Clinimetric Properties of Outcome Measures in Bronchiectasis in the UK

There is an increasing demand for researchers and regulatory bodies to use robust outcome measures in clinical trials which have evidence of validity, reliability, and responsiveness. There is currently little agreement on the core clinical endpoints that should be used in bronchiectasis. The importance of improving endpoint outcome measurement is well recognised and groups in other conditions have focused on activities to achieve consensus on a core set of outcomes for clinical trials. The Bronch-UK collaboration has explored the current evidence for clinimetric properties of commonly used outcome measures in bronchiectasis (e.g. forced expiratory volume in one second \[FEV1\], health related quality of life \[HRQoL\], and pulmonary exacerbations). The results of this extensive rigorous literature review of 68 papers clearly demonstrate that whilst there was good evidence for validity for key outcome measures in bronchiectasis there is little information available on their reliability (during periods of clinical stability) or response to treatment (effect sizes).

The aim of this study is to explore the clinimetric properties of a range of outcome measures, in order to make recommendations for their use in clinical trials in bronchiectasis.

Bronchiectasis is a persistent or progressive condition characterised by dilated thick-walled bronchi. The recent guidelines stipulate that high resolution computerised tomography scan (HRCT) is the radiological investigation of choice to establish the diagnosis of bronchiectasis. The key radiological features of bronchiectasis include bronchial wall dilation (internal lumen diameter greater than accompanying pulmonary artery) which is the characteristic feature of bronchiectasis.

Prevalence of bronchiectasis in most populations is largely inaccurate due to lack of recent studies. United Kingdom (UK) figures indicate prevalence figures of 100/100,000 based on studies undertaken in the 1950's but these did not involve use of high resolution computerised tomography scan for diagnosis. This number is five to ten times higher in people over 55 years of age. The mean age of death is 72 years.

The aetiology for bronchiectasis is variable, however, current data suggests that the most common causes are: post infectious; immunological; congenital; with a proportion also idiopathic.

Bronchiectasis is increasingly being recognised as a major cause of pulmonary morbidity. The signs and symptoms of bronchiectasis include chronic sputum production, shortness of breath and fatigue; all of which contribute to increased morbidity and may progress to respiratory failure and cor pulmonale.

The management of bronchiectasis incorporates an intense regime of prevention and treatment. These often include daily intake of inhaled and nebulised medications, antibiotic therapy, airway clearance, visits to GP and/or respiratory clinics and hospitalisation. The burden of treatment associated with bronchiectasis is therefore significant and is provided at a huge economic cost to the health service. Many of these treatments are provided in the absence of a sound evidence base and so there is a clear need to develop assessment tools for use both in clinical trials and in clinical practice.

There is an increasing demand for researchers and regulatory bodies to use robust outcome measures in clinical trials which have evidence of validity, reliability, and responsiveness. There is currently little agreement on the core clinical endpoints that should be used in bronchiectasis. The importance of improving endpoint outcome measurement is well recognised and groups in other conditions have focused on activities to achieve consensus on a core set of outcomes for clinical trials. The Bronch-UK collaboration has explored the current evidence for clinimetric properties of commonly used outcome measures in bronchiectasis (e.g. forced expiratory volume in one second \[FEV1\], health related quality of life \[HRQoL\], and pulmonary exacerbations). The results of this extensive rigorous literature review of 68 papers clearly demonstrate that whilst there was good evidence for validity for key outcome measures in bronchiectasis there is little information available on their reliability (during periods of clinical stability) or response to treatment (effect sizes).

