A 2x2 factorial randomised 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
| ISRCTN | ISRCTN89040295 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN89040295 |
| EudraCT/CTIS number | 2017-000664-14 |
| IRAS number | 214254 |
| ClinicalTrials.gov number | NCT04140214 |
| Secondary identifying numbers | CPMS 37574; 16178SE-AS, IRAS 214254 |
- Submission date
- 25/06/2018
- Registration date
- 06/07/2018
- Last edited
- 12/09/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Respiratory
Plain English Summary
Background and study aims
Bronchiectasis is a condition where the lungs' airways become widened, leading to a build-up of mucus that can make them more vulnerable to infection. Patients with bronchiectasis suffer from a persistent cough, daily sputum (saliva and mucus) production and recurrent exacerbations, affecting quality of life. This study is concerned with sputum production and exploring which combinations of treatments (hypertonic saline (HTS) and carbocisteine) might help patients bring up their sputum more easily. HTS is salty water that is delivered into the airways via a nebuliser, which converts it into a mist. This treatment takes ten minutes. Carbocisteine is taken as a capsule. Research has shown that these treatments can make it easier for patients to cough up sputum, resulting in potentially fewer exacerbations and hospital admissions, which could improve quality of life for people with bronchiectasis. These treatments are currently used in clinical care but there is not enough evidence to recommend them as part of standard care. The aim of this study is to find out whether HTS and/or carbocisteine result in better outcomes than usual care in patients with bronchiectasis.
Who can participate?
Patients with bronchiectasis
What does the study involve?
Participants are randomly allocated to one of four combinations of treatments: HTS and standard care, carbocisteine and standard care, a combination of HTS and carbocisteine with standard care, and standard care alone. Participants have to attend six additional appointments as part of the study over a 2-year period with five in year one. At the start of the study, information is collected about participants' smoking status, bronchiectasis characteristics, medications, medical history, exacerbation history, antibiotic use, and any airway clearance techniques used. A physical exam, vital signs and urine pregnancy test are completed. A questionnaire is completed with patients to explore any respiratory symptoms they may be experiencing since their last clinic visit. A lung function test is also performed and a range of health-related quality of life questionnaires are completed. At subsequent visits, lung function tests are repeated, exacerbation history is explored, vital signs are obtained and questionnaires are completed again. The nebulizer that patients use to deliver the hypertonic saline can record data about how the patient uses the nebuliser. This usage data is not reviewed with the patient until after they have completed the first year of the study. All patients are also be given a spirometer to perform lung function tests at home on a weekly basis. In addition, patients are asked to use their spirometers at the start of a suspected exacerbation. Patients are asked to bring their spirometer to each study visit. At the 52-week visit the patient is also asked to complete a questionnaire about using the spirometer and nebuliser. Follow-up at 104 weeks collects information about the patient’s quality of life, any exacerbations they have had or any antibiotics they have taken for exacerbations. If the patient is already taking part in studies that are currently collecting information on bronchiectasis patients are asked for permission to use this information. Otherwise they are invited to the study site for an additional visit.
What are the potential benefits and risks of participating?
Carbocisteine may help reduce exacerbations and hospitalisations for people with bronchiectasis, improving their overall quality of life. All participants in the study receive a device to test their lung function at home and are also monitored regularly throughout the study. This may improve the overall care they receive through earlier recognition of exacerbations. Ultimately it is hoped that this research will help guide the treatment of bronchiectasis for people in the future and this may benefit patients in the long term outside of the study. Depending on the group allocation, a participant’s treatment may be altered. A small number of people experience minor side effects from nebulising HTS such as wheezing, but the likelihood of this will be minimised by patients completing a drug response assessment on entry into the study. A small number of patients experience some minimal side effects (stomach discomfort, vomiting, skin rashes and allergies) associated with carbocisteine. Lung function procedures may cause the participant to cough, experience shortness of breath, or feel lightheaded, but there is no pain expected with these tests. Treatment will be provided if this occurs. This study will take place outside of the normal clinical management of participants. Participants will be required to attend up to six additional visits lasting about 2 hours. Appointments will be scheduled at a time convenient to participants, where possible in an attempt to minimise this burden.
Where is the study run from?
1. Altnagelvin Area Hospital (UK)
2. Royal Free Hospital (UK)
3. Royal Infirmary of Edinburgh (UK)
4. Freeman Hospital (UK)
5. Royal Brompton Hospital (UK)
6. Belfast City Hospital (UK)
7. Ninewells Hospital and Medical School (UK)
8. Princess Alexandra Hospital (UK)
9. The Ulster Hospital (UK)
10. Southampton General Hospital (UK)
When is the study starting and how long is it expected to run for?
