Clinical trial NCT04140214: Randomised Open Label Trial of Hypertonic Saline and Carbocisteine in Bronchiectasis (CLEAR)
Official title: A 2x2 Factorial Randomized 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bronchiectasis
Keywords: Respiratory
Mucoactive
Exacerbation
Hypertonic Saline
Carbocisteine
Airway Clearance
Lead sponsor: Belfast Health and Social Care Trust
Sponsor class: OTHER
Collaborators: name: Queen's University, Belfast
First posted: 2019-10-25
Enrollment: 288
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: A superiority, 2x2 factorial randomised open label trial with a 52-week follow-up period.
Primary purpose: TREATMENT

Brief summary: Patients with bronchiectasis (BE) suffer from a persistent cough, daily sputum expectoration, recurrent chest infections, and a poor health-related quality of life. Current guidelines for the management of BE highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum-removal as part of standard care. The investigators hypothesise that mucoactive agents (HTS or cabocisteine, or a combination of both) are effective in reducing exacerbations over a 52-week period, compared to usual care.

Detailed description: Mucus hypersecretion is a clinical feature of BE. This mucus-retention aids bacterial infection that can lead to pulmonary exacerbations, which further develops the "viscous cycle" of mucus-retention, infection, inflammation and tissue damage. Mucoactive drugs target this cycle by potentially increasing the ability to expectorate sputum and/or decrease mucus hypersecretion.

The current guidelines indicate that mucoactives in combination with airway clearance may be considered to enhance sputum expectoration in BE, but the evidence to support their use is limited. Furthermore, evidence for the effectiveness of hypertonic saline (HTS) and carbocisteine is insufficient to recommend them within the management of BE. However, EMBARC/BRONCH-UK data show that BE centres do prescribe mucoactives. This is important because adherence to therapies in BE in general is low, decreases as the number of prescribed medications increases, and is also related to poorer patient outcomes, including the number of pulmonary exacerbations and quality of life. Therefore, it is essential that only those drugs that are effective should be prescribed for patients with BE. There are cost considerations associated with mucoactives, and there is a risk of polypharmacy side effects.

Unlike BE, relatively strong evidence exists to favour the use of both HTS and carbocisteine within other respiratory conditions. Therefore, this trial will answer important clinical questions about whether similar benefits can be demonstrated in BE by using a pragmatic design to explore the specific effects of mucoactive agents, and directly support, or refute, more targeted use of these drugs.

Patients will be randomised to one of four treatment groups: (i) standard care and twice daily nebulised HTS (6%), (ii) standard care and carbocisteine, (iii) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (iv) standard care alone.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of BE on high resolution computed tomography(HRCT)/computed tomography (CT) scans
* BE must be the primary respiratory diagnosis
* One or more pulmonary exacerbations in the last year requiring antibiotics\*
* Production of daily sputum
* Stable 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

Exclusion Criteria:

* Age \<18 years old
* Patients with cystic fibrosis (CF)
* 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.
* Forced expiratory volume in one second (FEV1) \<30%
* If being treated with long term macrolides, on treatment for less than one month before joining study
* Patients on regular isotonic saline
* Treatment with HTS, carbocisteine or any mucolytics within the past 30 days
* Known contraindication or intolerance to hypertonic saline or carbocisteine
* Hypersensitivity to any of the active ingredients or the excipients of carbocisteine
* Active peptic ulceration
* Any heredity galactose intolerance, the 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 products within 30 days

Primary outcomes:
measure: Mean Number of Exacerbations
timeFrame: 52 weeks post-randomization
Secondary outcomes:
measure: Disease-Specific Health-Related Quality of Life
timeFrame: 52 weeks post-randomization
measure: Time to Next Exacerbation
timeFrame: Over 52 weeks post-randomization
measure: Number of Days of Antibiotics for Exacerbations
timeFrame: Over 52 weeks post-randomization
measure: Generic Health-Related Quality of Life (HRQoL)
timeFrame: Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.
measure: Health Service Use
timeFrame: 52 weeks post-randomization
measure: Quality Adjusted Life Years (QALY)
timeFrame: 52 weeks post-randomization
measure: Measurement of Health Impairment
timeFrame: Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.
measure: Patient Preferences for Treatment
timeFrame: Assessed at 2, 8, 26, and 52 weeks post-randomization.
measure: Number of Adverse Events
timeFrame: Over 52 weeks post-randomization
measure: Changes in Lung Function
timeFrame: 52 weeks post-randomization
measure: IMP Adherence
timeFrame: 52 weeks post-randomization
measure: HTS Adherence
timeFrame: 52 weeks post-randomization
Other outcomes:
Locations:
city: Aylesbury
country: United Kingdom
facility: Stoke Mandeville Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital, Belfast Health and Social Care Trust
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust
city: Blackpool
country: United Kingdom
facility: Blackpool Teaching Hospitals NHS Foundation Trust
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospitals
city: Brompton
country: United Kingdom
facility: Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust
city: Derry
country: United Kingdom
facility: Altnagelvin Area Hospital, Western Health and Social Care Trust
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School, NHS Tayside
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary Edinburgh, NHS Lothian
city: Hamstead
country: United Kingdom
facility: Royal Free Hospital, Royal Free London NHS Foundation Trust
city: Harlow
country: United Kingdom
facility: Princess Alexandra Hospital, The Princess Alexandra Hospital NHS Trust
city: Lancaster
country: United Kingdom
facility: Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS Foundation Trust
city: Llandough
country: United Kingdom
facility: Cardiff & Vale University Heath Board
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes University Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: North Shields
country: United Kingdom
facility: Northumbria NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford University Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: Southampton General Hospital, University Hospital Southampton NHS Foundation Trust
city: Wales
country: United Kingdom
facility: Royal Gwent Hospital, Aneurin Bevan University Health Board
city: West Bromwich
country: United Kingdom
facility: Sandwell & West Birmingham
Study officials:
affiliation: Queen's University, Belfast
name: J. Stuart Elborn
role: PRINCIPAL_INVESTIGATOR
References: