Clinical trial NCT03010449: LVR in Severe Emphysema Using Bronchoscopic Autologous Blood Instillation in Combination With Intra-bronchial Valves
Official title: A Single Arm Pilot Study of Lung Volume Reduction in Severe Emphysema Using Bronchoscopic Autologous Blood Instillation in Combination With Intra-bronchial Valves
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Emphysema
Keywords: Lung volume reduction treatment
Autologous blood instillation
Intra-bronchial valve (IBV)
Endobronchial valve
Lead sponsor: Royal Brompton & Harefield NHS Foundation Trust
Sponsor class: OTHER
First posted: 2017-01-05
Enrollment: 20
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A single arm pilot study of lung volume reduction in severe emphysema using bronchoscopic autologous blood instillation in combination with intra-bronchial valves.

Detailed description: Chronic obstructive pulmonary disease (COPD) is an umbrella term encompassing two entities causing progressive and ultimately disabling breathlessness. Emphysema is a process destructive of the airspaces distal to the terminal bronchioles, with loss of gas exchange tissue, of elastic recoil and of circumferential tethering of the small airways leading to their collapse on forced expiration. Chronic bronchitis is a disorder of the bronchi causing excess production and impaired mobilisation of mucus. Increased parasympathetic tone and progressive remodelling of airways impairs response to bronchodilators. Static and dynamic hyperinflation with a persistently expanded chest and flattened diaphragms despite increasing use of accessory respiratory muscles results in a disadvantaged respiratory pump.

Patients with severe emphysema and hyperinflation may benefit from lung volume reduction techniques designed to reduce gas trapping and to improve airflow, chest wall and lung mechanics. The best evidence exists for lung volume reduction surgery (LVRS), which however is not without risk and there is increasing interest in the development of bronchoscopic lung volume reduction (BLVR) techniques including emplacement of intra-bronchial valves and bronchoscopic instillation of blood products, which have been shown individually to improve lung function, exercise capacity, and quality of life.

Most of the experience in bronchoscopic lung volume reduction has been with endobronchial valves which were introduced in 2001. One-way valves are inserted into segmental airways to deflate the most emphysematous lobes of the lung, allowing compromised lesser diseased tissue to expand and regain its function. Reduction of hyperinflation and improved lung function, exercise capacity, and quality of life, have been observed using the intra-bronchial valve (IBV Valve System) by Olympus in patients with upper lobe-predominant emphysema. These improvements are most pronounced in those with radiologically intact lobar fissures, a surrogate observation thought to indicate an absence of collateral ventilation, which can be confirmed using the Chartis balloon catheter system. A combined approach of CT fissure analysis and Chartis measurement is suggested to ensure the appropriate selection of patients.

Bronchoscopic instillation of biological agents such as fibrinogen, thrombin or autologous blood into the sub-segmental airways induces lung volume reduction initially by airway obstruction and resorption atelectasis followed by a localised inflammatory reaction leading to tissue remodelling at the alveolar level, with fibrosis and contraction of the target lobe. Unlike the intra-bronchial valve, collateral ventilation is not an issue, seeming not to influence the outcome. The cost compares favourably with that of prosthetic implants. Preliminary data from phase 1 and 2 trials using fibrinogen and thrombin in patients with upper lobe-predominant emphysema demonstrated improvements in lung function, exercise capacity, and quality of life scores up to 6 months with a trend towards better outcomes in those receiving 20mls (versus 10mls) to each of eight sub-segmental sites (four per upper lobe). Most patients experienced a self-limiting inflammatory reaction characterised by fever, malaise, shortness of breath, pleuritic chest pain and/or leucocytosis within 24 hours. 11 of 50 patients (22%) in phase 2 experienced a procedure-related COPD exacerbation comparable to other forms of endoscopic lung volume reduction. Similar physiological and symptomatic outcomes were observed in patients with homogeneous emphysema with 20mls (versus 10mls) per sub-segment instillation. Bakeer et al compared bronchoscopic lung volume reduction in patients with heterogeneous emphysema using autologous blood (n=7) with fibrin glue (n=8). At 12 weeks, statistically significant improvements in hyperinflation, lung function, exercise capacity (6MWT), and quality of life scores were observed in both groups. COPD exacerbations were fewer compared to earlier studies, which the authors suggest may be due to the use of a triple lumen balloon catheter protecting surrounding sub-segments from overspill and unintended inflammatory responses.

The prospect of broadening the eligibility for intra-bronchial valve implantation to include those with collateral ventilation treated with autologous blood is attractive and not yet studied.

