Preliminary Study of Dornase Alpha to Treat Chest Infections Post Lung Transplant.

Study Description

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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 alpha 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 alpha, compared to isotonic saline, in the management of lower respiratory tract infections post lung transplant. Investigators hypothesize that dornase alpha will be more effective than isotonic saline.

The effect of a daily dose of dornase alpha 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.

Condition or disease	Intervention/treatment	Phase
Lung Transplant Infection; Lower Respiratory Tract Infection	Drug: Dornase Alpha; Drug: Isotonic Saline.	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	32 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	Single (Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Investigating the Role of Nebulised Mucolytic Therapy During Lower Respiratory Tract Infections Post Lung Transplantation.
Actual Study Start Date :	October 31, 2013
Actual Primary Completion Date :	August 23, 2017
Actual Study Completion Date :	August 23, 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Dornase Alpha; Once daily, 2.5ml inhaled dornase alpha.	Drug: Dornase Alpha; Once daily, 2.5ml inhaled dornase alpha (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.; Other Name: Pulomzyme.
Active Comparator: Isotonic Saline; Once daily, 5ml inhaled 0.9% normal saline.	Drug: 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.; Other Name: normal, 0.9% saline.

Outcome Measures

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Primary Outcome Measures :

1. Lung clearance index (LCI) - change [ Time Frame: Study inclusion, 1 month, 3 months ]

   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 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).

Secondary Outcome Measures :

1. Regular spirometry (FEV-1, FVC, FEF) - change [ Time Frame: Study inclusion, 1 month, 3 months. ]
   Pulmonary function testing.
2. Leicester Cough Questionnaire (LCQ) - change [ Time Frame: Study inclusion, 1 month, 3 months. ]
   Cough specific quality of life questionnaire. The LCQ is a 19-question tool, validated in chronic lung disease other than lung transplant(19).
3. St. George's Respiratory Questionnaire (SGRQ) - change [ Time Frame: Study inclusion, 1 month, 3 months. ]
   The SGRQ is a 2-part questionnaire, validated in chronic lung disease other than lung transplant(20).
4. Inpatient days [ Time Frame: Across study period (3 months). ]
   Number of days spent in the acute inpatient setting.
5. Oral, inhaled or IVAB days (for LRTI only). [ Time Frame: Over study period (3 months). ]
   Antibiotic use for the treatment of lower respiratory tract infections only.
6. Number of hospitalizations [ Time Frame: Over study period (3 months). ]
   Number of admissions to the acute setting.
7. Exacerbation rate. [ Time Frame: Over study period (3 months). ]

   As defined by:

   • Presentation to hospital and commencement of antibiotics (oral, inhaled or IV)
   • Worsening of symptom scores (Breathlessness, cough and sputum scale >1), sputum colour score (BronkoTest colour 3-5) (*See isolated secondary outcome measures for above).
8. C-reactive protein (CRP) - change [ Time Frame: Study inclusion, 1 month, 3 months. ]
   An inflammatory marker measured with routine blood tests on admission with LRTI. Taken during IP stay and routinely on OP follow-up. Existing / available data only will be used - no extra routine bloods will be taken on account of study inclusion.
9. Breathlessness, Cough and Sputum Scale (BCSS) - change [ Time Frame: Daily up to 3 months. ]
   Self-reported symptom severity, used as a daily patient diary. The BCSS is a 12 point self-reported symptom severity score, validated for daily use in COPD(21).
10. BronkoTest (sputum colour) - change [ Time Frame: Daily up to 3 months. ]
    Sputum colour chart. Sputum colour has been shown to correlate with physiological infection in other chronic lung disease groups(22).

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

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 / ICU / ventilator dependent
• Within 2 months of transplant date *Cystic Fibrosis will be stratified

Contacts and Locations

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Locations

Australia, Victoria
The Alfred
Melbourne, Victoria, Australia, 3000

Sponsors and Collaborators

The Alfred

The Alfred Research Trusts Small Project Grant.

Investigators

Principal Investigator:	Benjamin J Tarrant, B.Physio	The Alfred

More Information

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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. 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.

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.

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.

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.

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.

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.

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.

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. 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. Review. Update in: Cochrane Database Syst Rev. 2001;(1):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. Review.

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.

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. Review.

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. Review.

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.

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.

Responsible Party:	Benjamin Tarrant, Benjamin James Tarrant, The Alfred
ClinicalTrials.gov Identifier:	NCT01952470 History of Changes
Other Study ID Numbers:	342/13
First Posted:	September 30, 2013
Last Update Posted:	October 25, 2017
Last Verified:	October 2017

Keywords provided by Benjamin Tarrant, The Alfred:

Lung transplantation; Respiratory Tract Infections; Respiratory Therapy; Isotonic Solutions	Sodium Chloride; Postoperative complications; Postoperative care; dornase alpha

Additional relevant MeSH terms:

Infection; Communicable Diseases; Respiratory Tract Infections; Respiratory Tract Diseases