The CLEAR Trial: Investigating Hypertonic Saline and Carbocisteine for Bronchiectasis
The CLEAR Trial is a 2x2 factorial randomized trial led by Professor Stuart Elborn and Professor Judy Bradley to assess the effectiveness of hypertonic saline and carbocisteine for airway clearance in bronchiectasis patients over 52 weeks. The trial involves various study sites and potential new sites, aiming to determine the clinical and cost-effectiveness of these interventions compared to usual care. This initiative involves thorough training, screening procedures, informed consent, and collaborations with multiple healthcare professionals and institutions.
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The CLEAR The CLEAR Trial A 2x2 factorial randomised open label trial to determine the clinical and cost- effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in bronchiectasis (BE) Trial Chief Investigator: Professor Stuart Elborn, Queen s University Belfast Lead Applicant Physiotherapist: Professor Judy Bradley, Queen s University Belfast CLEAR_Site Initiation Training Part 1_Final v10.0 20/05/2021
Site Initiation Training Part 1: Background Site Initiation Training Part 1: Background Study Sites, Timelines & Contacts Study Background, Objectives & Outcomes Inclusion & Exclusion Criteria Trial Awareness for Patients Screening Procedures Informed Consent Sub studies and SWAT
Study Sites Study Sites Current Active Sites PI Trust 1 Dr Martin Kelly Western Health and Social Care Trust 2 Dr John Hurst Royal Free London NHS Foundation Trust 3 Prof Adam Hill NHS Lothian 4 Dr Anthony de-Soyza The Newcastle Upon Tyne Hospitals NHS Foundation Trust 5 Prof Michael Loebinger Royal Brompton and Harefield NHS Foundation Trust 6 Dr Damien Downey Belfast Health and Social Care Trust 7 Prof James Chalmers NHS Tayside 8 Dr Muhammed Anwar The Princess Alexandra Hospital NHS Trust 10 Dr Mary Carroll University Hospital Southampton NHS Foundation Trust 11 Dr Rory Convery Southern Health and Social Care Trust 12 Dr Timothy Gatheral University Hospitals of Morecambe Bay NHS Foundation Trust 14 Dr Anita Sullivan University Hospital Birmingham NHS Foundation Trust 15 Dr William Flight Oxford University Hospitals NHS Foundation Trust 16 Dr Alina Ionescu Aneurin Bevan University Health Board
New Study Sites New Study Sites* * Potential New Sites PI Trust John Steer Northumbria Healthcare NHS Foundation Trust Mitra Shahidi Buckinghamshire Healthcare NHS Trust Jamie Duckers Cardiff & Vale University Local Health Board Tarek Saba Blackpool Teaching Hospitals NHS Foundation Trust Eric Livingstone NHS Greater Glasgow & Clyde Paul Whitaker Bradford Teaching Hospitals NHS Foundation Trust Liz Fuller South Tyneside NHS Foundation Trust Veeresh Patil Milton Keynes University Hospital MHS Foundation Trust Anne Dunleavy St George s University Hospitals Foundation NHS Trust *Updated as of 29/04/2021
Study Study Timelines Timelines Study Milestones Site Research Management Permissions Feb 2019 To date, 151 patients have been randomised across the 14 active study sites. Pilot Study Recruitment Jun 2018 to Feb 2019 Main Study Recruitment Start Feb 2019 March 2020 to September 2021 Recruitment Paused The overall recruitment target for the study is patients 288 Recruitment restart following hibernation October 2021 Recruitment End September 2022 Analysis & Reporting Complete March 2024
Study Contacts Study Contacts Main Contact: CLEAR Trial Team Northern Ireland Clinical Trials Unit (NICTU) 7 Lennoxvale Malone Road Belfast BT9 5BY Tel: +4428 9615 1447 Email: CLEAR@nictu.hscni.net Clinical Trial Manager: Gavin Kennedy Clinical Trial Coordinator: Andrew Jackson Chief Investigator: Professor Stuart Elborn - s.elborn@qub.ac.uk Lead Applicant Physiotherapist: Professor Judy Bradley - judy.bradley@qub.ac.uk Sponsor: Belfast Health and Social Care Trust (BHSCT) Funder: National Institute for Health Research (NIHR)
CLEAR Study Background CLEAR Study Background Greater numbers of patients now being diagnosed with BE, with patients usually suffering from a persistent cough, chronic daily sputum expectoration, recurrent chest infections and a poor HRQoL. CLEAR is particularly concerned with exploring if HTS and carbocisteine, or a combination of these medicines, help patients bring up their sputum more easily. We want to find out if patients with bronchiectasis have fewer exacerbations if they use hypertonic saline, carbocisteine, or both of these medicines together for 52 weeks.
