Unravelling Targets of Therapy in Bronchial Thermoplasty in Severe Asthma

NCT02225392 | Completed DMC

• 3 other identifiers: NL45394.018.135.2.13.06490713477
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 3

Brief Summary

Approximately 5% of asthma patients suffer from severe asthma that is characterized by frequent asthma exacerbations resulting in significant morbidity and excessive utilisation of health care resources. Therefore, there is a strong need for improved therapeutic strategies for these patients. Insight in the pathogenesis and molecular pathways active in severe asthma is crucial to reach this goal. Bronchial Thermoplasty (BT) is a novel, innovative device-based treatment of severe asthma that is based on local, radiofrequent energy delivery in larger airways during bronchoscopy. Hypothesis: BT-induced clinical improvement in severe asthma is a consequence of reduction in airway smooth muscle (ASM) mass and (contractile/immunomodulatory) function, inflammation, neural innervation and/or vascular integrity resulting in altered airway remodelling. BT target identification and severe asthma phenotyping are critical for improved patient selection for BT and fundamental to discover novel, specific signalling pathways active in severe asthma.

Conditions

Asthma; Bronchial Asthma

Keywords

Bronchial thermoplasty; Severe asthma

Outcome Measures

Primary Outcomes (1)

• The change in airway smooth muscle (ASM) mass between immediate BT treated and the control group (N=20, randomized)

  The change in ASM mass as determined by the percentage of ASM surface area in airway biopsies between: * the immediate BT group and * the delayed BT group = control group

  Baseline, week 25

Secondary Outcomes (18)

• The change in ASM mass in airway biopsies before and after bronchial thermoplasty treatment (N=40, observational, before and after BT)

  Baseline, 25 weeks

• The change in structural airway remodelling after and during bronchial thermoplasty treatment

  Baseline, week 25

• The change in pre-and post bronchodilator FEV1 and related % reversibility between immediate BT treated and control group (N=20, randomized)

  Baseline, 24 week

• The change in PC20 methacholine between immediate BT treated and control group (N=20, randomized)

  Baseline, 24 week

• The change in Fraction of exhaled nitric oxide (FeNO) between immediate BT treated and control group (N=20, randomized)

  Baseline, 24 week

Other Outcomes (2)

• The change in Airway-resistance (sRaw)/-conductance(sGaw)/-mechanics (forced oscillation technique (FOT)) parameters after bronchial thermoplasty treatment

  Baseline, 24 weeks

• The change in exhaled volatile organic compounds (VOCs) after bronchial thermoplasty treatment

  Baseline, 24 weeks

Study Arms (2)

Delayed bronchial thermoplasty

ACTIVE COMPARATOR

After randomisation they will wait for 25 weeks (control group) and then start with bronchial thermoplasty. Bronchial thermoplasty (BT) will be performed using the Alair system (Boston Scientific, USA). Patients will undergo 3 bronchoscopy procedures with BT at least 3 weeks apart. Treatment sessions are designed to address different lobes of the lung with the right lower lobe treated during the first bronchoscopy, the left lower lobe treated during the second bronchoscopy, and both the right and left upper lobes treated in the third and final bronchoscopy. The right middle lobe and proximal airways including RC2 are left untreated.

Procedure: Bronchial thermoplasty; Device: Alair system (Boston Scientific, USA)

Immediate bronchial thermoplasty

EXPERIMENTAL

After randomisation they start immediate with bronchial thermoplasty treatment. Bronchial thermoplasty (BT) will be performed using the Alair system (Boston Scientific, USA). Patients will undergo 3 bronchoscopy procedures with BT at least 3 weeks apart. Treatment sessions are designed to address different lobes of the lung with the right lower lobe treated during the first bronchoscopy, the left lower lobe treated during the second bronchoscopy, and both the right and left upper lobes treated in the third and final bronchoscopy. The right middle lobe and proximal airways including RC2 are left untreated.

Procedure: Bronchial thermoplasty; Device: Alair system (Boston Scientific, USA)

Interventions

Bronchial thermoplasty PROCEDURE

Bronchial thermoplasty (BT) will be performed using the Alair system (Boston Scientific, USA). Patients will undergo 3 bronchoscopy procedures with BT at least 3 weeks apart. Treatment sessions are designed to address different lobes of the lung with the right lower lobe treated during the first bronchoscopy, the left lower lobe treated during the second bronchoscopy, and both the right and left upper lobes treated in the third and final bronchoscopy. The right middle lobe and proximal airways including RC2 are left untreated.

Delayed bronchial thermoplasty; Immediate bronchial thermoplasty

Alair system (Boston Scientific, USA) DEVICE

The alair system consist of a controller and a bastket catheter.

