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

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ClinicalTrials.gov Identifier: NCT04140214
Recruitment Status : Recruiting
First Posted : October 25, 2019
Last Update Posted : February 7, 2022
Sponsor:
Collaborator:
Queen's University, Belfast
Information provided by (Responsible Party):
Belfast Health and Social Care Trust

Tracking Information
First Submitted Date  ICMJE May 17, 2019
First Posted Date  ICMJE October 25, 2019
Last Update Posted Date February 7, 2022
Actual Study Start Date  ICMJE June 27, 2018
Estimated Primary Completion Date September 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 24, 2019)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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)
  • 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).
  • Number of Adverse Events [ Time Frame: Over 52 weeks post-randomization ]
    Reported by the PI or designee via interview with patients.
  • 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.
  • IMP Adherence [ Time Frame: 52 weeks post-randomization ]
    Assessed using IMP Accountability Logs
  • HTS Adherence [ Time Frame: 52 weeks post-randomization ]
    Assessed electronically via tracking of nebulizer use.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomised Open Label Trial of Hypertonic Saline and Carbocisteine in Bronchiectasis (CLEAR)
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Bronchiectasis
Intervention  ICMJE
  • Drug: Hypertonic saline
    Nebulized hypertonic saline solution (6%)
    Other Names:
    • MucoClear 6%
    • HTS
  • Drug: Carbocysteine 750 MG
    Carbocisteine tablet
    Other Name: Mucodyne
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Hypertonic saline
  • 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.
    Intervention: Drug: Carbocysteine 750 MG
  • 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.
    Interventions:
    • Drug: Hypertonic saline
    • Drug: Carbocysteine 750 MG
  • 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.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 24, 2019)
380
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2024
Estimated Primary Completion Date September 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Roisin Boyle 028 90 635794 CLEAR@nictu.hscni.net
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04140214
Other Study ID Numbers  ICMJE 16178SE-AS
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Belfast Health and Social Care Trust
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Belfast Health and Social Care Trust
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Queen's University, Belfast
Investigators  ICMJE
Principal Investigator: J. Stuart Elborn Queen's University, Belfast
PRS Account Belfast Health and Social Care Trust
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP