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

Sponsor

Belfast Health and Social Care Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT04140214

Collaborator

Queen's University, Belfast (Other)

380

Enrollment

Locations

Arms

75.1

Anticipated Duration (Months)

29.2

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bronchiectasis	Drug: Hypertonic saline Drug: Carbocysteine 750 MG	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

380 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention Model Description:

A superiority, 2x2 factorial randomised open label trial with a 52-week follow-up period.A superiority, 2x2 factorial randomised open label trial with a 52-week follow-up period.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 27, 2018

Anticipated Primary Completion Date :

Sep 30, 2024

Anticipated Study Completion Date :

Sep 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Standard Care and HTS Standard care and twice-daily nebulised HTS (MucoClear 6%, PARI Pharma). Participants will be instructed to administer a 1 x 4 mL ampoule twice daily for 52 weeks using the eFlow rapid nebuliser and eTrack controller (PARI Pharma).	Drug: Hypertonic saline Nebulized hypertonic saline solution (6%) Other Names: MucoClear 6% HTS
Experimental: Standard Care and Carbocisteine Standard care and carbocisteine (750 mg three-times-per-day until visit 3, reducing to 750 mg two times per day) over 52 weeks.	Drug: Carbocysteine 750 MG Carbocisteine tablet Other Names: Mucodyne
Experimental: Standard Care and Combination of HTS and Carbocisteine Standard care and combination of twice-daily nebulised HTS (MucoClear 6%, PARI Pharma) and carbocisteine. Participants will be instructed to administer a 1 x 4 mL ampoule twice daily for 52 weeks using the eFlow rapid nebuliser eFlow rapid nebuliser and eTrack controller (PARI Pharma). They will also be given carbocisteine (750 mg of three times per day until visit 3, reducing to 750 mg twice per day) over 52 weeks.	Drug: Hypertonic saline Nebulized hypertonic saline solution (6%) Other Names: MucoClear 6% HTS Drug: Carbocysteine 750 MG Carbocisteine tablet Other Names: Mucodyne
No Intervention: Standard Care Only Standard care over 52 weeks. Patients in the standard care group will use airway clearance techniques in the management of their BE.

Outcome Measures

Primary Outcome Measures

Mean Number of Exacerbations [52 weeks post-randomization]
Patient-reported exacerbations assessed using pre-defined criteria, including intensity and duration of symptoms, via modified Respiratory and Systemic Symptoms questionnaire.

Secondary Outcome Measures

Disease-Specific Health-Related Quality of Life [52 weeks post-randomization]
Respiratory symptoms domain of quality of life with BE (QoL B) questionnaire.
Time to Next Exacerbation [Over 52 weeks post-randomization]
Exacerbations assessed using pre-defined criteria, including intensity and duration of symptoms, via modified Respiratory and Systemic Symptoms questionnaire.
Number of Days of Antibiotics for Exacerbations [Over 52 weeks post-randomization]
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.
Generic Health-Related Quality of Life (HRQoL) [Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.]
EQ-ED-5L questionnaire; a validated questionnaire that provides a simple descriptive profile and a single index value for health status.
Health Service Use [52 weeks post-randomization]
Study-specific health-service use questionnaire to capture service use and details of prescribed medications (including antibiotics).
Quality Adjusted Life Years (QALY) [52 weeks post-randomization]
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).
Measurement of Health Impairment [Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.]
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)
Patient Preferences for Treatment [Assessed at 2, 8, 26, and 52 weeks post-randomization.]
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).
Number of Adverse Events [Over 52 weeks post-randomization]
Reported by the PI or designee via interview with patients.
Changes in Lung Function [52 weeks post-randomization]
Spirometry testing to measure lung function parameters, to include FEV1, FVC, FEF25-75 and FEV1% predicted.
IMP Adherence [52 weeks post-randomization]
Assessed using IMP Accountability Logs
HTS Adherence [52 weeks post-randomization]
Assessed electronically via tracking of nebulizer use.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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

Contacts and Locations

Locations

	Site	City	Country
1	Belfast City Hospital, Belfast Health and Social Care Trust	Belfast	United Kingdom
2	Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust	Birmingham	United Kingdom
3	Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust	Brompton	United Kingdom
4	Altnagelvin Area Hospital, Western Health and Social Care Trust	Derry	United Kingdom
5	Ninewells Hospital and Medical School, NHS Tayside	Dundee	United Kingdom
6	Royal Infirmary Edinburgh, NHS Lothian	Edinburgh	United Kingdom
7	Royal Free Hospital, Royal Free London NHS Foundation Trust	Hamstead	United Kingdom
8	Princess Alexandra Hospital, The Princess Alexandra Hospital NHS Trust	Harlow	United Kingdom
9	Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS Foundation Trust	Lancaster	United Kingdom
10	Freeman Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle	United Kingdom
11	Churchill Hospital, Oxford University Hospitals NHS Foundation Trust	Oxford	United Kingdom
12	Southampton General Hospital, University Hospital Southampton NHS Foundation Trust	Southampton	United Kingdom
13	Royal Gwent Hospital, Aneurin Bevan University Health Board	Wales	United Kingdom