Abstract
Bronchiectasis is an increasing clinical problem, with no licensed treatments because multiple recent clinical trials have failed to reach their primary endpoint. Difficulties in achieving “positive” bronchiectasis trials is reflected in a lack of agreement from trialists and regulators on what are the optimal endpoints. In addition to this, existing quality of life and symptom tools used in bronchiectasis trials are either not disease specific or are complex and have not been consistently responsive.A systematic review of published bronchiectasis trials was conducted to evaluate the use of endpoints in bronchiectasis trials. The definitions, methods of analysis and responsiveness of each endpoint was investigated. Particular attention was paid to the responsiveness of health-related quality of life questionnaires. The systematic review demonstrates a need for standardised definitions and design features to improve reproducibility and increase the likelihood of demonstrating statistically significant benefits with new therapies.
A post hoc analysis of the AIR-BX1 and 2 studies comparing inhaled aztreonam versus placebo in bronchiectasis with the primary endpoint of change in the quality of life bronchiectasis (QOL-B) respiratory symptom score was conducted. Individual items from QOL-B were extracted as representing severity of nine distinct symptoms as item-level analysis of questionnaire data may identify which specific symptoms respond best to treatment. By removing the total score, improvements in cough, sputum production and sputum colour were seen in the aztreonam group versus placebo throughout the trial period. Worsening of wheeze and breathlessness were also noted with aztreonam use. Patients with higher sputum production and sputum colour scores had a greater response on the overall QOL-B but in contrast, treating patients with lower levels of bronchitic symptoms resulted in shorter time to next exacerbation.
In response to these findings, a simple patient reported visual analogue outcome measure, the bronchiectasis impact measure (BIM) for use in clinical research including clinical trials was developed. Validation of the tool was performed over 6months, with results showing all 8 domains (cough, sputum, breathlessness, tiredness, daily activity, overall health, control, exacerbations) having excellent intraclass correlation. Internal consistency and test-retest reliability were also confirmed. Domains correlated strongly with bronchiectasis severity and exacerbation history. Both distribution and patient-based methods estimated the minimum clinically important difference (MCID) for each domain as 1.5 points on a 10-point scale. Statistically significant changes in all BIM domains were observed during an acute exacerbation.
This thesis brings together the findings from the systematic review and results from item-level analysis of symptoms response following inhaled antibiotic use to demonstrate the potentials of using a new, bronchiectasis-specific, health related questionnaire, co-designed with patients which has the ability to not only measure changes in individual symptoms but allows patients to determine their own MCID when beginning new treatment.
Date of Award | 2022 |
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Original language | English |
Awarding Institution |
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Sponsors | European Federation of Pharmaceutical Industries and Associations & European Respiratory Society |
Supervisor | James Chalmers (Supervisor) & Amelia Shoemark (Supervisor) |
Keywords
- Bronchiectasis
- Trial design
- Quality of life