Clinical trial NCT03053973: The Effects of Nocturnal Non-invasive Ventilation in Stable COPD
Official title: Nocturnal Non-Invasive Ventilation in COPD Patients With Stable Hypercapnic Respiratory Failure: Why and in Which Patient Might This be Effective?
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Noninvasive Ventilation
Keywords: COPD
airway inflammation
airway remodeling
health-related auality of life
forced expiratory volume 1 second
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2017-02-15
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel groups non-blinded randomised controlled trial
Primary purpose: TREATMENT

Brief summary: Rationale:

Application of long-term non-invasive ventilation (NIV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure (CHRF) has recently been shown to improve outcomes. However, the mechanism behind these improvements are unknown. We hypothesize that NIV stabilizes FEV1 via beneficial effects on inflammation and repair pathways in patients with COPD. In the present study we aim to investigate, in COPD patients with CHRF,

1. change in FEV1 after 3 months nocturnal NIV in stable hypercapnic COPD patients as compared to standard care
2. the relationship between FEV1 change and modification of systemic and airway inflammation and remodelling, lung hyperinflation, and airway morphology.
3. predictors of a favourable response to chronic NIV in COPD patients with CHRF. Study design: multicentre randomised controlled study investigating the effects of NIV on airway morphology, airway inflammation and remodelling in hypercapnic COPD patients including a control group that will postpone the initiation of NIV for 3 months. In addition we will investigate how patient demographics, patient and disease characteristics and systemic and airway inflammation predict the response to chronic NIV in severe stable COPD. To do this, all patients will be followed for 6 months after NIV initiation.

Main study parameters/endpoints: The main endpoint is the change FEV1 after 3 months. Furthermore, as we recognise that FEV1 might not be the most important patient-related outcome, we will assess which parameters affect health-related quality of life after 3 and 6 months.

Detailed description: Rationale: Application of long-term non-invasive ventilation (NIV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure (CHRF) has recently been shown to improve outcomes when applied with sufficiently high inspiratory pressures and adequate backup breathing frequencies (high-intensity NIV). Interestingly, it has been demonstrated that nocturnal NIV improves not only clinical but also physiological parameters like arterial carbon dioxide pressure (PaCO¬2¬) and forced expiratory volume in 1 second (FEV1) in patients with stable COPD. However, the mechanism behind these improvements are unknown. Furthermore, it is unclear whether this improvement in lung function influences health-related quality of life (HRQoL), the utmost goal of chronic NIV in COPD, or that other baseline patient- and ventilatory characteristics are more important in predicting a long-term beneficial effect.

We hypothesize that NIV stabilizes FEV1 via beneficial effects on inflammation and repair pathways in the airways of patients with COPD. We aim to study this hypothesis and to investigate the regulation of lung function, markers of inflammation and repair pathways in airway biopsies, bronchial wash and bronchial and nasal epithelium in response to home mechanical ventilation. The second goal of this study is to define a phenotype of patients with COPD, based on baseline characteristics and biomarkers, such as markers of inflammation, who will respond to NIV therapy with improvements in lung function and HRQoL.

Objectives:

1. To investigate change in FEV1 after 3 months nocturnal NIV in stable hypercapnic COPd patients as compared to standard care
2. To investigate the relationship between FEV1 change and modification of systemic and airway inflammation and remodelling, lung hyperinflation, and airway morphology.
3. To investigate predictors of a favourable response to chronic NIV in COPD patients with CHRF.

Study design: The study is multicentre randomised controlled study investigating the effects of NIV on airway morphology, airway inflammation and remodelling in hypercapnic COPD patients including a control group that will postpone the initiation of NIV for 3 months. To measure these parameters a bronchoscopy with a bronchial wash and bronchial biopsies and high-resolution CT-scanning we be done at baseline and after 3 months. In a addition we will investigate how patient demographics, patient and disease characteristics and systemic and airway inflammation predict the response to chronic NIV in severe stable COPD. To do this, all COPD patients initiated on NIV in our centre will be followed for 6 months after NIV initiation as part of the present study.