Delayed bronchial thermoplasty; Immediate bronchial thermoplasty

Eligibility Criteria

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

You may qualify if:

• Males or females age 18 or greater and 65 or less
• The diagnosis of asthma confirmed by at least one of the following as assessed at least once during the past 5 years before the study:
• Reversibility to β2-agonists ≥12% predicted and ≥200ml after 400μg inhaled salbutamol or equivalent
• Bronchial hyper-responsiveness to methacholine or histamine
• Peak-flow variability of \>20% over a period of 14 days
• Fall in FEV1 \>12% and \>200ml when tapering treatment (ICS, oral steroid, LABA and/or LTRA).
• Subject is taking regular maintenance medication (GINA step 4-5) for past 6 months that includes:
• Inhaled corticosteroid at a dosage ≥500μg fluticasone equivalent per day AND
• Long acting ß2-agonist at a dosage of ≥100μg per day salmeterol dose aerosol or equivalent).
• Per protocol bronchial hyper-responsiveness to methacholine (PC20\<4 mg/ml)
• Other asthma medications are acceptable (such as Leukotriene modifiers, Theophylline, Omalizumab treatment (or discontinuation for at least 6 months) Systemic corticosteroid use (≤20mg/day prednisone equivalent))
• Pre-bronchodilator FEV1 ≥50% predicted (stabilized on ICS/LABA) and post-bronchodilator FEV1 ≥60%
• ACQ \>1,5 for 2 weeks
• Non-smoker for 1 year or more (former smoker ≤15 pack years)
• Ability to undergo bronchoscopy and BT in the opinion of the investigator.

You may not qualify if:

• Asthma exacerbation during the prior 4 weeks.
• Subject has 5 or more hospitalizations for exacerbations of asthma in the previous year or 1 or more ICU admission for mechanical or endotracheal intubation for asthma in the previous year.
• Respiratory tract infection within past 4 weeks
• Subject has a known sensitivity to medications required to perform bronchoscopy
• Subject is using immunosuppressant therapy other than oral steroid therapy
• Subject is on anticoagulant medication including anti-platelet agents.
• Subject has bleeding diathesis, platelet dysfunction, thrombocytopenia with platelet count less than 125,000/mm2 or known coagulopathy (INR \>1.5).
• Subject has other respiratory diseases including interstitial lung disease, emphysema, cystic fibrosis, mechanical upper airway obstruction, Churg-Strauss syndrome, and allergic bronchopulmonary aspergillosis (total IgE of \>1000 Units/mL with positive specific IgE to aspergillus and evidence of central bronchiectasis).
• Subject has segmental atelectasis, lobar consolidation, significant or unstable pulmonary infiltrate, or pneumothorax, confirmed on x-ray. Bronchiectasis on HR-CT-of the chest, both centrally or peripherally will be excluded.
• Subject has clinically significant cardiovascular disease, including myocardial infarction, angina, cardiac dysrhythmia, conduction defect, cardiomyopathy, aortic aneurysm, or stroke at the discretion of the investigator
• Subject has uncontrolled hypertension (\>200mmHg systolic or \>100mmHg diastolic pressure).
• Subject uses an internal or external pacemaker or cardiac defibrillator.
• Other chronic diseases that in the opinion of the investigator would prevent participation in the trial or put the participant at risk by participation, e.g. liver, kidney, or nervous system
• Current smokers, and a history of cigarette smoking with \>15 pack years total
• Use of investigative drugs or intervention trials in the 4 months prior to enrolment or during the duration of the study

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• The Netherlands Asthma Foundation: collaborator
• Boston Scientific Corporation: collaborator

Study Sites (3)

Academisch Medisch Centrum

Amsterdam, North Holland, 1105 AZ, Netherlands

Location

University Medical Center Groningen

Groningen, 9700 RB, Netherlands

Location

Royal Brompton Hospital

London, SW3 6NP, United Kingdom

Location

Related Publications (3)

• Wijsman PC, Goorsenberg AWM, Keijzer N, d'Hooghe JNS, Ten Hacken NHT, Shah PL, Weersink EJM, de Brito JM, de Souza Xavier Costa N, Mauad T, Nawijn MC, Vonk JM, Annema JT, Burgess JK, Bonta PI. Airway wall extracellular matrix changes induced by bronchial thermoplasty in severe asthma. J Allergy Clin Immunol. 2024 Feb;153(2):435-446.e4. doi: 10.1016/j.jaci.2023.09.035. Epub 2023 Oct 5.

  PMID: 37805024 DERIVED

• Goorsenberg AWM, d'Hooghe JNS, Slats AM, van den Aardweg JG, Annema JT, Bonta PI. Resistance of the respiratory system measured with forced oscillation technique (FOT) correlates with bronchial thermoplasty response. Respir Res. 2020 Feb 12;21(1):52. doi: 10.1186/s12931-020-1313-6.

  PMID: 32050956 DERIVED

• d'Hooghe JNS, Ten Hacken NHT, Weersink EJM, Sterk PJ, Annema JT, Bonta PI. Emerging understanding of the mechanism of action of Bronchial Thermoplasty in asthma. Pharmacol Ther. 2018 Jan;181:101-107. doi: 10.1016/j.pharmthera.2017.07.015. Epub 2017 Jul 27.

  PMID: 28757156 DERIVED

MeSH Terms

Conditions

Asthma

Interventions

Bronchial Thermoplasty

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Catheter Ablation; Radiofrequency Ablation; Radiofrequency Therapy; Therapeutics; Ablation Techniques; Surgical Procedures, Operative

Study Officials

• Jouke T Annema, Prof. Dr.

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

• P I Bonta, Dr

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr. J.T. Annema

Study Record Dates

• First Submitted: July 30, 2014
• First Posted: August 26, 2014
• Study Start: April 1, 2014
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: December 5, 2022

Record last verified: 2022-12

Locations

GB (1); NL (2)