Bronchial thermoplasty for severe asthma

Transcription

1 Severe Refractory Asthma Meeting, Leuven, Belgium 20 th February 2014 Bronchial thermoplasty for severe asthma Professor Neil C Thomson Institute of Infection, Immunity & Inflammation University of Glasgow & Respiratory Medicine, Gartnavel General Hospital Glasgow, UK

2 Case History: clinic referral 28 yr old male Asthma like symptoms since childhood Non smoker Treatment Maintenance oral prednisolone 5 10 mg daily High dose combination therapy (inhaled fluticasone +salmeterol) Oral montelukast 10mg nocte Inhaled salbutamol PRN Unsuccessful trial of omazulamab Over a number of years Waking most nights Exacerbations requiring high dose oral steroids 2 to 3 times per year

3 Bronchial thermoplasty? GINA Asthma Guideline

4 Bronchial thermoplasty topics Pre clinical development Procedure Effectiveness risk/benefit ratio Guideline recommendations Selection criteria Future developments

5 Bronchial thermoplasty: preclinical development Hypothesis 12 Weeks Post bronchial thermoplasty treatment (Canine Model) Severe asthma UNTREATED Smooth muscle present TREATED Reduction in smooth muscle Temperature & decrease in airway responsiveness 55 o C Reduction in airway smooth muscle by thermal energy 65 o C 75 o C Danek et al. J Appl Physiol. 2004

6 Bronchial thermoplasty: equipment Alair System for Bronchial Thermoplasty Catheter is a flexible tube with an expandable wire array at the tip Radiofrequency Controller supplies energy via the catheter to heat the airway wall

7 Bronchial thermoplasty: procedure 3 1 * 2

8 Clinical studies of bronchial thermoplasty 3 randomized trials + 1 observational study Long term follow up AIR BT & 98 Sham patients Randomized, double blinded, sham controlled trial Safety, quality of life improvement & healthcare utilization Severe persistent asthma 276 RISA 3 15 BT & 17 control patients BT randomized vs standard of care Safety & medication reduction Severe refractory asthma 86 AIR 2 55 BT & 54 control patients Randomized vs standard of care Safety & efficacy Moderate & severe asthma 71 Feasibility 1 16 BT patients Safety Mild to severe asthma 16 1 Cox et al., AJRCCM 2006; Cox et al., AJRCCM Cox et al., NEJM 2007; Thomson et al., BMC Pulm Med Pavord et al., AJRCCM 2007; Pavord et al., AJRCCM Castro et al., AJRCCM 2010; Wechsler et al JACI 2013

9 Asthma Intervention Research (AIR)2 Trial Enrollment 2:1 randomisation (BT: Sham Control) 297 subjects randomised in 30 centres Primary outcome Change in AQLQ score between 6 and 12 months between BT and sham control Secondary outcomes Severe exacerbations, ER visits, lung function, safety outcomes Castro et al AJRCCM 2010

10 AIR2 Trial: asthma quality of life (AQLQ) and healthcare utilisation AQLQ score Healthcare utilisation events: (post treatment) BT 32% 84% Mean Difference = 0.21 Posterior Probability of Superiority = 96.0% Castro et al AJRCCM 2009

11 Summary RCTs of bronchial thermoplasty Efficacy outcome AIR Trial NEJM 2007 (n=109) BT vs usual care RISA Trial AJRCCM 2007 (n=32) BT vs usual care AIR2 Trial AJRCCM 2010 (n=297) BT vs sham control AQLQ score Exacerbations ER visits (Mild) (Severe) ACQ score PEF/FEV 1 PC 20 (High ICS subgroup)

12 AIR2 Trial: short term safety Respiratory related adverse events during treatment phase: Main symptoms: wheeze, cough, chest discomfort, dyspnoea, productive cough, and discolored sputum Majority occur within 1 day and resolve within 7 days Higher number of hospital admission for respiratory related events: RR 3.8 (95%CI 1.39 to 10.24, p=0.009) Wu et al J Int Med Res 2011

13 Bronchial thermoplasty: long term safety 5 year safety data: Feasibility, AIR1, RISA & AIR2 studies AIR1 Trial RISA Trial Thomson et al BMC Pulm Med 2011 Pavord et al Annal Allergy, Asthma & Immunol 2013

14 Bronchial thermoplasty: long term follow up AIR2 Trial 5 yr follow up Severe exacerbation rates ER visit rates Wechsler et al JACI 2013

15 Risk/ benefit assessment 1 year 5 years

16 Guideline recommendations International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma 2014 Bronchial thermoplasty is performed in adults with severe asthma only in the context of an Institutional Review Board approved independent systematic registry or a clinical study Draft BTS/SIGN Asthma Guideline 2014 Bronchial thermoplasty is a modestly effective treatment option for selected patients with moderate to severe asthma who have poorly controlled asthma despite maximal therapy Grade of recommendation: A

