Bronchial Thermoplasty: Mechanism of Action and Defining Asthma Phenotype

NCT ID: NCT02075151

Last Updated: 2014-03-03

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2018-05-31

Brief Summary

According to World Health Organization (WHO) estimates, more than 200 million people suffer from asthma worldwide and in 2009, the disease had claimed 250,000 lives globally. Autopsy reports suggest 2 phenotypes of severe asthma: one that is characterized by intense airway inflammation with mucus plugging, and the other by severe bronchoconstriction causing respiratory failure in the absence of significant airway inflammation. However, it is not easy to stratify patients according to phenotypes without bronchoscopy. Although severe asthma comprises only 10% of affected individuals, it accounts for more than half of the total healthcare spending on asthma. Inhaled corticosteroids are effective by suppressing production of multiple pro-inflammatory mediators, unfortunately efficacy plateaus. Addition of long acting beta agonist and anti-cholinergic agent to inhaled corticosteroids offers some measure of relief but effective treatment of severe asthma remains an unmet goal, resulting in intensive utilization of healthcare resources. In 2010, the United States Food and Drug Administration (FDA) approved bronchial thermoplasty (BT) as an adjunctive therapy for severe asthma. BT is radiofrequency ablation of airway smooth muscle via bronchoscopy with each patient undergoing three procedures which targets different lobes of the lung 3 weeks apart. Studies have demonstrated improved symptom control allowing discontinuation of oral steroids in some patients as well as reductions in exacerbations, hospitalizations and use of rescue medications. No development of airway strictures or bronchiectasis, and regeneration of normal epithelium after BT has been observed. At present, it remains unclear if BT benefits all asthma phenotypes or if BT has any effect on airway inflammation and remodeling.

The hypothesis of this study is that bronchial thermoplasty is likely to benefit all severe asthma phenotypes, and achieves this by exerting an effect on airway inflammation and remodelling.

The specific aims of the study are: 1) to better define the asthma phenotype who will benefit from BT by microarray and gene expression profiling; 2) to study effects of BT on airway inflammation; 3) to define its role in the overall asthma management algorithm

Conditions

Asthma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bronchial Thermoplasty

Bronchial thermoplasty

Group Type: OTHER

Bronchial Thermoplasty

Intervention Type: PROCEDURE

Bronchial thermoplasty

Interventions

Bronchial Thermoplasty

Bronchial thermoplasty

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Males and females between 21-65 years of age
• Poorly controlled severe persistent asthma (ACT score < 20) despite high-dose inhaled steroids (>500 mcg fluticasone/day or >800 mcg budesonide/day) in combination with inhaled long-acting Beta-2 agonist and/or anticholinergic agent. Other drugs include leukotriene modifiers, omalizumab (if used for at least 1 year prior), and oral corticosteroids 10mg/day or less
• Stopped smoking for > 1 year and <10 pack-years
• Stable maintenance asthma medications for 4 weeks
• Pre-bronchodilator FEV1 >60% predicted

Exclusion Criteria

• Males and females <21 and >65 years of age
• Presence of pacemaker, internal defibrillator, or other implantable electronic devices
• Known sensitivity to medications required to perform bronchoscopy, including lignocaine and benzodiazepines
• Patients previously treated with Bronchial Thermoplasty (BT)
• Use of immunosuppressant (excluding oral steroids)
• Increased risk of adverse events associated with bronchoscopy or anesthesia (including pregnancy, uncontrolled coronary artery disease, acute or chronic renal failure, and uncontrolled hypertension)
• Inability to cease antiplatelet or anticoagulant therapy prior to procedure

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kay Leong Khoo, MD

Role: PRINCIPAL_INVESTIGATOR

National University Hospital, Singapore

Locations

National University Hospital

Singapore, , Singapore

Countries

Singapore

Facility Contacts

Kay Leong Khoo, MD

Role: primary

khoo_kay_leong@nuhs.edu.sg

65-67795555

References

HOUSTON JC, DE NAVASQUEZ S, TROUNCE JR. A clinical and pathological study of fatal cases of status asthmaticus. Thorax. 1953 Sep;8(3):207-13. doi: 10.1136/thx.8.3.207. No abstract available.

Reference Type: BACKGROUND

PMID: 13102418 (View on PubMed)

Kuyper LM, Pare PD, Hogg JC, Lambert RK, Ionescu D, Woods R, Bai TR. Characterization of airway plugging in fatal asthma. Am J Med. 2003 Jul;115(1):6-11. doi: 10.1016/s0002-9343(03)00241-9.

Reference Type: BACKGROUND

PMID: 12867228 (View on PubMed)

Saetta M, Di Stefano A, Rosina C, Thiene G, Fabbri LM. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am Rev Respir Dis. 1991 Jan;143(1):138-43. doi: 10.1164/ajrccm/143.1.138.

Reference Type: BACKGROUND

PMID: 1986670 (View on PubMed)

Hogg JC. Varieties of airway narrowing in severe and fatal asthma. J Allergy Clin Immunol. 1987 Sep;80(3 Pt 2):417-9. doi: 10.1016/0091-6749(87)90065-0. No abstract available.

