord injury patients with administration of recombinant human 
DNase. Intensive Care Medicine 1996;22(6):582-4. 
5. 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;41:61-66. 
6. 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;106(5):661-7. 
7. Kellett F, Robert NM. Nebulised 7% hypertonic saline improves lung 
function and quality of life in bronchiectasis. Respir Med 2011;105:1831-
1835. 
8. 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. N Eng J Med 1994; 
331:637-42. 
9. Safdar A, Shelburne SA, Evans SE, Dickey BF. Inhaled therapeutics for 
prevention and treatment of pneumonia. Expert Opin 2009; Jul;8(4):435-
49. 
10. International Society for Heart and Lung Transplantation. J Heart Lung 
Transplant 2012; Oct; 31(10): 1045-1095. 
11. Munro PE, Button BM, Bailey M, Whitford H, Ellis S, Snell G. Should lung 
transplant recipients routinely perform airway clearance techniques? A 
randomized trial. Respirology 2008; 13. 1053-1060.  
12. Veale D, Glasper PN, Gascoigne A, Dark JH, Gibson GJ, Corris PA. Ciliary 
beat frequency in transplanted lungs. Thorax 1993;48:629-631. 
13. Herve P, Silbert D, Cerrina J, Simonneau G, Dartevelle P. Impairement of 
bronchial mucociliary clearance in long-term survivors of heart/lung and 
double-lung transplantation. The Paris-Sud lung transplant group. Chest 
1993;103(1):59-63. 
14. Humplik BI, Sandrock D, Aurisch R, Richter W, Ewert R, Munz DL. 
Scintigraphic results in patients with lung transplants: a prospective 
comparative study. Nucl Med 2005;44(2):62-68.   
15. Reid DW, Walters EH, Johns DP, Ward C, Burns GP, Liakakos P, Williams 
TJ, Snell GI. Bronchial hyperresponsiveness and the bronchiolitis 
obliterans syndrome after lung transplantation. J Heart Lung Transplant 
2005;24:489-92. 
16. Liakakos P, Snell GI, Ward C, Johns DP, Bamford TL, Williams TJ, Walters 
EH. Bronchial hyperresponsiveness in lung transplant recipients: lack of 
correlation with airway inflammation. Thorax 1997;52:551-556. 
17. Crockett A, Cranston JM, Alpers JH, Latiner KM. Mucolytics for 
bronchiectasis. Cochrance Database of Systematic Reviews 2001, Issue 1. 
Art. No.:CD001289. DOI: 10.1002/14651858.CD001289. 


Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
6 
18. Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, Kerrigan S, 
Gustafsson P, Ratjen F. The effect of dornase alpha on ventilation 
inhomogeneity in patients with cystic fibrosis. Eur Respir J 2011;37:806-
812. 
19. 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;65:379-383.    
20. 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;124(6):2182-91. 
21. Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S. 
Standardizing measurement of chronic obstructive pulmonary disease 
exacerbations. Am J Respir Crit Care Med 2011;183:323-329. 
22. 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;56:366-372.   
23. 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. 
24. 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. 
25. 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;140:58-61. 
 

ICF_001.pdf: 
 
Participant Information & Consent Form, Version 6, 23/09/14 
PI&CF Page 1/8 
 
 
 
Participant Information and Consent Form 
 
Alfred Health 
 
Full Project Title:  
 
Investigating the role of nebulised mucolytic therapy during lower 
respiratory tract infections post lung transplantation. 
 
Co-Principal Researchers: 
   
 
Benjamin James Tarrant, Prof. Greg Snell. 
Associate Researchers: 
 
Assoc. Prof. Anne Holland, Assoc. Prof. Bruce Thompson, Mrs Louise Fuller, Dr 
Brenda Button, Mr Steven Ivulich. 
 
1. 
Introduction 
 
You are invited to take part in this research project. This is because you have 
had a lung transplant and have been diagnosed with a lung infection. The 
research project aims to find out the effect of inhaled, nebulised medication as 
part of the treatment of your lung infection and increased sputum production. 
This Participant Information and Consent Form tells you about the research 
project. It explains what is involved to help you decide if you want to take part. 
Please read this information carefully. Ask questions about anything that you 
don’t understand or want to know more about. Before deciding whether or not to 
take part, you might want to talk about it with a relative, friend or your local 
health worker. 
Participation in this research is voluntary. If you don’t wish to take part, you 
don’t have to. If you decide you want to take part in the research project, you 
will be asked to sign the consent section. By signing it you are telling us that 
you: 
 
• 
understand what you have read; 
• 
consent to take part in the research project; 
• 
consent to be involved in the procedures described; 
• 
consent to the anonymous use of your personal and health information as 
described 
 
You will be given a copy of this Participant Information and Consent Form to 
keep. 
 