July 2017 to September 2024
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
Prof. Judy Bradley
judy.bradley@qub.ac.uk
Contact information
Scientific
School of Medicine, Dentistry and Biomedical Sciences
NI Clinical Research Facility
U Floor
Belfast City Hospital
Lisburn Road
Belfast
BT9 7AB
United Kingdom
 ORCID ID |
0000-0002-7423-135X |
|---|---|
| Phone | +44 (0)28 9504 0342 |
| judy.bradley@qub.ac.uk |
Public
Northern Ireland Clinical Trials Unit
1st Floor Elliot Dynes
The Royal Group of Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
| CLEAR@nictu.hscni.net |
Public
NICTU
1st Floor Elliot Dynes Building
Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
| Phone | +44 (0) 28961 51447 |
|---|---|
| AndrewX.Jackson@nictu.hscni.net |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A 2x2 factorial randomised 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 |
| Study acronym | CLEAR |
| Study hypothesis | HTS (6%) and/or the oral mucolytic carbocisteine will result in better outcomes than usual care over 52 weeks in patients with bronchiectasis. |
| Ethics approval(s) | North East – Tyne & Wear South Research Ethics Committee, 20/12/2017, ref: 17/NE/0339 |
| Condition | Bronchiectasis |
| Intervention | Treatment allocation will be assigned using an automated randomisation process. Eligible participants will be allocated to one of the four treatment groups (three intervention groups or one standard care group) in a 1:1:1:1 ratio using a central randomisation system. Randomisation will be stratified by site, to minimise baseline imbalances in antibiotic use due to exacerbations in the last year (2-3 times, >3 times) and based on current use of macrolides (yes, no). Intervention 1: Standard care and twice daily nebulised HTS (6%) over 52 weeks Intervention 2: Standard care and carbocisteine (750 mg three times per day until visit 3 reducing to 750 mg twice per day) over 52 weeks Intervention 3: Standard care and a combination of twice daily nebulised HTS (6%) and 750 mg of carbocisteine three times per day until visit 3* reducing to 750 mg twice per day) over 52 weeks Intervention 4: Control: standard care over 52 weeks The study treatment period is 52 weeks, after which follow-up will take place at week 104. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Hypertonic saline, carbocisteine |
| Primary outcome measure | Mean number of exacerbations over 52 weeks; exacerbations diagnosed as they occur via interview with patients and completion of the Respiratory and Systemic Symptoms questionnaire (RSSQ) |
| Secondary outcome measures | 1. Disease-specific health-related quality of life (HRQoL) at 52 weeks measured using the respiratory symptoms domain of quality of life with bronchiectasis (QoL B) questionnaire completed at baseline, 2 weeks, 8 weeks, 26 weeks and 52 weeks 2. Time to next exacerbation post-randomisation measured in days, with exacerbations diagnosed as they occur via interview with patients and completion of the RSSQ 3. Number of days of antibiotics related to exacerbations over 52 weeks assessed via interview with patients at 2, 8, 26 and 52 weeks 4. Generic health-related quality of life (HRQoL) measured using the EQ-5D-5L questionnaire at baseline, 2 weeks, 8 weeks, 26 weeks and 52 weeks 5. Health Service use over 52 weeks assessed via completion of a questionnaire completed at baseline, 2 weeks, 8 weeks, 26 weeks and 52 weeks 6. Quality Adjusted Life Years (QALYs) over 52 weeks calculated by assessment of generic HRQoL measured using the EQ-5D-5L questionnaire completed at baseline, 2 weeks, 8 weeks, 26 weeks and 52 weeks 7. Health impairment measured using the St George’s Respiratory Questionnaire (SGRQ) at baseline, 2 weeks, 8 weeks, 26 weeks and 52 weeks 8. Patient preferences for treatment measured using a Treatment Satisfaction Questionnaire at 2, 8, 26, and 52 weeks 9. Adverse events over 52 weeks recorded as they occur by the PI or designee via interview with patients 10. Lung function over 52 weeks measured by spirometry testing at baseline, 2 weeks, 8 weeks, 26 weeks and 52 weeks 11. Adherence to HTS and carbocisteine over 52 weeks assessed via interview with patients at 2, 8, 26, and 52 weeks |
| Overall study start date | 01/07/2017 |
| Overall study end date | 30/09/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 288; UK Sample Size: 288 |
| Total final enrolment | 288 |
| Participant inclusion criteria | Current inclusion criteria as of 06/10/2022: 1. Diagnosis of BE on high resolution computed tomography (HRCT)/computed tomography (CT) scans 2. BE must be the primary respiratory diagnosis 3. One or more pulmonary exacerbations in the last year requiring antibiotics* 4. Production of daily sputum 5. Stable for 14 or more days before the first study visit with no changes to treatment 6. Willing to continue any other existing chronic medication throughout the study 7. 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 Previous inclusion criteria: 1. Diagnosis of BE on high resolution computed tomography (HRCT)/computed tomography (CT) scans 2. BE must be the primary respiratory diagnosis 3. Two or more pulmonary exacerbations in the last year requiring antibiotics* 4. Production of daily sputum 5. Stable for 14 or more days before the first study visit with no changes to treatment 6. Willing to continue any other existing chronic medication throughout the study 7. 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 |
