Clinical trial NCT02813811: Laminar Airflow in Severe Asthma for Exacerbation Reduction - 48 Month Follow-up.
Official title: A Prospective, Single Arm, Cohort Study of Nocturnal Temperature-controlled Laminar Airflow (TLA) Treatment (Airsonett®) in Patients With Allergic Asthma to Determine the Effect of Long-term Treatment on Exacerbation Frequency.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Asthma
Keywords: Temperature-controlled Laminar Airflow
Exacerbation frequency
Lead sponsor: Portsmouth Hospitals NHS Trust
Sponsor class: OTHER_GOV
Collaborators: name: Airsonett AB
First posted: 2016-06-27
Enrollment: 77
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 3 populations of adults (aged ≥16yrs) with allergic asthma will be invited to participate:

1. Patients receiving TLA treatment as part of the 4-year post trial provision period following participation in The LASER Trial where they were in the active treatment study group.
2. Patients receiving TLA treatment as part of the 4-year post trial provision period following participation in The LASER Trial where they were in the placebo treatment study group.
3. Patients starting TLA treatment for asthma who did not participate in The LASER Trial.

Brief summary: Temperature-controlled Laminar Airflow (TLA) treatment delivered by the Airsonett treatment device is a new treatment for patients with allergic asthma.

The LASER Trial (temperature-controlled Laminar Airflow in Severe asthma for Exacerbation Reduction - LASER) is a trial, currently evaluating whether the Airsonett device is able to reduce the frequency of asthma attacks in patients with allergic asthma. (www.lasertrial.co.uk)

Participants who successfully complete at least 6 months of follow-up in the LASER trial are eligible for the post trial provision of 4 years of an active TLA treatment device.

To date there is no long term performance data available to show whether there is any sustained benefit from the long term use of the Airsonett device, whether any improvement in asthma control or quality of life is maintained and whether patients will continue to use the treatment device beyond 12 months (the length of the longest previous trials of TLA treatment.)

The investigators plan to assess the performance of the Airsonett device by recording the frequency of asthma attacks in patients over a 4-year period (48 months.) The investigators also wish to evaluate the effect of long term TLA treatment on asthma control, quality of life, healthcare resource use and patient acceptability of longer term use of the Airsonett device.

Participants will be sent and asked to complete a series of questionnaires on a 6 monthly basis over the 48 month study period. Questionnaires will be returned by post to a single study centre based in Portsmouth, UK. Participants will also be contacted by telephone on a 6 monthly basis by a member of the trial team to collect information about their medication, healthcare resource use and whether they have had any asthma attacks since their last contact.

Participants will not be expected to visit the study centre during the trial.

Detailed description: Asthma affects over 5.4 million people in the UK with nearly 500,00 experiencing severe symptoms and frequent exacerbations that are inadequately controlled with available treatments. The burden of severe asthma on the NHS is enormous accounting for 80% of total asthma cost. In 2009 there were 1131 deaths due to asthma, with those whose asthma remains poorly-controlled facing the greatest risk. Patients with severe asthma bear the greatest burden of asthma morbidity and experience more frequent and severe exacerbations which reduce their quality of life, impair their ability to work and place an enormous burden of anxiety on them and their families. There is also an increased risk of significant depression. 1 in 5 asthmatics in the UK report serious concerns that their next asthma attack will kill them. As highlighted in the 2010 Asthma UK report, 'Fighting for Breath,' these patients also face discrimination from employers, healthcare professional s and society as a whole as a result of their asthma.

Current treatments including oral corticosteroids, 'steroid-sparing' immunosuppressants and monoclonal antibody therapies are often of limited efficacy and have potentially serious side effects (steroids, immunosuppressive agents) or are prohibitively expensive (monoclonal antibodies). The adverse effects of long-term oral steroids include adrenal suppression, decreased bone mineral density, diabetes and increased cardiovascular mortality. The anti-IgE treatment Omalizumab® has been shown to reduce exacerbations by up to 50% and improve quality of life in severe allergic asthma but costs up to £26,640 per year, which is substantially more than the current annual rental cost of a TLA device (£2,088).

Patients with poorly controlled, severe, allergic asthma are left with a significant unmet clinical need and a specific requirement for cost-effective therapies which reduce systemic steroid exposure by reducing the frequency of severe exacerbations.

The Department of Health Outcomes Strategy for COPD and Asthma (2011) recognised the huge burden that poorly-controlled asthma places on people's lives and the NHS, and spelt out the political commitment to improve asthma control and reduce asthma related emergency healthcare needs and deaths. The 2013 British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) national asthma guidelines and 2010 WHO consultation on severe asthma have highlighted an urgent need for research in severe asthma, acknowledging the limitations of available treatments in severe asthma and the dearth of clinical trials upon which to base management recommendations. Asthma UK emphasised in its research strategy for 2012 document that new therapies able to reduce symptoms and prevent exacerbations will improve clinical outcomes and patient well-being and reduce the cost of treating severe asthma within the NHS.