 
 
 


 
Participant Information & Consent Form, Version 6, 23/09/14 
PI&CF Page 2/8 
2. 
What is the purpose of this research project? 
 
The aim of this project is to compare inhaled, nebulised dornase alfa to normal, 
isotonic saline. Dornase alfa is a drug approved for use in Australia in cystic 
fibrosis to thin mucous. Normal saline is a medication commonly used to help 
thin mucous. To our knowledge, neither therapy has been scientifically 
investigated or approved for use post lung transplant. Both therapies are 
currently used at this hospital to treat lung infections post lung transplant, but 
we are unsure of their effects beyond patient reports. 
 
Participation in the research project will require performing an initial assessment 
during the inpatient hospital stay, and three subsequent visits to The Alfred 
hospital for follow-up assessment both during and on completion of the study. 
Each assessment session will take around 60 minutes. We will try to do these on 
days when you are already coming to The Alfred for other appointments.  
Dornase alfa is approved and registered for use in Australia, Europe and the 
United States of America to treat cystic fibrosis. However it is not approved in 
any country to treat patients who have had a lung transplant. Therefore, it is an 
experimental treatment for lung infections post lung transplant. This means that 
it must be tested to see if it is an effective treatment for post transplant patients 
diagnosed with a lung infection who have more sputum. Lung infections have 
very different effects post lung transplant compared to other diseases. This 
means we cannot be sure results in other studies are applicable in this patient 
type.   
 
Overall, 32 adults with lung infections post lung transplant will be taking part in 
this project through The Alfred.  
The results of this study will be used by Benjamin Tarrant to form part of his 
Master of Applied Science research. 
This research has been funded by an Alfred Small Project Grant. 
 
3. 
What does participation in this research project involve? 
 
You will be participating in a randomised controlled research project. Sometimes 
we do not know which treatment is best for treating a condition. To find out we 
need to compare different treatments. People are allocated randomly into groups 
and each group has a different treatment. The results are compared to see if one 
is better. In this study, there is a one in two chance of receiving either 
treatment, dornase alfa or normal saline. 
 
Both treatment (dornase alfa) and control (normal saline) study groups involve a 
once daily administration of the inhaled, nebulised product at a standard dose. 
All equipment required will be supplied to you at no cost while you are taking 
part in the study. This is in the form of a small nebuliser pump and handset. 
Each administration takes approximately 10 minutes. Taking the medication 
involves pouring a set amount of the liquid into the nebuliser pump, which 
creates a fine mist that can be inhaled through a mouthpiece. Treatment lasts for 
1-month after your initial dose in hospital. There is no requirement for treatment 
in the follow-up phase, from 1-3 months after starting the study.  
 
 


 
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There are a number of assessments made throughout the study period. An initial 
assessment is performed at the beginning of the study. Follow-up assessments 
are performed at 4 weeks and 3 months after starting the study. This consists of 
lung function testing and 2 questionnaires, performed at The Alfred. Each 
assessment will take approximately 1 hour.  
 
Each day you will also be asked to complete a short questionnaire, along with 
matching your sputum to a colour chart and reporting the amount you clear. This 
will take approximately 2 minutes to complete. Study staff will also look at your 
hospital record to collect other important information that will help compare 
treatments. This will consist of: how many lung infections you need to come to 
hospital for and the amount of time you spend in hospital; the number of lung 
infections you have over the study period including those treated out of hospital; 
how many times you need medication to treat your lung infection and the 
monitoring of your blood tests. Blood tests will only be taken as per the normal 
standard of care for you. Study staff will ask you to retain all used and un-used 
medication packages to help monitor the amount of medication used. These will 
be collected at each assessment appointment. 
 
This research project has been designed to make sure the researchers interpret 
the results in a fair and appropriate way and avoids study staff or participants 
jumping to conclusions.  
 
You will not be paid for participating in this research project. All tests and 
medical care required as part of the research project will be provided to you free 
of charge. You will have to pay for the treatment medicines according to hospital 
policy. The price will depend on whether you have concession for medications. A 
1-month supply of either medication costs $33.60 full priced, or $5.90 with 
concession. Medication will be free if you have already reached The Alfred’s 
medication safety net. If you do not know if you have reached this amount 
please ask one of the study staff. 
 
4. 
What do I have to do? 
 
Participation in this trial involves no restrictions in normal daily activities or 
physical exercise. All your normal medications will be continued, with the 
addition of the inhaled nebulised medication for the 1-month treatment period. 
Participants will be asked whether there are any factors that may stop them from 
being available for all assessment points as explained above. If you are already 
on either of these 2 inhaled medications, this may stop you from participating in 
the study. Your study staff should also explain to you which treatments or 
medications need to be stopped for the time you are involved in the research 
project. 
 