CLEAR Study Aim CLEAR Study Aim To deliver a UK multicentre study that will determine the clinical and cost-effectiveness of hypertonic saline HTS (6%) and carbocisteine for airway clearance versus usual care over 52 weeks in BE using a 2x2 factorial randomised open label trial
Primary Objective Primary Objective Primary Objective: To determine whether HTS (6%) and/or carbocisteine reduce the mean number of exacerbations over 52 weeks post-randomisation Primary Outcome Measure: Mean number of exacerbations over 52 weeks
Secondary Objectives Secondary Objectives To determine if HTS/carbocisteine: Improve disease specific health related quality of life (HRQoL) at 52 weeks Reduce time to next exacerbation Reduce number of days of antibiotics related to exacerbations over 52 weeks Improve generic HRQoL Are acceptable from a patient satisfaction perspective at 52 weeks Are associated with Adverse Events (AEs) Improve lung function over 52 weeks To assess: The cost-effectiveness of the four treatment options Patient adherence to HTS and carbocisteine over 52 weeks and how this impacts the overall results
Secondary Outcome Measures Secondary Outcome Measures Disease-specific HRQoL (respiratory symptoms of domain of QoL-B) at 52 weeks Time to next exacerbation post-randomisation Number of days of antibiotics related to exacerbations over 52 weeks Generic HRQoL Health Service use over 52 weeks QALY over 52 weeks Measurement of health impairment using the SGRQ Patient preferences for treatment Adverse Events over 52 weeks Lung function over 52 weeks Adherence to HTS and carbocisteine over 52 weeks
Patients with BE will be recruited from a maximum of 24 sites (including representation from the BRONCH-UK, EMBARC, NIHR or NICRN portfolio) Patient eligibility assessed Randomised to study using an automated concealed randomisation (n=288) Patient excluded: Failure to meet inclusion criteria Consent declined Other reasons Intervention 2: Standard care and carbocisteine 750 mg administered 3x daily until visit 3 then 750 mg administered twice daily n=72 Intervention 3: Standard care and nebulised HTS (6%) twice daily and carbocisteine 750 mg administered 3x daily until visit 3 then 750 mg administered twice daily n=72 Intervention 4: Standard care n=72 Intervention 1: Standard care and nebulised HTS (6%) twice daily n=72 Analysis at year 1: n= expected greater than 243 Patients lost to follow-up in primary outcome (15%) Primary outcome: Mean number of exacerbations in 52 weeks Secondary outcomes: QoL-B, Time to next exacerbation, HRQoL, Healthcare Service Use, QALY, SGRQ, Patient Preferences, Adverse Events, Lung Function, Adherence to HTS and carbocisteine. *Please note: The 2 year follow up will only be done for a proportion of those recruited. Only those recruited before the implementation of protocol v5.0 will be followed up to 2 years. Analysis at year 2: n= expected greater than 126* QoL-B Exacerbation history and antibiotic use, lung function
Inclusion Criteria Inclusion Criteria Diagnosis of BE on high resolution computed tomography (HRCT)/computed tomography (CT) scans BE must be the primary respiratory diagnosis Two or more pulmonary exacerbations in a 1 year period in the past 2 years requiring antibiotics* Production of daily sputum** Stable from a respiratory point of view for 14 or more days before the first study visit with no changes to treatment*** Willing to continue any other existing chronic medication throughout the study Female subjects must be either surgically sterile, postmenopausal, or agree to use effective contraception during the treatment period of the trial * This can include patient-reported exacerbations ** This includes patients who expectorate sputum on a daily basis and/or patients that expectorate sputum on most days but experience difficulty in expectoration on other days. *** This inclusion refers to chest treatment however some antibiotics (e.g. for a urinary tract infection (UTI) may have chest coverage and need to be considered.
