Clinical trial NCT03672994: Exhaled Breath Metabolomic Biomarkers in the Acutely Breathless Patient
Official title: Exhaled Breath Metabolomic Biomarkers in the Acutely Breathless Patient
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Asthma
COPD
Heart Failure
Community-acquired Pneumonia
Healthy
Breathlessness
Keywords: Acute Breathlessness
Breathomics
Lead sponsor: University of Leicester
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: Engineering and Physical Sciences Research Council, UK
name: Loughborough University
name: University Hospitals, Leicester
name: Owlstone Ltd
name: B & S ANALYTIK GmbH
name: Advion Biosciences Ltd
First posted: 2018-09-17
Enrollment: 650
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Prospective participants with self reported acute breathlessness, either requiring admission or a change in baseline treatment, presenting within University Hospitals of Leicester (UHL).

Patients with confirmed acute airway exacerbation or heart failure decompensation as part of other research studies at the NIHR Leicester BRC may also be included.

Age- and/or home environment matched adult/spousal/parent and sibling healthy volunteers will be recruited where possible on the admissions unit or in the research units across both sites at a separate visit.

A stable state control population will also be recruited to compare with the unstable state. This will consist of participants with a confirmed diagnosis matched with the acute care population but not in the exacerbation state.

Brief summary: An acute study carried out across three acute admissions units within Leicestershire. The study is aimed at discovery and validation of volatile organic compounds (VOCs) in exhaled breath. Participants will be recruited and tested within 24 hours of admission and once recovered, up to 6 months following discharge.

Detailed description: A prospective real world observational study carried out across three acute admissions units. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community acquired pneumonia and acute exacerbation of asthma or COPD will be recruited within 24 hours of admission. These will be matched to healthy volunteers from a similar environment. Additionally, school age children admitted with severe asthma will be evaluated and breath samples will be collected. All participants will undergo breath sampling on admission and upon recovery, up to six months following discharge. A range of online technologies including: proton-transfer-reaction mass spectrometry (PTR-MS), gas chromatography ion mobility spectrometry (GC-IMS), atmospheric pressure chemical ionisation- mass spectrometry (APCI-MS) and offline technologies including gas chromatography mass spectroscopy (GC-MS) and comprehensive two-dimensional gas chromatography-mass spectrometry (GCxGC-MS) will be utilised for VOC discovery and replication. For offline technologies a standardised CE marked breath sampling device (ReCIVA®) will be used. All recruited participants will be characterised using existing blood biomarkers including C - reactive protein (CRP), brain derived natriuretic peptide (BNP), Troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing including hand held forced oscillation technique (FOT) and fractional exhaled nitric oxide (FeNO), sputum cell counts and echocardiography for heart failure and COPD patients. Additional samples will be collected for bio-banking including urine, serum, plasma and sputum supernatants and plugs.

Eligibility criteria: Inclusion Criteria:

(i) Able to give informed consent for participation in the study. (ii) Male or Female, aged 16 years or above (adult cohort) and 5-15 years for paediatric patients attending the acute care paediatric pathway.

(iii) Capable (in the opinion of the EMBER clinical research investigator(s) of providing serial breath samples.

(iv) Diagnosed with acute breathlessness as one of the primary indicator reasons by the clinical acute care team. This is not a requirement for healthy subjects or matched controls.

(v) One of the indicator provisional diagnoses identified in section 7.1 following senior review by the clinical acute care team. This is not a requirement for healthy subjects or matched controls (vi) Able (in the Investigators opinion) and willing to comply with all study requirements.

(vii) Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study.

(viii) Ability to understand English.

Exclusion Criteria:

(i) Female participants who are known to be pregnant, lactating or planning pregnancy during the course of the study.

(ii) Current participation in a clinical trial of an investigative medicinal product or within 3 months or 5.5 half-lives of the IMP whichever is longer.

(iii) Active or clinically suspected pulmonary tuberculosis (iv) In the opinion of the treating physician, breath sampling during the acute admission would be clinically unsafe or inappropriate due to the patient's condition or poor prognosis. Examples include malignancy or autoimmune disease with anticipated survival of under 1 year, and chronic renal replacement therapy.

(v) Unable or unwilling to give informed consent by visit 1b. (vi) Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.

Primary outcomes:
measure: Discovery of exhaled breath biomarkers
timeFrame: 0-6 months
Secondary outcomes:
measure: Patient defined breathlessness
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: COPD Assessment Test (CAT) (Questionnaire)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: NASA task load index
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Asthma quality of life questionaire (AQLQ)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Asthma control questionnaire (ACQ)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: extended Medical Research Council (eMRC) Dyspnea Scale
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Visual analogue score (VAS) total and individual dyspnoea, cough and wheeze (100mm) scores
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: NewYork Heart Association Dyspnoea score (NYHA)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Sputum collection for assessment of purulence, cytology and metagenomics
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Pre and post bronchodilator (BD) spirometry to assess lung function
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: fraction exhaled nitric oxide (FeNO) assessing airway inflammation
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Hand held oscillometry assessing small airway lung function
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Quadriceps ultrasound measuring quadriceps size as a degree of frailty
timeFrame: visit 1a (first visit)
measure: Four meter gait
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Exacerbation history
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: DECAF score assessing in hospital mortality in COPD patients
timeFrame: visit 1a (first visit)
measure: CURB65 score assessing mortality in Pneumonia patients
timeFrame: visit 1a (first visit)
measure: BTS asthma severity score
timeFrame: visit 1a (first visit)
measure: Meta analysis global group in chronic heart failure (MAGGIC - risk calculator)
timeFrame: visit 1a (first visit)
measure: Sputum differential Cell Count
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Breath volatile organic compound (VOC) profiling
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Serum/Plasma Inflammatory Biomarkers
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Full blood count (FBC)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: C-reactive protein (CRP)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Troponin-I
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: B-type naturitic peptide (BNP)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: RNA (PAXgene)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: DNA (PAXgene)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Age
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Smoking status, calculated using pack years (no. of cigarettes smoked per day X no. of years smoked divided by 20
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: BMI in kg/m^2
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Gender
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Heart rate
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Blood pressure
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Oxygen saturations
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Temperature
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Medical history
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Current medications
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Physical examination
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: 12 lead Electrocardiogram (ECG)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Echocardiogram (ECHO)
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Chest Xray
timeFrame: visit 1a
measure: Height
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Weight
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Ethnicity
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
measure: Review of adverse events and serious adverse events
timeFrame: visit 1a (first visit), visit 2 (0-6 months)
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: NIHR Leicester Biomedical Research Centre - Respiratory, Glenfield Hospital
state: Leicestershire
Study officials:
affiliation: University of Leicester
name: Salman Siddiqui, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ibrahim W, Wilde M, Cordell R, Salman D, Ruszkiewicz D, Bryant L, Richardson M, Free RC, Zhao B, Yousuf A, White C, Russell R, Jones S, Patel B, Awal A, Phillips R, Fowkes G, McNally T, Foxon C, Bhatt H, Peltrini R, Singapuri A, Hargadon B, Suzuki T, Ng LL, Gaillard E, Beardsmore C, Ryanna K, Pandya H, Coates T, Monks PS, Greening N, Brightling CE, Thomas P, Siddiqui S. Assessment of breath volatile organic compounds in acute cardiorespiratory breathlessness: a protocol describing a prospective real-world observational study. BMJ Open. 2019 Mar 8;9(3):e025486. doi: 10.1136/bmjopen-2018-025486.