5. 
What are the possible benefits? 
 
We cannot guarantee or promise that you will receive any benefits from this 
research; however, possible benefits may include the ability to cough and clear 
sputum easier, an improvement in lung function and a decrease in the impact of 
lung infections on your quality of life. 
 
 


 
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6. 
What are the possible risks? 
 
When first taking dornase alfa, you may experience a change in your voice, 
cough or discomfort in your throat. Inhaled isotonic saline can cause shortness of 
breath, a salty taste, cough or tightness in the chest. These side effects are 
usually mild and short-lived. You will be assessed by study staff and not included 
in the study if you are at an increased risk of experiencing any side effects. When 
first taking the medication, an Alfred staff member will supervise you. 
 
The most likely unforeseen event that may occur is that you are deemed to 
require more intensive treatment for your lung infection with special breathing 
exercises. Any change in treatment will be based on your symptoms and 
assessment by the treating physiotherapist, in discussion with the lung 
transplant medical team. You will return to the normal study treatment if and 
when it is safe to do so. 
 
7. 
Do I have to take part in this research project? 
 
Participation in any research project is voluntary. If you do not wish to take part, 
you do not have to. If you decide to take part and later change your mind, you 
are free to withdraw from the study at a later stage. 
Your decision whether to take part or not, or to take part and then withdraw, will 
not affect your relationship with the researchers or the Alfred Hospital. The 
treatment you receive will not be affected by your decision regarding 
participation in this research project. 
Should you decide not to take part in this research project, access to study 
medications will be based on assessment by the treating medical team and 
access to any necessary equipment, as occurs in current standard practice. 
 
8. 
What will happen to my test samples? 
 
The blood tests that study staff will monitor during this research project will 
already be collected after your lung transplant as routine care. They will help 
monitor your lung infection. No additional blood tests will be needed if you decide 
to take part in this study. These results will only be used for this research 
project. On initial analysis blood test results will be individually identifiable via 
electronic records to study staff as per standard care. Samples will be destroyed 
after analysis as per Alfred Pathology protocol. Blood test results used by study 
staff for the purpose of this project alone will be stored securely in the 
Physiotherapy Department and coded in such a way that personal information 
will not be identifiable.    
 
9. 
What if new information arises during this research project? 
 
Sometimes during the course of a research project, new information becomes 
available about the treatment that is being studied. If this happens, Benjamin 
Tarrant will tell you about it and discuss with you whether you want to continue 
in the research project. If you decide to withdraw, your research team will make 
arrangements for your regular health care to continue. If you decide to continue 
in the research project you will be asked to sign an updated consent form. 
 


 
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Also, on receiving new information, Benjamin Tarrant might consider it to be in 
your best interests to withdraw you from the research project. If this happens, 
he will explain the reasons and arrange for your regular health care to continue. 
 
10. 
Can I have other treatments during the research project? 
 
Participation in this study involves a 1 in 2 chance of receiving either medication 
to help you manage your lung infection. No other inhaled medications used to 
help you clear your sputum can be used during the study period.   
You will be asked to stop any lung clearance exercises for the duration of the 
study period (3 months). This includes any breathing exercises with or without 
equipment, which you may already use to help clear your sputum. 
As already stated, you can continue to perform whole body exercise (eg: 
walking, running, cycling, weight training) with no restrictions and there will be 
no change to your normal medications used to manage your lung transplant. 
 
11. 
What if I withdraw from this research project? 
 
If you decide to withdraw from the project, please notify a member of the 
research team before you withdraw. This notice will allow that person or the 
research supervisor to discuss any health risks or special requirements linked to 
withdrawing. If you do withdraw your consent during the research project, the 
relevant study staff will not collect additional personal information from you, 
although personal information already collected will be retained to ensure that 
the results of the research project can be measured properly and to comply with 
law. You should be aware that data collected by study staff up to the time you 
withdraw will form part of the research project results. If you do not want them 
to do this, you must tell them before you join the research project. 
 
12. 
What happens when the research project ends? 
 
The availability of either the treatment drug (dornase alfa) or the comparison 
drug (isotonic saline) after completion of the study will be decided by the treating 
medical team. We cannot guarantee that either medication will be available as an 
ongoing treatment. 
 
13. 
How will I be informed of the final results of this research project? 
 
A summary of the overall results of the project will be prepared at the 
completion of the research project. If you are interested in reading about the 
results of this study, you can contact Benjamin Tarrant who will provide you with 
a summary copy of the project results, alternatively if you would like a copy of 
the results sent to you on completion of the project please tick this box.  ! 
If you would like details regarding your performance on any of the individual 
assessment tasks (eg. lung function tests) these can be provided upon request at 
the completion of the study. 
 
