Randomised Open Label Trial of Hypertonic Saline and Carbocisteine in Bronchiectasis (CLEAR)

Belfast Health and Social Care Trust288 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (20)

Stoke Mandeville Hospital

Aylesbury, United Kingdom

Belfast City Hospital, Belfast Health and Social Care Trust

Belfast, United Kingdom

Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust

Birmingham, United Kingdom

Blackpool Teaching Hospitals NHS Foundation Trust

Blackpool, United Kingdom

Bradford Teaching Hospitals

Bradford, United Kingdom

Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust

Brompton, United Kingdom

Ninewells Hospital and Medical School, NHS Tayside

Dundee, United Kingdom

Royal Infirmary Edinburgh, NHS Lothian

Edinburgh, United Kingdom

Royal Free Hospital, Royal Free London NHS Foundation Trust

Hamstead, United Kingdom

Princess Alexandra Hospital, The Princess Alexandra Hospital NHS Trust

Harlow, United Kingdom

...and 10 more locations

Outcomes

Primary Outcomes

Mean Number of Exacerbations

Patient-reported exacerbations assessed using pre-defined criteria, including intensity and duration of symptoms, via modified Respiratory and Systemic Symptoms questionnaire.

Time frame: 52 weeks post-randomization

Secondary Outcomes

Disease-Specific Health-Related Quality of Life

Respiratory symptoms domain of quality of life with BE (QoL B) questionnaire.

Time frame: 52 weeks post-randomization

Time to Next Exacerbation

Exacerbations assessed using pre-defined criteria, including intensity and duration of symptoms, via modified Respiratory and Systemic Symptoms questionnaire.

Time frame: Over 52 weeks post-randomization

Number of Days of Antibiotics for Exacerbations

Days of antibiotic use directly related to pulmonary exacerbation; assessed using pre-defined criteria for exacerbations, including intensity and duration of symptoms via modified Respiratory and Systemic Symptoms questionnaire and through interview with participant.

Time frame: Over 52 weeks post-randomization

Generic Health-Related Quality of Life (HRQoL)

EQ-ED-5L questionnaire; a validated questionnaire that provides a simple descriptive profile and a single index value for health status.

Time frame: Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.

Health Service Use

Study-specific health-service use questionnaire to capture service use and details of prescribed medications (including antibiotics).

Time frame: 52 weeks post-randomization

Quality Adjusted Life Years (QALY)

Calculated by assessment of generic HRQoL measured using the EQ-5D-5L questionnaire. Responses will be converted to utility scores using the tariff recommended by NICE in their Guide to Technology Appraisal at the time of analysis. Currently this is the Crosswalk Value Set. The area under the curve method will be used to calculate Quality adjusted life years (QALYs).

Time frame: 52 weeks post-randomization

Measurement of Health Impairment

St. Georges Respiratory Questionnaire; designed to measure health impairment in those with COPD and asthma, and validated for use in the BE population. Part 1 : Symptoms component (frequency \& severity) with a 1, 3 or 12-month recall (best performance with 3- and 12-month recall); Part 2: Activities that cause or are limited by breathlessness; Impact components (social functioning, psychological disturbances resulting from airways disease) refer to current state as the recall. Scores range from 0 to 100, with higher scores indicating more limitations. Scaling of items Part I (Symptoms): several scales; Part II (Activity and Impacts): dichotomous (true/false) except last question (4-point Likert scale)

Time frame: Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.

Patient Preferences for Treatment

Measured via the TSQM version II questionnaire to assess four key dimensions of treatment satisfaction: effectiveness; side effects; convenience; and global satisfaction (score 0-100, higher scores indicate better satisfaction).

Time frame: Assessed at 2, 8, 26, and 52 weeks post-randomization.

Number of Adverse Events

Reported by the PI or designee via interview with patients.

Time frame: Over 52 weeks post-randomization

Changes in Lung Function

Spirometry testing to measure lung function parameters, to include FEV1, FVC, FEF25-75 and FEV1% predicted.

Time frame: 52 weeks post-randomization

IMP Adherence

Assessed using IMP Accountability Logs

Time frame: 52 weeks post-randomization

HTS Adherence

Assessed electronically via tracking of nebulizer use.

Time frame: 52 weeks post-randomization

Randomised Open Label Trial of Hypertonic Saline and Carbocisteine in Bronchiectasis (CLEAR)

Overview

Conditions

Interventions

Eligibility

Locations (20)

Outcomes

Primary Outcomes

Secondary Outcomes