Exclusion Criteria Exclusion Criteria Age <18 years old Patients with cystic fibrosis Patients with COPD as a primary respiratory diagnosis Current smokers, female ex-smokers with greater than 20 pack years and male ex- smokers with greater than 25 pack years FEV1 <30% If being treated with long term macrolides or other long term antibiotic, on treatment for less than one month before joining the study# Patients on regular isotonic saline## Treatment with HTS, carbocisteine or any mucoactives within the past 30 days### #If a patient is currently prescribed long term macrolides or other long term antibiotic they must have had no change to their treatment within the 30 days prior to randomisation i.e. if they are prescribed macrolides on a seasonal basis they must not have stopped or started treatment within the 30 days prior to being randomised. ##Short term use of isotonic saline for exacerbation management is not an exclusion criteria. In addition patients using isotonic saline as a mixer for colomycin or using saline nasal sprays are not excluded ### Patients who use HTS and/or carbocisteine very occasionally or PRN i.e. during an exacerbation and have not used within 30 days prior to randomisation are not excluded.
Exclusion Criteria Exclusion Criteria Known contraindication or intolerance to HTS or carbocisteine Hypersensitivity to any of the active ingredients or the excipients of carbocisteine Active peptic ulceration Any hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption Patients unable to swallow oral capsules Women who are pregnant or lactating Participation in other trials of investigational medicinal products within 30 days Please Note: Please ensure local COVID guidance is followed with regards to the conduct of clinical trial activities. Patients should not be recruited until 1 month post recovery from COVID (discussed on a case by case basis).
HTS/ HTS/Carbocisteine Carbocisteine Washout Washout If the patient is currently prescribed HTS, carbocisteine or other mucoactives for the treatment of their BE and the patient wants to be part of the trial, the patient and physician can decide to do a washout Informed consent should be taken prior to washout Patients should stop regular mucoactive treatment for at least 30 days Confirmation of eligibility and baseline assessments completed following the washout The patient cannot be randomised until after the washout and eligibility is confirmed
Smoking Pack Smoking Pack Years Years Calculation Calculation For ex-smokers the number of pack years must be calculated to confirm eligibility: Number of pack years If a patient has smoked a different number of cigarettes per day a manual calculation must be completed e.g. = No. of cigarettes smoked per day 20 X No. of years smoked 20 per day X 20 years = 20 pack years PLUS 10 per day X 10 years = 5 pack years TOTAL: 25 PACK 20 20 YEARS Pipe Smokers: 1 pipe = 2.5 cigarettes Pack Years Calculator URL: https://www.smokingpackyears.com/
Trial Awareness for Patients Trial Awareness for Patients Patient information posters to be displayed in your clinics Patient newsletters to be displayed in your clinics or provided to currently enrolled and potential participants
Screening and Recruitment Log Screening and Recruitment Log Record all patients screened Unique Screening ID for each patient is assigned sequentially: format of SXXNNNN Prefix S denotes screening XX will be your site number NNNN will be allocated sequentially to each patient screened starting at 0001 e.g. at Site 01 the first patient screened would have Screening ID S010001 Record Patient Name, Hospital Number, DOB and Screening Date This log will remain at site and should not be sent onto NICTU as it contains patient identifiers Record if patient is eligible for the trial. There is a key provided listing reasons for non-eligibility For patients given a SWAT recruitment pack, record the unique Pack Identifying Number Patients who decide to participate will be invited for a baseline visit
Screening and Recruitment Log Screening and Recruitment Log Record if patient randomised. There is a key provided listing reasons for non-randomisation Record date randomised and Subject ID (assigned by Sealed Envelopes): format of RSSNNN Prefix R denotes randomisation SS will be your site number NNN will be allocated sequentially to each patient recruited at your site starting at 001 e.g. At Site 01 the first patient recruited would have Subject ID R01001 Retain Screening & Recruitment Log Web-based MACRO Screening database Additional webinar training will be arranged Input data onto the MACRO database by the 1st Monday of each month as we will review during our Trial Management Group meeting Bi-weekly telephone calls with the NICTU coordinator to discuss screening and recruitment, exacerbations, and other FAQs until your site is established
Screening and Recruitment Log Screening and Recruitment Log An electronic Screening Log (Excel spreadsheet) will be sent to your site