 
 
 
 
 


 
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14. 
What will happen to information about me? 
Any information obtained for this research project that can identify you will be 
treated as confidential and securely stored. It will be disclosed only with your 
permission or in compliance with the law. In any publication and/or presentation, 
information will be provided anonymously so that you cannot be identified. 
Information about you may be obtained from your health records held at Alfred 
Health for the purpose of this research. By signing the consent form you agree to 
the study team accessing health records if they are relevant to your participation 
in this research project. Information about your participation in this research 
project may be recorded in your health records. 
 
During the study, the data will only be accessible to researchers. It will be 
securely stored in The Alfred Physiotherapy Department and coded in such a way 
that personal details cannot be identified. At the completion of the project, the 
data will be archived indefinitely, accessible only to the hospital ethics committee 
for auditing purposes. You are being asked to provide consent to the use of your 
data for this project only. 
 
15. 
Can I access research information kept about me? 
 
In accordance with relevant Australian and/or Victorian privacy and other 
relevant laws, you have the right to access the information collected and stored 
by the researchers about you. Please contact one of the researchers named at 
the end of this document if you would like to access your information. 
Further, in accordance with regulatory guidelines, the information collected in 
this research project will be kept indefinitely. You must be aware that the 
information may become de-identified at some point and access to information 
about you after this point will not be possible. 
 
16. 
Complaints and compensation 
 
If you suffer any injuries or complications as a result of this research project, you 
should contact the study team as soon as possible and you will be assisted with 
arranging appropriate medical treatment. If you are eligible for Medicare, you 
can receive any medical treatment required to treat the injury or complication, 
free of charge, as a public patient in any Australian public hospital. 
 
17. 
Who has reviewed the research project? 
 
All research in Australia involving humans is reviewed by an independent group 
of people called a Human Research Ethics Committee (HREC).  The ethical 
aspects of this research project have been approved by the HREC of The Alfred.  
 
This project will be carried out according to the National Statement on Ethical 
Conduct in Human Research (2007). This statement has been developed to 
protect the interests of people who agree to participate in human research 
studies. 


 
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18. 
Consent 
 
I have read, or have had this document read to me in a language that I 
understand, and I understand the purposes, procedures and risks of this 
research project as described within it. 
 
I have had an opportunity to ask questions and I am satisfied with the answers I 
have received. 
 
I freely agree to participate in this research project, as described.  
 
I understand that I will be given a signed copy of this document to keep. 
 
 
Participant’s name (printed) …………………………………………………… 
 
Signature  
 
 
 
 
 
 
Date 
 
 
Declaration by researcher*: I have given a verbal explanation of the research 
project, its procedures and risks and I believe that the participant has 
understood that explanation. 
 
 
Researcher’s name (printed) …………………………………………………… 
 
Signature  
 
 
 
 
 
 
Date 
 
 
Note: All parties signing the consent section must date their own signature. 
 
 
 
 
 


 
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19. 
Who can I contact? 
 
The person you may need to contact will depend on the nature of your query. 
Therefore, please note the following: 
 
For further information or appointments: 
 
If you want any further information concerning this project or if you have any 
medical problems which may be related to your involvement in the project (for 
example, any side effects), you can contact co-principal investigator: 
 
Benjamin Tarrant on 03 9076 3450 (b.tarrant@alfred.org.au)  
 
You may also contact the following persons:  
 
Name: 
Dr Brenda Button 
Role:  
Senior Clinician Physiotherapist – Cystic Fibrosis 
 
 
Respiratory Stream Leader 
 
 
Telephone: 03 9076 3450 
Email: 
b.button@alfred.org.au 
 
For Complaints: 
 
If you have any complaints about any aspect of the project, the way it is being 
conducted or any questions about your rights as a research participant, then you 
may contact   
 
Name: 
Ms Emily Bingle 
Position:  
Research Governance Officer, Ethics & Research Governance, Alfred 
Health. The Alfred Hospital, Commercial Rd, Melbourne 3004 
Telephone: 03 9076 3619 
Email: 
research@alfred.org.au 
 
You will need to tell Ms Bingle the name of one of the researchers above. 
 
Further enquiries and/or complaints can also be addressed to: 
 
The Secretary, Faculty Human Ethics Committee 
Faculty of Health Sciences, La Trobe University, Victoria, 3086  
Telephone:  03 9479 3583 
 
 
 
Fax:  
03 9479 5733 
 
Email: 
health@latrobe.edu.au