Spirometry is a method of assessing lung function by measuring the volume of air that the patient is able to expel from the lungs after a maximal inspiration. Spirometry is a method for measuring the speed and volume of airflow and is seen as the "gold standard" of testing lung function. Forced expiratory volume in one second (FEV1) in healthy individuals and those with early disease mostly reflects proximal airways, however, the annual rate of change in FEV1 in bronchiectasis is very small and FEV1 is not very responsive to many treatments especially in mild disease. In recent years other measures of lung function are emerging as potential outcome measures in bronchiectasis. The pathological changes in bronchiectasis involve the small airways. Forced expiratory flow between 25 and 75% (FEF25-75) of forced vital capacity (FVC) has been proposed as a sensitive measure of early airways dysfunction. The major barriers to the use of this are that FEF25-75 is very dependent on patient effort, is less reproducible than FEV1 and has poorly defined normal ranges in different age groups. Lung clearance index measured by multiple breath washout (MBW) is a measure of ventilation inhomogeneity and is considered to reflect abnormalities of the smaller airways. Small airway disease caused by inflammation and obstruction leads to ventilation heterogeneity. This will therefore cause an increased number of breaths to remove a tracer gas due to uneven gas mixing and subsequently an increased lung clearance index.

To date, the majority of studies using the lung clearance index have been conducted in cystic fibrosis. These studies have shown that lung clearance index is more sensitive than spirometry at detecting early lung pathology and that it is a sensitive and repeatable clinical endpoint. It has been used as a secondary end-point in the UK cystic fibrosis gene therapy multidose study; Invacaftor study; hypertonic saline study; and, DNase study.

The investigators have conducted some preliminary studies to explore the use of lung clearance index in bronchiectasis and have shown that lung clearance index is repeatable over short periods of time and a more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis. Further research is needed to provide data on long term repeatability during periods of stability (noise) and also establish its responsiveness to change (effect size).

Multiple questionnaires including the St Georges Respiratory Questionnaire (SGRQ); Quality of Life - Bronchiectasis (QOL-B) Questionnaire; and, EuroQol 5 Dimension (EQ-5D) have been used to capture the impact of health related quality of life (HRQoL)/patient reported symptoms in bronchiectasis. There is no comparative data to direct choice of the most appropriate questionnaire for use in clinical trials. With respect to individual questionnaires there is also the need to provide data on long term repeatability and reliability.

Aims:

The aim of this study is to explore the clinimetric properties of a range of outcome measures, in order to make recommendations for their use in clinical trials in bronchiectasis. These measures include: lung function (spirometry, lung clearance index); health related quality of life (HRQoL) assessment \[St Georges Respiratory Questionnaire (SGRQ); Quality of Life - Bronchiectasis (QOL-B) Questionnaire; EuroQol 5 Dimension (EQ-5D)\]; and, blood (white cell count, c-reactive protein) and sputum (microbiology, inflammatory markers) processing.

Specific Objectives:

* To ascertain the relative stability (least noise) of these potential outcome measures in bronchiectasis over a one year timeframe.
* To ascertain the relative effect size of these outcome measures over a pulmonary exacerbation signal interval (greatest signal-to-noise ratio).
* To compare clinimetric properties (reliability, validity and responsiveness to change) of the health related quality of life (HRQoL) questionnaires.

Eligibility Criteria:
Inclusion Criteria

* Proven and documented diagnosis of non-cystic fibrosis idiopathic or post-infectious bronchiectasis by high resolution computerised tomography scan including two or more lobes and dilated airways compatible with bronchiectasis at initial diagnosis.
* Able to perform an acceptable spirometry session - defined as three acceptable or usable efforts per American Thoracic Society/European Respiratory Society criteria.
* Able to perform an acceptable LCI session.
* Participants must be able and willing to read and comprehend written instructions, and comprehend and complete the questionnaires required by the protocol
* After full explanation, participants must have signed an informed consent form indicating that they understand the purpose of and the procedures required for the study and are willing to participate in the study.
* Participant 18 years of age or above.

Exclusion Criteria

* Women who are pregnant, lactating or in whom pregnancy cannot be excluded.
* Anyone who is participating in or has participated in a clinical trial of an investigational medical product (IMP) within four weeks of first visit.
* Any clinical or genetic features of cystic fibrosis.