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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 288
- 试验地点
- 20
- 主要终点
- Mean Number of Exacerbations
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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).
干预措施: Hypertonic saline (Drug)
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.
干预措施: Carbocysteine 750 MG (Drug)
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.
干预措施: Hypertonic saline (Drug)
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.
干预措施: Carbocysteine 750 MG (Drug)
结局指标
主要结局
Mean Number of Exacerbations
时间窗: 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.
次要结局
- Health Service Use(52 weeks post-randomization)
- HTS Adherence(52 weeks post-randomization)
- Patient Preferences for Treatment(Assessed at 2, 8, 26, and 52 weeks post-randomization.)
- Changes in Lung Function(52 weeks post-randomization)
- IMP Adherence(52 weeks post-randomization)
- Disease-Specific Health-Related Quality of Life(52 weeks post-randomization)
- Time to Next Exacerbation(Over 52 weeks post-randomization)
- Generic Health-Related Quality of Life (HRQoL)(Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.)
- Quality Adjusted Life Years (QALY)(52 weeks post-randomization)
- Number of Adverse Events(Over 52 weeks post-randomization)
- Number of Days of Antibiotics for Exacerbations(Over 52 weeks post-randomization)
- Measurement of Health Impairment(Assessed at baseline, and 2 weeks, 8 weeks, 26 weeks and 52 weeks post-randomization.)