Study population: Patients who have an indication for NIV (COPD Global Initiative of Obstructive Lung Disease (GOLD) III or IV and a PaCO2 \> 6.0 kilopascal (kPa) in stable disease) in the Netherlands will be asked to participate.

For investigating airway inflammation, to ensure safety during the bronchoscopies, patients with severe gas exchange derangements (i.e. PaCO2 \> 8.0 kPa and /or partial arterial oxygen pressure (PaO2)\<6.5 kPa at rest during spontaneous breathing), and instable cardiac comorbidities will be excluded. These patients will be included to be followed for 6 months prospectively after NIV initiation, according to the same protocol, however, without CT-scanning and bronchoscopies.

Main study parameters/endpoints: The main endpoint is the change FEV1 after 3 months. Several markers of blood and airway inflammation and remodeling will be assessed to analyse mechanisms of FEV1 improvements.

Furthermore, as we recognise that FEV1 might not be the most important patient-related outcome, we will assess which parameters affect health-related quality of life after 3 and 6 months. For this, parameters of the total group of patients will be used.

Eligibility criteria: Inclusion Criteria:

* Indication to initiate chronic NIV in COPD patients (GOLD stage III or IV: FEV1/ forced expiratory volume (FVC)\< 70% and FEV1\< 50% predicted; PaCO2 \> 6.0 kilopascal (kPa) in stable condition, which means no COPD exacerbation for 4 weeks and a pH \> 7.35)
* Age \> 18 years
* Written informed consent is obtained

Exclusion Criteria:

For the randomised Inflammation part a potential subject who meets any of the following criteria will be excluded from participation in this study:

* Oral corticosteroids or roflumilast
* A history of lung volume reduction surgery
* Body mass index (BMI) \> 35 kg/m2
* Obstructive sleep apnoea (OSA) (apnoea/hypopnea index (AHI) \>15/hr): to exclude OSA a polygraphy will be done at baseline
* PaCO2 ≥ 8.0 kPa or PaO2 \< 6.5 kPa at rest without oxygen
* Instable cardiac comorbidities (left ventricular ejection fraction (LVEF) \<40%, instable coronary artery disease, instable heart failure)

Primary outcomes:
measure: FEV1
timeFrame: baseline, 3 months
measure: Health-Related Quality of Life
timeFrame: baseline, 3 months, 6 months
Secondary outcomes:
measure: Safety: the number of adverse events will be recorded.
timeFrame: baseline, 3 months, and 6 months
measure: Health-related quality of life assessed with the SF-36
timeFrame: baseline, 3 months, 6 months
measure: Anxiety and depression
timeFrame: baseline, 3 months, 6 months
measure: Activities and Restrictions,
timeFrame: baseline, 3 months, 6 months
measure: Caregiver Burden
timeFrame: baseline, 3 months, 6 months
measure: Dyspnoea
timeFrame: baseline, 3 months, 6 months
measure: Gas exchange day
timeFrame: baseline, 3 months, 6 months
measure: Gas exchange night
timeFrame: baseline, 3 months, 6 months
measure: Respiratory muscle activity
timeFrame: baseline, 3 months
measure: Spirometry
timeFrame: baseline, 3 months, 6 months
measure: Exercise tolerance
timeFrame: baseline, 3 months, 6 months
measure: Peripheral muscle function
timeFrame: baseline, 3 months
measure: Compliance with the ventilator
timeFrame: baseline, 3 months, 6 months
measure: Venous blood
timeFrame: Baseline, 3 months
measure: Urine albumin to Creatinine ratio
timeFrame: Baseline, 3 months
measure: Nasal epithelium markers of remodelling and repair
timeFrame: Baseline, 3 months
measure: Airway abnormalities
timeFrame: Baseline, 3 months
measure: Airway inflammation and remodeling
timeFrame: Baseline, 3 months
measure: HRQoL assessed with CCQ
timeFrame: Baseline, 3 months, 6 months
measure: Patient-ventilator asynchrony
timeFrame: baseline, 3 months
measure: Lung volumes
timeFrame: baseline, 3 months, 6 months
measure: Emphysema
timeFrame: baseline, 3 months
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Peter J Wijkstra, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: