Investigating the Role of Nebulised Mucolytic Therapy During Lower Respiratory Tract Infections Post Lung Transplantation.
Phase: PHASE2
Conditions: Lung Transplant Infection, Lower Respiratory Tract Infection
Sponsor: The Alfred

Module Two: Drugs & Therapeutic Devices, Version 4 – 27/10/13 
Clinical Protocol  
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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  

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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.   
 
 

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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. 
 
 
 
 
 

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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. 
 
 
 
 
 

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