More than 70% of severe asthmatic patients are sensitised to common aeroallergens and/or moulds and the level of allergen exposure determines symptoms; those exposed to high allergen levels are at increased risk of exacerbations and hospital admissions. Domestic exposure to allergens is also known to act synergistically with viruses in sensitised patients to increase the risk and severity of exacerbations. Allergen avoidance has been widely recognised as a logical way of treating these patients . In controlled conditions, long-term allergen avoidance in sensitised asthmatics reduces airway inflammation with consequent symptomatic improvement, further supported by high-altitude, clean-air studies. Unfortunately, effective methods of allergen reduction have proved elusive, with current measures unable to reduce allergen load sufficiently to yield a consistent clinical improvement, thus leaving a significant gap in the potential strategies for reducing asthma severity through allergen reduction.

At night airborne particles are carried by a persistent convection current established by the warm body, transporting allergens from the bedding area to the breathing zone . Proof-of-concept studies have shown the TLA device reduces the total number of airborne particles \>0.5μm in the breathing zone by 3000-fold (p\<0.001), cat allergen exposure by 7-fold (p=0.043) and significantly reduces the increase in particles generated when turning in bed for all particle sizes . When compared to a best in class traditional air cleaners TLA is able to reduce exposure to potential allergens by a further 99%30. We postulate that this highly significant reduction in nocturnal exposure, targeted to the breathing zone, explains why TLA may succeed in an area where so many other measures, including air filters, have failed.

The TLA device when compared to placebo, has proven efficacy on asthma-related quality of life and bronchial inflammation (measured by exhaled nitric oxide) in a pan European multicentre Phase III study , (n=282, age range 7-70 years). The greatest benefit was seen in the more severe asthma patients requiring higher intensity treatment (GINA Steps 4-5) and in patients with poorly controlled asthma (Asthma Control Test \<18). GINA Steps 4-5 are consistent with BTS/SIGN Guideline treatment Steps 4-5 (inhaled corticosteroid dose ≥1000µg/day beclomethasone (BDP) equivalent plus an additional controller medication such as a long acting ß2-agonist, leukotriene receptor antagonist or a sustained release theophylline). Whilst not powered to ascertain an effect on exacerbations, a post-hoc analysis showed a decreased exacerbation rate in more severe patients treated with TLA when compared with placebo with a trend towards significance (mean 0.23 TLA; 0.57 placebo p=0.07). A cost-effectiveness analysis based on the results from this trial also found no significant differences in ED visits, hospitalisation days, medication usage, and therefore overall costs between the two study groups . This lack of significant findings probably reflected the fact that the trial was not powered to detect differences in exacerbations, a predictor of increased asthma healthcare resource use and costs . Despite the lack of a significant reduction in healthcare resource use and associated costs, subsequent economic modelling showed that TLA would be cost-effective in Sweden at the current monthly rental price (SEK 2,000, ≈ £167), mainly due to increases in quality of life.

In order to address this important research question in severe allergic asthma, The LASER Trial, a multi-centre, randomised, double blind, placebo-controlled, parallel group trial is currently assessing whether nocturnal use of the TLA treatment device Airsonett® is able to reduce the frequency of severe asthma exacerbations in patients with poorly controlled, severe, allergic asthma. The LASER Trial received funding from the National Institute for Health Research Health Technology Assessment Programme.

In the LASER Trial, participants receive 12 months of treatment. Half of the participants receive an active TLA device and half receive a device which has been deactivated (a 'placebo' device.) Neither the patients nor researchers will know which device an individual participant has received. All participants who complete at least 6 months of follow-up within the LASER trial will be eligible for treatment with an active TLA device for 4 years regardless of whether they received an active or placebo device during the trial.

LASER-48 is the follow on study from The LASER Trial where the investigators will ask participants to continue to report their asthma attacks and symptoms during a 4 year (48-month) follow-up period by means of questionnaires to monitor whether the treatment device has an impact on their asthma symptoms and quality of life.

To reduce the burden on study participants, they will not be required to visit a hospital clinic for follow-up appointments but they will be contacted on a 6 monthly basis to gather information about their asthma symptoms, their asthma medications and whether they have been required to visit their GP or hospital for their asthma.

Participants will be free to withdraw from the study at any time without giving a reason for doing so.