17 BTS/SIGN Asthma Guideline 2014: Good practice points Assessment and treatment for bronchial thermoplasty should be undertaken in centres that have expertise in the assessment of difficult to control asthma and in fibreoptic bronchoscopic procedures. The balance of risks and benefits of bronchial thermoplasty treatment should be discussed with patients being considered for the procedure. Longer term follow up of treated patients is recommended. In the UK all patients undergoing bronchial thermoplasty should have demographic and procedure details recorded in the British Thoracic Society Difficult Asthma Registry. Further research is recommended into factors that identify patients who will or will not benefit from bronchial thermoplasty treatment. Draft BTS/SIGN Asthma Guideline ed

18 Who to consider for bronchial thermoplasty? Systematic approach to the evaluation of difficult to control asthma Bousquet J et al, JACI 2010 Bel E et al, Thorax 2011 Heaney L et al, Thorax 2010

19 Who to consider for bronchial thermoplasty? Patients who are potential candidates for bronchial thermoplasty Adults years Moderate to severe asthma phenotype: symptomatic despite treatment with high dose ICS + LABA Able to safely undergo bronchoscopy per hospital guidelines Patients who are not candidates for bronchial thermoplasty Patients that have a pacemaker, internal defibrillator, or other implantable electronic device Patients that have a known sensitivity to medications required to perform bronchoscopy, including lidocaine Patients that have previously been treated with the bronchial thermoplasty

20 Who to consider for bronchial thermoplasty? Warnings and precautions Post bronchodilator FEV 1 < 65% predicted. Use of oral corticosteroids in excess of 10 mgs per day for asthma. Intubation for asthma, or ICU admission for asthma within the prior 24 months Any of the following within the past 12 months: 4 or more lower respiratory tract infections 3 or more hospitalizations for respiratory symptoms 4 or more OCS pulses for asthma exacerbation Use of short acting bronchodilator in excess of 12 puffs per day within 48 hs of bronchoscopy

21 Clinical service: Bronchial thermoplasty at Gartnavel Hospital, Glasgow, UK Patients n=10 Clinical outcomes at 12 months post treatment Beneficial response

22 Personalised medicine & bronchial thermoplasty TARGET BIOMARKER Bronchial thermoplasty Airway smooth muscle?? Potential mode(s) of action Reduced airway smooth muscle mass Reduced airway smooth muscle contractility Reduced inflammatory cytokine secretion from airway smooth muscle Alterations in airway epithelial, neural or inflammatory cell function Placebo effect

23 Reduced airway smooth muscle mass Asthma Baseline 3 wk post bronchial thermoplasty Gordon et al J Asthma 2013

24 Reduced airway smooth muscle response to increase in temperature In vitro airway smooth muscle response to temperature Heat treatment at 65 O C Contraction: reduced Acetylcholine (Ach) Relaxation: unaffected agonist Actin myosin interaction Temperature sensitive Black tracing: Heat treated at 65 O C Gray tracing: Heat treated at 37 O C Dyrda et al Am J Respir Cell Mol Biol 2011

25 Bronchial thermoplasty: future developments Long term efficacy & safety A multicenter, open label, single arm study [Bronchial Thermoplasty in Severe Persistent Asthma (PAS2)] US (ClinicalTrials.gov Identifier: NCT ). The primary endpoint: severe exacerbations Study aims to enrolling 300 patients Predictors of response A prospective observational study of baseline clinical, physiologic, biologic and imaging predictors of response to bronchial thermoplasty with the aim of recruiting 190 subjects (ClinicalTrials.gov Identifier: NCT ). Does increased bronchial smooth muscle mass predicts those patients with severe asthma who will obtain greatest benefit from the procedure? (ClinicalTrials.gov Identifier: NCT ).

26 Bronchial thermoplasty: future research Treatment procedure Hyperpolarized xenon (HXe) Magnetic Resonance Imaging (MRI) scanning can be used to prioritize the order of airway treatment by bronchial thermoplasty and allow treatment to be completed in a single session (ClinicalTrials.gov Identifier: NCT ). Mechanism of action A study to determine whether bronchial thermoplasty destroys nerve receptors [Transient receptor potential vanilloid type 1 (TRPV1)] or unmyelinated nerve fibers located in the mucosa and attenuate central and local axon induced bronchoconstriction (ClinicalTrials.gov Identifier: NCT ). Effects of bronchial thermoplasty on airway smooth muscle mass in asthma (ClinicalTrials.gov Identifiers: NCT and NCT )

27 Bronchial thermoplasty: conclusions 1 Bronchial thermoplasty is a modestly effective treatment option for selected patients with moderate to severe asthma who have poorly controlled asthma despite maximal therapy. Assessment and treatment should be undertaken in centres that have expertise in the assessment of difficult to control asthma and in fibreoptic bronchoscopic procedures. The balance of risks and benefits of bronchial thermoplasty treatment should be discussed with patients being considered for the procedure. Outpatient hospital procedure performed over 3 treatment sessions, routinely under moderate sedation, by a trained pulmonologist

28 Bronchial thermoplasty: conclusions 2 Longer term follow up of treated patients is recommended. Future research is needed to: Confirm long term efficacy & safety of the procedure Identify mode(s) of action of bronchial thermoplasty Factors that predict a beneficial clinical response

29 Thank you Respiratory Medicine Institute of Infection, Immunity & Inflammation & Gartnavel General Hospital Glasgow, UK