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Exhaled Breath Metabolomic Biomarkers in the Acutely Breathless Patient (EMBER)

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ClinicalTrials.gov Identifier: NCT03672994
Recruitment Status : Recruiting
First Posted : September 17, 2018
Last Update Posted : April 17, 2019
Sponsor:
Collaborators:
Medical Research Council
Engineering and Physical Sciences Research Council, UK
Loughborough University
University Hospitals, Leicester
Owlstone Ltd
B & S ANALYTIK GmbH
Advion Biosciences Ltd
Information provided by (Responsible Party):
University of Leicester

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.

Condition or disease
Asthma COPD Heart Failure Community-acquired Pneumonia Healthy Breathlessness

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.

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Study Type : Observational
Estimated Enrollment : 650 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Exhaled Breath Metabolomic Biomarkers in the Acutely Breathless Patient
Actual Study Start Date : February 2, 2017
Actual Primary Completion Date : December 30, 2018
Estimated Study Completion Date : April 30, 2019

Resource links provided by the National Library of Medicine


Group/Cohort
Asthma
Patients with prior confirmed diagnosis of bronchial asthma
Chronic Obstructive Pulmonary Disease
Patients with prior confirmed COPD
Pneumonia
Patients with X-ray confirmed community acquired pneumonia
Heart failure
Patients with confirmed heart failure
Healthy volunteers
Healthy participants with no otherwise known cardiorespiratory condition



Primary Outcome Measures :
  1. Discovery of exhaled breath biomarkers [ Time Frame: 0-6 months ]
    To evaluate the sensitivity, specificity, positive and negative predictive value of metabolomic biomarkers in exhaled breath samples to identify acute breathlessness, defined as one or more of (i) patient defined acute breathlessness and/or a (ii) 1 unit increase in Extended Medical Research Council breathlessness score (eMRC)


Secondary Outcome Measures :
  1. Patient defined breathlessness [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Participants are asked to provide information on their state of breathlessness

  2. COPD Assessment Test (CAT) (Questionnaire) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Evaluation and rehabilitation education guidance on the respiratory and motor functions of patients with chronic obstructive pulmonary disease. The CAT has a scoring range of 0-40, with Since COPD is a progressive disease, a fi xed target score for all patients cannot be set. In Practice, a target for improvement in individual patient CAT scores may be set, based on an holistic assessment of the patient. A change of 2 units suggests a meaningful difference. This test should be used in conjunction with the eMRC and forced expiratory volume in one second (FEV1) to determine COPD health assessment of participants.

  3. NASA task load index [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Evaluation breath testing work load using mental, physical, temporal, performance, effort and frustration. Participants are asked to mark a scale based on how demanding the task was for each of the domains above.

  4. Asthma quality of life questionaire (AQLQ) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Evaluation quality of life in asthmatic patients based on their level of activity, symptoms, environment and emotion.

  5. Asthma control questionnaire (ACQ) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Measure of asthma control

  6. extended Medical Research Council (eMRC) Dyspnea Scale [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Assessing respiratory breathlessness symptoms (Grade 0-5b, with Grade 0 being breathlessness with strenuous exercise to Grade 5b being breathlessness for daily activities like dressing).

  7. Visual analogue score (VAS) total and individual dyspnoea, cough and wheeze (100mm) scores [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    The participant is asked to place a mark (X) on the scale at the point that best describes their health currently. Minimum score 0mm (better outcome), maximum score 100mm (worse outcome) for each section of the scale (dyspnoea, cough, wheeze).

  8. NewYork Heart Association Dyspnoea score (NYHA) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Assessing grades of breathlessness specifically designed for heart failure patients

  9. Sputum collection for assessment of purulence, cytology and metagenomics [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Participants are asked to provide a spontaneous sputum sample assessing purulence, cytology and metagenomics

  10. Pre and post bronchodilator (BD) spirometry to assess lung function [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    To assess lung function

  11. fraction exhaled nitric oxide (FeNO) assessing airway inflammation [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    To assess airway inflammation in asthmatics. Patients are asked to blow into a mouthpiece for few seconds which detects the amount of exhaled nitric oxide.

  12. Hand held oscillometry assessing small airway lung function [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    To assess small airway lung function

  13. Quadriceps ultrasound measuring quadriceps size as a degree of frailty [ Time Frame: visit 1a (first visit) ]
    To assess degree of frailty and muscle breakdown during hospital admission. Participants have their quadriceps muscle size measured using an ultrasound machine.

