Using Multiomics to Define Mechanisms of RhinoVirus-induced Chronic Obstructive Pulmonary Disease Exacerbations to Develop Novel Therapies and Therapeutic Targets
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Lower Respiratory Symptom Score (LRSS)
研究概览
简要总结
The goal of this study is to examine exacerbations of chronic obstructive pulmonary disease (COPD) caused by a common cold virus called rhinovirus, to identify new treatments. Exacerbations are flare-ups of respiratory symptoms which are a major cause of ill health in people with COPD, and are most commonly caused by viruses.
The main questions the study aims to answer are:
- What processes in the body occur in response to rhinovirus infection, and do the differences between people with COPD and healthy volunteers explain why people with COPD develop more severe illness and exacerbations?
- Can treatments be identified that target these processes to reduce the severity and frequency of exacerbations in people with COPD?
The study will compare eligible participants with COPD to healthy volunteers, and will involve intentionally infecting each participant with rhinovirus in a controlled environment. They will undergo baseline investigations prior to infection including a first bronchoscopy. Post-infection each participant will undergo a range of tests, including a second bronchoscopy, to compare how processes in the body, and especially the lungs, differ between people who do and do not have COPD.
详细描述
Study Rationale:
The investigators aim to understand the biological mechanisms that underlie exacerbations of Chronic Obstructive Pulmonary Disease (COPD) to drive the discovery of new treatments.
COPD is the 4th leading cause of death worldwide, causing 3.5 million deaths in 2021. Acute exacerbations of COPD (AECOPD) involve sudden flare-ups of symptoms, commonly triggered by viral infections, and are the major cause of COPD morbidity, mortality and healthcare costs. Developing new treatments for AECOPD requires a better understanding of the processes occurring in the lungs, before and during exacerbations. Naturally-occurring AECOPD are challenging to study in a way that allows reliable measurement of disease mechanisms, and repeated lung sampling can be impractical and potentially dangerous.
The investigators have therefore developed a human rhinovirus challenge experimental model of AECOPD. This involves infecting participants with a common cold virus called rhinovirus (RV). These studies have demonstrated that RV causes mild-to-moderate exacerbations in 95% of COPD subjects, that confounding factors can be controlled to take reliable measurements, and that repeated sampling of the lungs and respiratory tract can safely and easily be performed in a controlled research environment.
The investigators will compare people who have COPD with people who do not have COPD, including smokers and non-smokers, to identify the processes important in COPD. Researchers will measure a range of clinical and scientific outcomes, using cutting-edge 'multiomics' techniques to understand mechanisms in RV-induced AECOPD to an extent that has not been achieved before.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 40 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •for COPD subjects
- •Male or female sex
- •Age ≥40 years and ≤75 years at the time of signing the consent form
- •Medical history or clinical diagnosis of COPD
- •Significant smoking history, defined as:
- •Cumulative smoking history of at least 20 pack years
- •Permitted to currently use, or have history of use of, e-cigarettes/vapes
- •COPD spirometry criteria:
- •Post bronchodilator FEV1 of <80% and ≥50% predicted for age and height (equivalent to GOLD criteria stage 2 for 'Moderate' severity COPD9)
- •Post-bronchodilator FEV1/FVC ratio <0.7
- •β-agonist reversibility: an improvement of less than 12% predicted FEV1 and less than 200mL after 200 micrograms of salbutamol or equivalent short acting beta-2 agonist bronchodilator.
- •History of acute exacerbations of COPD as defined by the participant answering "yes" to the question: "do your COPD symptoms get noticeably worse when you catch a cold?"
- •Clinically stable with no COPD exacerbations within 8 weeks prior to enrolment
- •Permitted to take short and long-acting bronchodilators including beta agonists and muscarinic antagonist inhalers
- •Co-morbidity criteria:
- •Permitted to have a past medical history of asthma, allergic rhinitis and seasonal rhinitis, but not currently active within 8 weeks prior to enrolment
- •Absence of current or previous history of significant respiratory disease, other than COPD, asthma and allergic rhinitis
- •Permitted to have a positive skin test for atopy
- •Inclusion Criteria for non-smoking controls
- •Male or female sex
- •Age ≥ 40 years and ≤ 75 years at the time of signing the consent form
- •No history or clinical diagnosis of COPD
- •No significant smoking history, defined as:
- •Less than 5 pack year cumulative smoking history
- •Has not smoked or used e-cigarettes/vapes in the last 1 year
- •Controls spirometry criteria
- •FEV1 of ≥80% predicted for age and height
- •FEV1/FVC ratio ≥0.7
- •Co-morbidity criteria:
- •Permitted to have a past medical history of asthma, allergic rhinitis and seasonal rhinitis, but not currently active in the 8 weeks prior to enrolment
- •Absence of current or previous history of significant respiratory disease, other than asthma and allergic rhinitis
- •Permitted to have a positive skin test for atopy.