At the end of the study after the last participant has completed their 48 months of follow-up, the data will be analysed to help determine whether longer term treatment with the TLA (Airsonett) device is able to reduce the frequency of asthma attacks, improve asthma symptoms, improve asthma related quality of life and remain a cost-effective and acceptable treatment for patients with severe allergic asthma.

Eligibility criteria: Inclusion Criteria:

The participant must meet ALL of the following criteria to be considered eligible for the study:

* Male or Female, aged 16 years or above.
* Using the TLA treatment device, Airsonett®, for the treatment of asthma.
* Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

• Unable to comprehend the study and provide informed consent, e.g. insufficient command of English in the absence of someone to adequately interpret.

Primary outcomes:
measure: Frequency of severe asthma exacerbations over the 48-month follow up period.
timeFrame: 48 months
Secondary outcomes:
measure: Current asthma control
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months
measure: Exacerbation Frequency
timeFrame: 48 months
measure: Oral Corticosteroid Use
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months
measure: Frequency of Hospital Admissions for Asthma
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months
measure: Health Related Quality of Life - Mini Asthma Quality of Life Questionnaire
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months
measure: Health Related Quality of Life - EQ-5D-5L health questionnaire
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months
measure: Sino-nasal Symptoms
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months
measure: Health Economics
timeFrame: 48 months
measure: TLA Treatment Acceptability
timeFrame: 12, 24, 36 and 48 months
Other outcomes:
Locations:
city: Portsmouth
country: United Kingdom
facility: Portsmouth Hospitals NHS Trust, Queen Alexandra Hospital
state: Hampshire
Study officials:
affiliation: Consultant Respiratory Physician and Director of Research & Innovation
name: Prof Anoop J Chauhan, MB ChB, MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE, Bleecker ER, Brightling CE, Burney P, Bush A, Busse WW, Casale TB, Chan-Yeung M, Chen R, Chowdhury B, Chung KF, Dahl R, Drazen JM, Fabbri LM, Holgate ST, Kauffmann F, Haahtela T, Khaltaev N, Kiley JP, Masjedi MR, Mohammad Y, O'Byrne P, Partridge MR, Rabe KF, Togias A, van Weel C, Wenzel S, Zhong N, Zuberbier T. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010 Nov;126(5):926-38. doi: 10.1016/j.jaci.2010.07.019.
citation: Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006 Aug 26;368(9537):780-93. doi: 10.1016/S0140-6736(06)69288-X.
citation: Hoskins G, McCowan C, Neville RG, Thomas GE, Smith B, Silverman S. Risk factors and costs associated with an asthma attack. Thorax. 2000 Jan;55(1):19-24. doi: 10.1136/thorax.55.1.19.
citation: Tough SC, Hessel PA, Ruff M, Green FH, Mitchell I, Butt JC. Features that distinguish those who die from asthma from community controls with asthma. J Asthma. 1998;35(8):657-65. doi: 10.3109/02770909809048968.
citation: Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, Fitzgerald JM. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1804-9. doi: 10.1164/ajrccm.157.6.9708092.
citation: Campbell MJ, Holgate ST, Johnston SL. Trends in asthma mortality. Data on seasonality of deaths due to asthma were omitted from paper but editorial's author did not know. BMJ. 1997 Oct 18;315(7114):1012. No abstract available.
citation: Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. Chest. 2004 Mar;125(3):1081-102. doi: 10.1378/chest.125.3.1081.
citation: Nejtek VA, Brown ES, Khan DA, Moore JJ, Van Wagner J, Perantie DC. Prevalence of mood disorders and relationship to asthma severity in patients at an inner-city asthma clinic. Ann Allergy Asthma Immunol. 2001 Aug;87(2):129-33. doi: 10.1016/s1081-1206(10)62206-5.
citation: Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med. 2009 Jul;103(7):975-94. doi: 10.1016/j.rmed.2009.01.003. Epub 2009 Apr 15.
citation: Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, Beeh KM, Ramos S, Canonica GW, Hedgecock S, Fox H, Blogg M, Surrey K. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005 Mar;60(3):309-16. doi: 10.1111/j.1398-9995.2004.00772.x.
citation: Heaney LG, Brightling CE, Menzies-Gow A, Stevenson M, Niven RM; British Thoracic Society Difficult Asthma Network. Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry. Thorax. 2010 Sep;65(9):787-94. doi: 10.1136/thx.2010.137414.