  14. Four meter gait [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    physical performance - measure of frailty

  15. Exacerbation history [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    participants are asked to provide information on recent exacerbations of airway disease

  16. DECAF score assessing in hospital mortality in COPD patients [ Time Frame: visit 1a (first visit) ]
    DECAF score has a minimum score of 1 (better outcome) and a maximum score of 6(worse outcome) used for assessment of severity of COPD exacerbation measures eMRC score, Eosinopenia, consolidation, acidemia and atrial fibrillation

  17. CURB65 score assessing mortality in Pneumonia patients [ Time Frame: visit 1a (first visit) ]
    CURB65 is used in assessment of 30 day mortality of Pneumonia based on confusion, urea, respiratory rate, blood pressure and age.Scores range from 1 (better outcome) to 5 (worse outcome)

  18. BTS asthma severity score [ Time Frame: visit 1a (first visit) ]
    BTS asthma severity score is used in assessment of asthma severity based on peak flow, respiratory rate, oxygen levels, altered level of consciousness, arrythmia, hypotension, cyanosis, silent chest and respiratory effort. Patients are then classified into mild (better outcome), moderate, severe and life threatening (worse outcome).

  19. Meta analysis global group in chronic heart failure (MAGGIC - risk calculator) [ Time Frame: visit 1a (first visit) ]
    Assessment of heart failure severity based on age, gender, diabetes, COPD, heart failure diagnosed in the last 18 months, current smoker, NYHA class, b blockers, ACEI or ARB, BMI, systolic BP, creatinine and ejection fraction

  20. Sputum differential Cell Count [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Differential Cell Count to assess inflammation at exacerbation events.

  21. Breath volatile organic compound (VOC) profiling [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Participants are asked to provide a breath sample to measure VOC using Compact Mass Spectrometer (CMS), Gas chromatography ion mobility spectrometer (GC-IMS), gas chromatography mass spectrometer (GC-MS), Proton transfer reaction time of flight mass spectrometer (PTR-Tof-MS), gas chromatography gas chromatography mass spectrometer (GCxGC-MS).

  22. Serum/Plasma Inflammatory Biomarkers [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    To assess systemic inflammation. Plasma/ serum biomarkers are exploratory and we do not have a specific list of biomarkers yet.

  23. Full blood count (FBC) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Blood Biochemistry

  24. C-reactive protein (CRP) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Blood Biochemistry

  25. Troponin-I [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Blood Biochemistry

  26. B-type naturitic peptide (BNP) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Blood biochemistry

  27. RNA (PAXgene) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Blood Biochemistry

  28. DNA (PAXgene) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Blood Biochemistry

  29. Age [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  30. Smoking status, calculated using pack years (no. of cigarettes smoked per day X no. of years smoked divided by 20 [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  31. BMI in kg/m^2 [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  32. Gender [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  33. Heart rate [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Vital signs

  34. Blood pressure [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Vital signs

  35. Oxygen saturations [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Vital signs

  36. Temperature [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Vital signs

  37. Medical history [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    medical history

  38. Current medications [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Medical history

  39. Physical examination [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Physical examination

  40. 12 lead Electrocardiogram (ECG) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    cardiac function

  41. Echocardiogram (ECHO) [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    cardiac function

  42. Chest Xray [ Time Frame: visit 1a ]
    Respiratory function

  43. Height [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  44. Weight [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  45. Ethnicity [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Demographics

  46. Review of adverse events and serious adverse events [ Time Frame: visit 1a (first visit), visit 2 (0-6 months) ]
    Review of untoward medical occurrences



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03672994


Contacts
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Contact: Amisha Singapuri, Bsc Hons 01162583072 amisha.singapuri@uhl-tr.nhs.uk
Contact: Wadah Ibrahim, MBBS, MRCP 01162583370 wadah.ibrahim@uhl-tr.nhs.uk

Locations
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United Kingdom
NIHR Leicester Biomedical Research Centre - Respiratory, Glenfield Hospital Recruiting
Leicester, Leicestershire, United Kingdom, LE3 9QP
Contact: Amisha Singapuri, Bsc Hons    01162583370 ext 3072    amisha.singapuri@uhl-tr.nhs.uk   
Contact: Wadah Ibrahim, MBBS, MRCP    01162583370    wadah.ibrahim@uhl-tr.nhs.uk   
Sponsors and Collaborators
University of Leicester
Medical Research Council
Engineering and Physical Sciences Research Council, UK
Loughborough University
University Hospitals, Leicester
Owlstone Ltd
B & S ANALYTIK GmbH
Advion Biosciences Ltd
Investigators
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Principal Investigator: Salman Siddiqui, Professor University of Leicester
  Study Documents (Full-Text)

Documents provided by University of Leicester:
Study Protocol  [PDF] April 1, 2018
Informed Consent Form  [PDF] April 1, 2018


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Leicester
ClinicalTrials.gov Identifier: NCT03672994     History of Changes
Other Study ID Numbers: UNOLE0569
First Posted: September 17, 2018    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Leicester:
Acute Breathlessness
Breathomics

Additional relevant MeSH terms:
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Heart Failure
Pneumonia
Dyspnea
Heart Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Respiration Disorders
Signs and Symptoms, Respiratory
Signs and Symptoms