- •Inclusion Criteria for smoking controls
- •Identical to non-smoking controls, with the exception of smoking history:
- •Cumulative smoking history of at least 20 pack years.
- •Permitted to currently use, or have history of use of, e-cigarettes/vapes
排除标准
- •Participants with other causes of chronic airflow limitation, including but not limited to:
- •Bronchiectasis including cystic fibrosis
- •Bronchiolitis obliterans
- •Carcinoma of the bronchus
- •Fibrosis such as tuberculosis (TB), idiopathic pulmonary fibrosis
- •Presence of any significant systemic disease, that in the opinion of the investigator would (a) make participation in the study unduly risky, or (b) significantly interfere with important outcomes being measured.
- •For example, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric conditions.
- •Pregnant, planning to become pregnant, testing positive for pregnancy at the screening visit test, or nursing females during and within 30 days of treatment.
- •Treatment with oral, inhaled or nasal corticosteroids within 8 weeks prior to enrolment.
- •Treatment with antibiotics in the 8 weeks preceding enrolment.
- •Treatment with nasal medications, anti-leukotrienes, anti-histamine at the time of the study.
- •Presence (at screening) of serum rhinovirus-A16 neutralising antibodies in a titre >1:
- •Individuals with close contact to at risk patient group, including:
- •Infants (less than 6 months);
- •The extremely elderly or infirm;
- •Pregnant and/or breastfeeding women;
- •Patients with immunosuppression (e.g., human immunodeficiency virus (HIV), transplant recipients on anti-rejection medications, those undergoing chemo- or immuno-therapy).
- •Other factors that in the opinion of the investigator are considered a risk.
- •Participation in other clinical research studies that, in the opinion of the investigator, would (a) make participation in the study unduly risky, or (b) significantly interfere with important outcomes being measured in this or other studies, or (c) present an unacceptable visit burden to the participant.
研究组 & 干预措施
COPD Subjects
Participants who meet the diagnostic criteria for COPD
干预措施: Rhinovirus-A16 (Biological)
Non-Smoking Controls
Participants who do not meet COPD diagnostic criteria, and who do not have a significant smoking history
干预措施: Rhinovirus-A16 (Biological)
Smoking Controls
Participants who do not meet COPD diagnostic criteria, and who do have a significant smoking history
干预措施: Rhinovirus-A16 (Biological)
结局指标
主要结局
Lower Respiratory Symptom Score (LRSS)
时间窗: Participants will record this score daily, from the date of the baseline visit to the final day of their involvement in the study (expected to be day 42).
Participants will be asked to record their lower respiratory tract symptom scores daily prior to and in the 42 days following viral infection with rhinovirus A-16. Participants will rate their shortness of breath, wheeze, cough, sputum quality and quantity. Total score ranges from 0-17, with higher scores indicating more severe symptoms.
次要结局
- Upper Respiratory Symptom Score (URSS)(Participants will record this score daily, from the date of the baseline visit to the final day of their involvement in the study (expected to be day 42).)
- EXAcerbations of Chronic pulmonary disease Tool-Patient Reported Outcomes (EXACT-PRO)(Participants will record this score daily, from the date of the baseline visit to the final day of their involvement in the study (expected to be day 42).)
- Forced Expiratory Volume in 1 second (FEV1)(FEV1 will be measured at baseline, on day 0 and every following visit (days 1, 2, 3, 4, 5, 7, 9, 12, 15, 21 and 42).)
- Airway Oscillometry(Investigators will measure participants' airway oscillometry at baseline and clinical visits days 0, 3, 5, 9, 12, 15, 21, 42.)
- Fractional exhaled nitric oxide (FeNO)(Investigators will measure participants' FeNO at baseline and at clinical visits on days 0, 3, 5, 9, 12, 15, 21, 42)
- Viral load(Nasal lavage and nasal swabs will be performed at baseline and on all post inoculation visits. Sputum will be collected at baseline and on visits on days 0, 1, 3, 5, 9, 12, 15, 21 and 42. BAL will be acquired via bronchoscopy at baseline and day 7.)
- Cellular interferon response to rhinovirus infection(Studies performed on cells extracted at baseline (pre-inoculation) bronchoscopy.)
- Immunological response to rhinovirus infection(Blood will be taken at baseline and at visits on day 0, 1, 3, 5, 7, 9, 12, 15, 21, 42. Nasosorption will be performed at baseline and all visits post inoculation. Bronchial biopsies, bronchosorption will be via bronchoscopy at baseline and day 7.)
- Evaluation of the respiratory microbiome(Sputum will be collected at baseline and on visits on days 0, 1, 3, 5, 9, 12, 15, 21 and 42. BAL will be acquired via bronchoscopy at baseline and day 7.)