| Participant exclusion criteria | 1. Age <18 years old 2. Patients with CF 3. Patients with COPD as a primary respiratory diagnosis 4. Current smokers, female ex-smokers with greater than 20 pack years and male ex-smokers with greater than 25 pack years 5. FEV1<30% 6. If being treated with long term macrolides, on treatment for less than 1 month before joining study 7. Patients on regular isotonic saline 8. Treatment with HTS, carbocisteine or any mucolytics within the past 30 days 9. Known intolerance or contraindication to HTS or carbocisteine. 10. Hypersensitivity to any of the active ingredients or the excipients of carbocisteine 11. Active peptic ulceration 12. Any heredity galactose intolerance, the Lapp-Lactase deficiency or glucose-galactose malabsorption. 13. Patients unable to swallow oral capsules. 14. Women who are pregnant or lactating 15. Participation in another Clinical Trial of an Investigational Product within 30 days |
| Recruitment start date | 27/06/2018 |
| Recruitment end date | 30/09/2023 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
Study participating centres
Londonderry
BT47 6SB
United Kingdom
Hampstead
London
NW3 2QG
United Kingdom
Edinburgh
EH16 4SA
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Chelsea
London
SW3 6NP
United Kingdom
Belfast
BT9 7AB
United Kingdom
Dundee
DD1 9SY
United Kingdom
Harlow
CM20 1QX
United Kingdom
Dundonald
BT16 1RH
United Kingdom
Southampton
SO16 6YD
United Kingdom
Sponsor information
Hospital/treatment centre
Royal Victoria Hospital Site
Grosvenor Road
Belfast
BT12 6BA
Northern Ireland
United Kingdom
| Phone | +44 (0)28 9063 6349 |
|---|---|
| ResearchSponsor@belfasttrust.hscni.net | |
"ROR" |
https://ror.org/02tdmfk69 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 30/09/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Manuscript preparation is in progress for publication of the study protocol in a peer-reviewed journal. In accordance with the open access policies proposed by the NIHR the trialists aim to publish the following within approximately one year of the overall trial end date: 1. The trial protocol 2. The clinical findings of the trial 3. A paper describing the cost-effectiveness in the NHS setting in high quality peer-reviewed open access (via PubMed Central) journal. In addition, a lay person’s summary will be sent to local and national patient support and liaison groups including the European Lung Foundation BE Patient Advisory Group and the British Lung Foundation (UK), as well as similar organisations in devolved nations. A report of the study findings will be sent to the INVOLVE registry. This is an open-access database which registers research health care projects involving members of the public as partners in the research process. Following peer reviewed publication, appropriate key findings will also be posted on institutional websites available to the general public. In addition, the most significant results will be communicated through press releases to ensure dissemination to the broader public and research participants. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 19/12/2019 | 23/12/2019 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
12/09/2024: Study website added.
12/10/2023: Total final enrolment added.
15/09/2023: IRAS and ClinicalTrials.gov numbers added.
07/11/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/11/2022 to 30/09/2023.
2. The overall trial end date was changed from 30/09/2023 to 30/09/2024.
3. The intention to publish date was changed from 30/09/2024 to 30/09/2025.
06/10/2022: The following changes were made to the trial record:
1. The inclusion criteria were updated.
2. The target number of participants was changed from 'Planned Sample Size: 380; UK Sample Size: 380' to 'Planned Sample Size: 288; UK Sample Size: 288'.
14/09/2022: The recruitment end date was changed from 30/09/2022 to 01/11/2022.
29/12/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2020 to 30/09/2022.
2. The overall trial end date was changed from 30/06/2022 to 30/09/2023.
3. The intention to publish date was changed from 30/06/2023 to 30/09/2024.
30/11/2020: One public contact has been removed and another has been added.
10/08/2020: Recruitment to this study is no longer paused.
24/04/2020: Due to current public health guidance, recruitment for this study has been paused.
23/12/2019: Publication reference added.
22/03/2019: The condition was updated from "Specialty: Respiratory Disorders, Primary sub-specialty: Respiratory disorders; UKCRC code/ Disease: Respiratory/ Chronic lower respiratory diseases" to "Bronchiectasis".
22/10/2018: A public contact has been added.
19/10/2018: The recruitment start date was changed from 18/06/2018 to 27/06/2018.
