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

• ClinicalTrials.gov Identifier: NCT04140214
• Recruitment Status: Recruiting
• First Posted: October 25, 2019
• Last Update Posted: October 25, 2019
• Sponsor: Belfast Health and Social Care Trust
• Collaborator: Queen's University, Belfast
• Information provided by (Responsible Party): Belfast Health and Social Care Trust

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 (Clinical Trial)
• Estimated 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.
• 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: June 27, 2018
• Estimated Primary Completion Date: August 31, 2021
• Estimated Study Completion Date: August 31, 2022

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 Name: 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 Name: 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 :

1. Mean Number of Exacerbations [ Time Frame: 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 :

1. Disease-Specific Health-Related Quality of Life [ Time Frame: 52 weeks post-randomization ]
   Respiratory symptoms domain of quality of life with BE (QoL B) questionnaire.
2. Time to Next Exacerbation [ Time Frame: Over 52 weeks post-randomization ]
   Exacerbations assessed using pre-defined criteria, including intensity and duration of symptoms, via modified Respiratory and Systemic Symptoms questionnaire.
3. Number of Days of Antibiotics for Exacerbations [ Time Frame: 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.
4. Generic Health-Related Quality of Life (HRQoL) [ Time Frame: 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.
5. Health Service Use [ Time Frame: 52 weeks post-randomization ]
   Study-specific health-service use questionnaire to capture service use and details of prescribed medications (including antibiotics).
6. Quality Adjusted Life Years (QALY) [ Time Frame: 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).
7. Measurement of Health Impairment [ Time Frame: 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)

8. Patient Preferences for Treatment [ Time Frame: 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).
9. Number of Adverse Events [ Time Frame: Over 52 weeks post-randomization ]
   Reported by the PI or designee via interview with patients.
10. Changes in Lung Function [ Time Frame: 52 weeks post-randomization ]
    Spirometry testing to measure lung function parameters, to include FEV1, FVC, FEF25-75 and FEV1% predicted.
11. IMP Adherence [ Time Frame: 52 weeks post-randomization ]
    Assessed using IMP Accountability Logs
12. HTS Adherence [ Time Frame: 52 weeks post-randomization ]
    Assessed electronically via tracking of nebulizer use.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

Contacts

Contact: Roisin Boyle; 028 90 635794; CLEAR@nictu.hscni.net

Locations

United Kingdom

Belfast City Hospital, Belfast Health and Social Care Trust; Recruiting

Belfast, United Kingdom

Principal Investigator: Damien Downey

Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust; Not yet recruiting

Birmingham, United Kingdom

Principal Investigator: Anita Sullivan

Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust; Recruiting

Brompton, United Kingdom

Principal Investigator: Michael Loebinger

Altnagelvin Area Hospital, Western Health and Social Care Trust; Recruiting

Derry, United Kingdom

Principal Investigator: Martin Kelly

Ninewells Hospital and Medical School, NHS Tayside; Recruiting

Dundee, United Kingdom

Principal Investigator: James Chalmers

Royal Infirmary Edinburgh, NHS Lothian; Recruiting

Edinburgh, United Kingdom

Principal Investigator: Adam Hill

Royal Free Hospital, Royal Free London NHS Foundation Trust; Recruiting

Hamstead, United Kingdom

Principal Investigator: John Hurst

Princess Alexandra Hospital, The Princess Alexandra Hospital NHS Trust; Recruiting

Harlow, United Kingdom

Principal Investigator: Muhammad Anwar

Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS Foundation Trust; Recruiting

Lancaster, United Kingdom

Principal Investigator: Timothy Gatheral

Freeman Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust; Recruiting

Newcastle, United Kingdom

Principal Investigator: Anthony De Soyza

Churchill Hospital, Oxford University Hospitals NHS Foundation Trust; Recruiting

Oxford, United Kingdom

Principal Investigator: William Flight

Southampton General Hospital, University Hospital Southampton NHS Foundation Trust; Recruiting

Southampton, United Kingdom

Principal Investigator: Mary Carroll

Royal Gwent Hospital, Aneurin Bevan University Health Board; Recruiting

Wales, United Kingdom

Principal Investigator: Andreea Alina Ionescu

Sponsors and Collaborators

Belfast Health and Social Care Trust

Queen's University, Belfast

Investigators

• Principal Investigator: J. Stuart Elborn; Queen's University, Belfast

More Information

• Responsible Party: Belfast Health and Social Care Trust
• ClinicalTrials.gov Identifier: NCT04140214
• Other Study ID Numbers: 16178SE-AS
• First Posted: October 25, 2019
• Last Update Posted: October 25, 2019
• Last Verified: October 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Belfast Health and Social Care Trust:

Respiratory; Mucoactive; Exacerbation; Hypertonic Saline; Carbocisteine; Airway Clearance

Additional relevant MeSH terms:

Bronchiectasis; Bronchial Diseases; Respiratory Tract Diseases; Carbocysteine; Anti-Infective Agents, Local; Anti-Infective Agents; Expectorants; Respiratory System Agents