Furthermore, the mechanisms of actions of intra-bronchial valves and of autologous blood instillation are not fully understood and may extend beyond lung volume reduction. In valve procedures where volume reduction has not been achieved, clinically meaningful improvements in quality of life independent of lung function have been described. Recruitment of compressed lung, restoration of elastic recoil and redirection of airflow are some of the postulated effects that are likely to involve the small airways. This may be investigated, for example, with multiple breath nitrogen washout (MBNW) which is a sensitive marker of small airways disease and can measure ventilation inhomogeneity, functional residual capacity and estimate trapped gas volumes. Impulse oscillometry (IOS) yields information on airway resistance and reactance (a measure of compliance) and distinguishes between large and small airway resistance.

Eligibility criteria: Inclusion Criteria:

1. Age 40 or older
2. Diagnosis of severe COPD
3. Stopped smoking for at least 6 months prior to entering the study.
4. Completed a pulmonary rehabilitation program within 12 months prior to treatment and/or regularly performing maintenance respiratory rehabilitation if initial supervised therapy occurred more than 12 months prior to baseline testing.
5. Received Influenza vaccination consistent with local recommendations and/or policy.
6. Read, understood and signed the Informed Consent form.
7. Dyspnea scoring ≥2 on mMRC scale of 0-4.
8. FEV1%pred \<45% and FEV1/FVC \<60%.
9. TLC%pred \>100% AND RV%pred \>175%.
10. RV/TLC \>55%
11. CT thorax must demonstrate heterogeneous emphysema and a disrupted interlobar fissure (75-90% intact) in the treatment lobe. Scans will be analysed using in-house software to calculate a heterogeneity score and percentage fissure integrity.
12. Chartis balloon catheter assessment confirms the presence of collateral ventilation in the target lobe.

Exclusion Criteria:

1. Patient unable to provide informed consent.
2. Subject has a history of recurrent clinically significant respiratory infections, defined as 3 or more hospitalizations for respiratory infection during the year prior to enrolment.
3. Subject has clinically significant bronchiectasis.
4. Alpha-1 AT deficiency.
5. Medical history of asthma.
6. Subject has co-morbidities that may significantly reduce ability to improve exercise capacity (e.g., severe arthritis, planned knee surgery) or baseline limitation on 6MWT is not due to dyspnoea.
7. Subject has evidence of other severe disease (such as, but not limited to, lung cancer or renal failure), which in the judgment of the investigator may compromise survival of the subject for the duration of the study.
8. Subject is pregnant or lactating, or plans to become pregnant within the study timeframe.
9. Subject has an inability to tolerate bronchoscopy under conscious sedation or general anaesthesia.
10. Subject has severe gas exchange abnormalities as defined by: PaCO2 \>8.0 kPa and/or PaO2 \< 6.0 kPa (on room air).
11. FEV1 \<15% predicted and Total lung CO uptake (TLCO) \<20% predicted.
12. Subject has an inability to walk \>140 meters in 6 minutes.
13. Subject has severe pulmonary hypertension defined by right ventricular systolic pressure \>45 mm Hg measured on transthoracic echocardiogram.
14. Subject has giant bullae \>1/3 lung volume.
15. Lung nodule requiring surgery.
16. Subject has had previous LVR surgery, lung transplantation or lobectomy.
17. Subject has been involved in pulmonary drug or device studies within 30 days prior to this study.
18. Subject is taking \>10 mg prednisone (or equivalent dose of a similar steroid) daily.
19. Subject requires high level chronic immunomodulatory therapy to treat a moderate to severe chronic inflammatory autoimmune disorder.
20. Subject is on an antiplatelet (such as Plavix) or anticoagulant therapy (such as Warfarin or NOAC) which cannot be stopped prior to the procedure.
21. Subject has a known sensitivity or allergy to Nickel.
22. Subject has a known sensitivity to drugs required to perform bronchoscopy.
23. Subject has any other disease, condition(s) or habit(s) that would interfere with completion of study and follow up assessments, would increase risks of bronchoscopy or assessments, or in the judgment of the investigator would potentially interfere.

Primary outcomes:
measure: Change in FEV1 between baseline and 6 months follow-up after lung volume reduction treatment.
timeFrame: 6 months
Secondary outcomes:
measure: Change from baseline in CT lobar volumes 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in SGRQ 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in dyspnoea score 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in RV 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in TLC 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in RV/TLC 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in TLCO 6 months post treatment
timeFrame: 6 months
measure: Change from baseline in lung compliance 6 months post-treatment
timeFrame: 6 months
measure: Change from baseline in ventilation inhomogeneity 6 months post-treatment.
timeFrame: 6 months
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Royal Brompton & Harefields Hospital
Study officials:
affiliation: Royal Brompton & Harefields Hospital
name: Pallav L Shah, MBBS MD FRCP
role: PRINCIPAL_INVESTIGATOR
References:
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