Informed Consent Informed Consent Must be obtained from the patient prior to conducting any trial specific procedures The informed consent form (ICF) must be signed and dated by the patient and the study staff taking consent Original ICF: To be retained in the Investigator Site File Copy of Information Sheet & ICF: To be filed in the patient s medical notes To be given to patient GP Letter to be sent for enrolled patients
Co Co- -Enrollment Enrollment Sites selected are recruiting to Bronch-UK or EMBARC Patients that are not enrolled on either Bronch-UK or EMBARC will be offered the chance to enrol on these studies The follow-up visit at year 2 will be done in tandem with the annual Bronch-UK or EMBARC study visits
Sub Sub- -Studies Studies Sub-Study 1 Title: Validity and sensitivity of the EMBARC definition for exacerbations in bronchiectasis Aim: To compare the criteria in the EMBARC definition to the criteria of a modified Fuch s definition for diagnosing pulmonary exacerbations in BE patients your site?: What additional does this mean for Nothing Sub-Study 2 Title: Spirometry Sub-Study Aim: To explore the use of mySpiroSense for remote spirometry during periods of stability and at the start and end of exacerbations in BE patients
Study Within Study Within A A Trial (SWAT) Trial (SWAT) SWAT Title: Optimising Recruitment and Retention: Implementing Studies Within A Trial (SWATs) with the CLEAR trial What additional does this mean for your site?: There are 3 different SWATs SWAT A & B (implemented simultaneously) SWAT C SWAT A/B: PI signs a bundle of invitation letters at start Aims: SWATs A & B: Explore if the nature of the signature and inclusion of a photograph on the invitation letter or introductory material given to potential participants impacts on their recruitment to the trial. SWAT C: Explore if giving enrolled participants a thank you note at the end of each study-related visit impacts on their retention in the trial. of study SWAT C: Give out thank you cards
SWATs A & B SWATs A & B SWAT A Investigate the nature of the signature on the invitation letter: 1. Personalised letter with wet ink signature by the local PI 2. Generic letter with electronic printed signature SWAT B Investigate the inclusion of a generic doctor-patient photograph on the invitation letter: 1. Generic doctor patient photograph on invitation letter 2. No photograph
SWATs A & B SWATs A & B Sites will be sent a bundle of SWAT recruitment packs Each pack will be labelled with a unique Pack Identifying Number and will contain: 1 of the 4 different invitation letters Copy of the localised patient information sheet Copy of localised consent form Packs can be posted or given directly to patients Keep the bundle in order and give pack out consecutively from the top If more than one member of staff is recruiting, packs may be split into equal bundles Record the Pack Identifying Number against the patient s Screening ID on the Screening Log Sites will initially receive a bundle of packs. When 50% of packs are remaining, contact the NICTU to obtain more
SWAT SWAT C C Sites will be provided with envelopes labelled with a unique number that corresponds to the Subject ID assigned to randomised patients by the automated randomisation system Within each envelope there will be instructions on what should be provided to the patient at the end of each study visit and what code to record in the Case Report Form (CRF): Generic printed thank you card Code 01 Personalised wet ink signed thank you card Code 02 No thank you card Code 03 If a site is not participating the SWAT they should record N/A in the patient s CRF Sites will initially receive enough envelopes for your agreed patient target, please contact NICTU when you need more If visit is performed remotely, thank you cards (for code 01 & 02) can be posted out to patients along with their new questionnaires etc.
EME Sputum Sub EME Sputum Sub- -study* (*only in participating sites) (*only in participating sites) study* Aim: Is the mechanism of action of hypertonic saline and/or carbocisteine in the treatment of patients with bronchiectasis due to a decrease in sputum viscoelasticity, inflammation and bacterial load?
EME Sputum Sub EME Sputum Sub- -study* (*only in participating sites) (*only in participating sites) study* Primary Objective: to measure sputum viscosity (G ) and elasticity (G ) (which combined give a single summary measure of sputum viscoelasticity called the yield stress, Tc) at the initial visit and 2 weeks following commencement of treatment with HS and/or CS. Secondary Objectives: 1). Measure sputum viscoelasticity (yield stress, Tc), at 8 weeks following commencement of treatment with HS and/or CS. 2). Evaluate sputum inflammation as measured by IL-6, IL-8 and 8-isoprostane levels at the initial visit, 2 and 8 weeks following commencement of treatment with HS and/or CS. 3). Evaluate sputum bacterial load/composition at the initial visit, 2 and 8 weeks following commencement of treatment with HS and/or CS. The overall aim of this study is to provide mechanistic insight into the action of HS and/or CS in bronchiectasis
