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

Bronchiectasis Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04140214
• Other study ID #: 16178SE-AS
• Status: Recruiting
• Phase: Phase 3
• Start date: June 27, 2018
• Est. completion date: September 30, 2024

Study information

• Verified date: September 2023
• Source: Belfast Health and Social Care Trust
• Contact: Andrew Jackson
• Phone: 028 90 635794
• Email: CLEAR[@]nictu.hscni.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 288
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bronchiectasis

Intervention

Drug:
• Hypertonic saline
Nebulized hypertonic saline solution (6%)
• Carbocysteine 750 MG
Carbocisteine tablet

Locations

Country	Name	City	State
United Kingdom	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	Altnagelvin Area Hospital, Western Health and Social Care Trust	Derry
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	Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS Foundation Trust	Lancaster
United Kingdom	Cardiff & Vale University Heath Board	Llandough
United Kingdom	Milton Keynes University Hospital	Milton Keynes
United Kingdom	Freeman Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle
United Kingdom	Northumbria NHS Foundation Trust	North Shields
United Kingdom	Churchill Hospital, Oxford University Hospitals NHS Foundation Trust	Oxford
United Kingdom	Southampton General Hospital, University Hospital Southampton NHS Foundation Trust	Southampton
United Kingdom	Royal Gwent Hospital, Aneurin Bevan University Health Board	Wales
United Kingdom	Sandwell & West Birmingham	West Bromwich

Sponsors (2)

Lead Sponsor	Collaborator
Belfast Health and Social Care Trust	Queen's University, Belfast

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	52 weeks post-randomization
Secondary	Disease-Specific Health-Related Quality of Life	Respiratory symptoms domain of quality of life with BE (QoL B) questionnaire.	52 weeks post-randomization
Secondary	Time to Next Exacerbation	Exacerbations assessed using pre-defined criteria, including intensity and duration of symptoms, via modified Respiratory and Systemic Symptoms questionnaire.	Over 52 weeks post-randomization
Secondary	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.	Over 52 weeks post-randomization
Secondary	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.	Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.
Secondary	Health Service Use	Study-specific health-service use questionnaire to capture service use and details of prescribed medications (including antibiotics).	52 weeks post-randomization
Secondary	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).	52 weeks post-randomization
Secondary	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)	Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.
Secondary	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).	Assessed at 2, 8, 26, and 52 weeks post-randomization.
Secondary	Number of Adverse Events	Reported by the PI or designee via interview with patients.	Over 52 weeks post-randomization
Secondary	Changes in Lung Function	Spirometry testing to measure lung function parameters, to include FEV1, FVC, FEF25-75 and FEV1% predicted.	52 weeks post-randomization
Secondary	IMP Adherence	Assessed using IMP Accountability Logs	52 weeks post-randomization
Secondary	HTS Adherence	Assessed electronically via tracking of nebulizer use.	52 weeks post-randomization