Reference Type: BACKGROUND

PMID: 3624696 (View on PubMed)

Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV, Reed CE, Hunt LW, Gleich GJ. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis. 1993 Sep;148(3):713-9. doi: 10.1164/ajrccm/148.3.713.

Reference Type: BACKGROUND

PMID: 8368644 (View on PubMed)

Good JT Jr, Kolakowski CA, Groshong SD, Murphy JR, Martin RJ. Refractory asthma: importance of bronchoscopy to identify phenotypes and direct therapy. Chest. 2012 Mar;141(3):599-606. doi: 10.1378/chest.11-0741. Epub 2011 Aug 11.

Reference Type: BACKGROUND

PMID: 21835905 (View on PubMed)

Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008 Aug 1;178(3):218-224. doi: 10.1164/rccm.200711-1754OC. Epub 2008 May 14.

Reference Type: BACKGROUND

PMID: 18480428 (View on PubMed)

Wahidi MM, Kraft M. Bronchial thermoplasty for severe asthma. Am J Respir Crit Care Med. 2012 Apr 1;185(7):709-14. doi: 10.1164/rccm.201105-0883CI. Epub 2011 Nov 10.

Reference Type: BACKGROUND

PMID: 22077066 (View on PubMed)

Lee P, Khoo KL. A review of current bronchoscopic interventions for obstructive airway diseases. Ther Adv Respir Dis. 2012 Oct;6(5):297-307. doi: 10.1177/1753465812455448. Epub 2012 Aug 9.

Reference Type: BACKGROUND

PMID: 22878625 (View on PubMed)

Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigo R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Deslattes Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X. The sequence of the human genome. Science. 2001 Feb 16;291(5507):1304-51. doi: 10.1126/science.1058040.

Reference Type: BACKGROUND

PMID: 11181995 (View on PubMed)

Verrills NM, Irwin JA, He XY, Wood LG, Powell H, Simpson JL, McDonald VM, Sim A, Gibson PG. Identification of novel diagnostic biomarkers for asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1633-43. doi: 10.1164/rccm.201010-1623OC. Epub 2011 Mar 18.

Reference Type: BACKGROUND

PMID: 21471098 (View on PubMed)

Mann M, Hendrickson RC, Pandey A. Analysis of proteins and proteomes by mass spectrometry. Annu Rev Biochem. 2001;70:437-73. doi: 10.1146/annurev.biochem.70.1.437.

Reference Type: BACKGROUND

PMID: 11395414 (View on PubMed)

Naaby-Hansen S, Waterfield MD, Cramer R. Proteomics--post-genomic cartography to understand gene function. Trends Pharmacol Sci. 2001 Jul;22(7):376-84. doi: 10.1016/s0165-6147(00)01663-1.

Reference Type: BACKGROUND

PMID: 11431033 (View on PubMed)

Zhao J, Zhu H, Wong CH, Leung KY, Wong WS. Increased lungkine and chitinase levels in allergic airway inflammation: a proteomics approach. Proteomics. 2005 Jul;5(11):2799-807. doi: 10.1002/pmic.200401169.

Reference Type: BACKGROUND

PMID: 15996009 (View on PubMed)

Wong WS, Zhao J. Proteome analysis of chronically inflamed lungs in a mouse chronic asthma model. Int Arch Allergy Immunol. 2008;147(3):179-89. doi: 10.1159/000142040. Epub 2008 Jul 2.

Reference Type: BACKGROUND

PMID: 18594147 (View on PubMed)

Quesada Calvo F, Fillet M, Renaut J, Crahay C, Gueders M, Hacha J, Paulissen G, Foidart JM, Noel A, Rocks N, Leprince P, Cataldo D. Potential therapeutic target discovery by 2D-DIGE proteomic analysis in mouse models of asthma. J Proteome Res. 2011 Sep 2;10(9):4291-301. doi: 10.1021/pr200494n. Epub 2011 Aug 3.

Reference Type: BACKGROUND

PMID: 21751807 (View on PubMed)

Liao W, Goh FY, Betts RJ, Kemeny DM, Tam J, Bay BH, Wong WS. A novel anti-apoptotic role for apolipoprotein L2 in IFN-gamma-induced cytotoxicity in human bronchial epithelial cells. J Cell Physiol. 2011 Feb;226(2):397-406. doi: 10.1002/jcp.22345.

Reference Type: BACKGROUND

PMID: 20665705 (View on PubMed)

Fitzpatrick AM, Higgins M, Holguin F, Brown LA, Teague WG; National Institutes of Health/National Heart, Lung, and Blood Institute's Severe Asthma Research Program. The molecular phenotype of severe asthma in children. J Allergy Clin Immunol. 2010 Apr;125(4):851-857.e18. doi: 10.1016/j.jaci.2010.01.048.

Reference Type: BACKGROUND

PMID: 20371397 (View on PubMed)

Other Identifiers

DSRB/2013/00144

Identifier Type: -

Identifier Source: org_study_id