citation: Custovic A, Taggart SC, Francis HC, Chapman MD, Woodcock A. Exposure to house dust mite allergens and the clinical activity of asthma. J Allergy Clin Immunol. 1996 Jul;98(1):64-72. doi: 10.1016/s0091-6749(96)70227-0.
citation: Tunnicliffe WS, Fletcher TJ, Hammond K, Roberts K, Custovic A, Simpson A, Woodcock A, Ayres JG. Sensitivity and exposure to indoor allergens in adults with differing asthma severity. Eur Respir J. 1999 Mar;13(3):654-9. doi: 10.1183/09031936.99.13365499.
citation: Langley SJ, Goldthorpe S, Craven M, Morris J, Woodcock A, Custovic A. Exposure and sensitization to indoor allergens: association with lung function, bronchial reactivity, and exhaled nitric oxide measures in asthma. J Allergy Clin Immunol. 2003 Aug;112(2):362-8. doi: 10.1067/mai.2003.1654.
citation: Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, Mitchell H, McNiff-Mortimer K, Lynn H, Ownby D, Malveaux F. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med. 1997 May 8;336(19):1356-63. doi: 10.1056/NEJM199705083361904.
citation: Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ. 2002 Mar 30;324(7340):763. doi: 10.1136/bmj.324.7340.763.
citation: Custovic A, Simpson A, Chapman MD, Woodcock A. Allergen avoidance in the treatment of asthma and atopic disorders. Thorax. 1998 Jan;53(1):63-72. doi: 10.1136/thx.53.1.63. No abstract available.
citation: van Velzen E, van den Bos JW, Benckhuijsen JA, van Essel T, de Bruijn R, Aalbers R. Effect of allergen avoidance at high altitude on direct and indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma. Thorax. 1996 Jun;51(6):582-4. doi: 10.1136/thx.51.6.582.
citation: Peroni DG, Boner AL, Vallone G, Antolini I, Warner JO. Effective allergen avoidance at high altitude reduces allergen-induced bronchial hyperresponsiveness. Am J Respir Crit Care Med. 1994 Jun;149(6):1442-6. doi: 10.1164/ajrccm.149.6.8004296.
citation: Grootendorst DC, Dahlen SE, Van Den Bos JW, Duiverman EJ, Veselic-Charvat M, Vrijlandt EJ, O'Sullivan S, Kumlin M, Sterk PJ, Roldaan AC. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids. Clin Exp Allergy. 2001 Mar;31(3):400-8. doi: 10.1046/j.1365-2222.2001.01022.x.
citation: Gotzsche PC, Johansen HK. House dust mite control measures for asthma: systematic review. Allergy. 2008 Jun;63(6):646-59. doi: 10.1111/j.1398-9995.2008.01690.x.
citation: Sublett JL. Effectiveness of air filters and air cleaners in allergic respiratory diseases: a review of the recent literature. Curr Allergy Asthma Rep. 2011 Oct;11(5):395-402. doi: 10.1007/s11882-011-0208-5.
citation: Boyle RJ, Pedroletti C, Wickman M, Bjermer L, Valovirta E, Dahl R, Von Berg A, Zetterstrom O, Warner JO; 4A Study Group. Nocturnal temperature controlled laminar airflow for treating atopic asthma: a randomised controlled trial. Thorax. 2012 Mar;67(3):215-21. doi: 10.1136/thoraxjnl-2011-200665. Epub 2011 Nov 30.
citation: Schauer U, Bergmann KC, Gerstlauer M, Lehmann S, Gappa M, Brenneken A, Schulz C, Ahrens P, Schreiber J, Wittmann M, Hamelmann E; all members of the German Asthma Net (GAN). Improved asthma control in patients with severe, persistent allergic asthma after 12 months of nightly temperature-controlled laminar airflow: an observational study with retrospective comparisons. Eur Clin Respir J. 2015 Jul 29;2. doi: 10.3402/ecrj.v2.28531. eCollection 2015.
citation: Brodtkorb TH, Zetterstrom O, Tinghog G. Cost-effectiveness of clean air administered to the breathing zone in allergic asthma. Clin Respir J. 2010 Apr;4(2):104-10. doi: 10.1111/j.1752-699X.2009.00156.x.
citation: Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999 Oct;14(4):902-7. doi: 10.1034/j.1399-3003.1999.14d29.x.
citation: Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005 May;99(5):553-8. doi: 10.1016/j.rmed.2004.10.008. Epub 2004 Nov 26.
citation: Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini Asthma Quality of Life Questionnaire. Eur Respir J. 1999 Jul;14(1):32-8. doi: 10.1034/j.1399-3003.1999.14a08.x.
citation: Pickard AS, Wilke C, Jung E, Patel S, Stavem K, Lee TA. Use of a preference-based measure of health (EQ-5D) in COPD and asthma. Respir Med. 2008 Apr;102(4):519-36. doi: 10.1016/j.rmed.2007.11.016. Epub 2008 Jan 3.
citation: Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009 Oct;34(5):447-54. doi: 10.1111/j.1749-4486.2009.01995.x.
citation: Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993 Nov;4(5):353-65. doi: 10.2165/00019053-199304050-00006.