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

NCT01952470 | Completed Phase 2 Results

• 2 other identifiers: 342/13DOI:10.1111/tri.13400
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• Lung Clearance Index 2% (LCI2%)

  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).

  1 month, 3 months

Secondary Outcomes (15)

• Multiple Breath Washout (MBW)

  1 month, 3 months

• Functional Residual Capacity (FRC)

  1 month, 3 months

• Forced Expiratory Volume in 1 Second (FEV1) Liters

  1 month, 3 months.

• Forced Expiratory Volume in 1 Second (FEV1) Percent.

  1 month, 3 months

• Forced Vital Capacity (FVC) Liters

  1 month, 3 months

Study Arms (2)

Dornase Alfa

EXPERIMENTAL

Once daily, 2.5ml inhaled dornase alfa.

Drug: Dornase Alfa

Isotonic Saline

ACTIVE COMPARATOR

Once daily, 5ml inhaled 0.9% normal saline.

Drug: Isotonic Saline.

Interventions

Dornase Alfa DRUG

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.

Also known as: Pulmozyme.

Dornase Alfa

Isotonic Saline. DRUG

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.

Also known as: normal, 0.9% saline.

Isotonic Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Alfred: lead
• The Alfred Research Trusts Small Project Grant.: collaborator
• Dr Carey Denholm and Laura Denholm: collaborator

Study Sites (1)

The Alfred

Melbourne, Victoria, 3000, Australia

Location

Related Publications (21)

• 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.

  PMID: 22975094 BACKGROUND

• 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.

  PMID: 8380268 BACKGROUND

• 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.

  PMID: 18721181 BACKGROUND

• 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.

  PMID: 8346493 BACKGROUND

• 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.

  PMID: 15861274 BACKGROUND

• 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.

  PMID: 2502056 BACKGROUND

• 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.

  PMID: 7503821 BACKGROUND

• 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.

  PMID: 8553310 BACKGROUND

• 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.

  PMID: 8814475 BACKGROUND

• 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.

  PMID: 16265663 BACKGROUND

• Crockett AJ, Cranston JM, Latimer KM, Alpers JH. Mucolytics for bronchiectasis. Cochrane Database Syst Rev. 2000;(2):CD001289. doi: 10.1002/14651858.CD001289.

  PMID: 10796636 BACKGROUND

• 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.

  PMID: 19370568 BACKGROUND

• 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.

  PMID: 16421364 BACKGROUND

• 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.

  PMID: 22349069 BACKGROUND

• 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.

  PMID: 19538104 BACKGROUND

• 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.

  PMID: 20693248 BACKGROUND

• 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.

  PMID: 20435858 BACKGROUND

• 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.

  PMID: 18825348 BACKGROUND

• 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.

  PMID: 11936514 BACKGROUND

• 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.

  PMID: 14665499 BACKGROUND

• 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.

  PMID: 11312405 BACKGROUND

MeSH Terms

Conditions

Respiratory Tract Infections; Postoperative Complications

Interventions

dornase alfa; Sodium Chloride

Condition Hierarchy (Ancestors)

Infections; Respiratory Tract Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

Pre-existing/new diagnoses CLAD +/- LRTI; Participants deviating from protocol; Potential for performance bias; Infection control excluded viral LRTI; Single center trial; Participants were \>2 months post-tx.

Results Point of Contact

• Title: Benjamin James Tarrant
• Organization: Alfred Health

b.tarrant@alfred.org.au

+61404455658

Study Officials

• Benjamin J Tarrant, B.Physio

  The Alfred

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Benjamin James Tarrant

Study Record Dates

• First Submitted: August 31, 2013
• First Posted: September 30, 2013
• Study Start: October 31, 2013
• Primary Completion: August 23, 2017
• Study Completion: August 23, 2017
• Last Updated: August 28, 2019
• Results First Posted: August 28, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)