Abstract
Background: Chronic or refractory breathlessness is common and distressing with few effective treatment options. New treatments urgently need to be developed and trialled.Conducting clinical trials in advanced illness can be challenging, with difficulties recruiting and retaining participants. Outcome measures that capture changes important to people living with breathlessness are also necessary.
Aim: To explore the feasibility of, and ways to optimise recruitment, retention, and outcome measures in a double blind randomised controlled trial of mirtazapine for chronic or refractory breathlessness.
Methods: This thesis reports a mixed-methods study embedded within a randomised trial comprising semi-structured qualitative interviews and quantitative outcome measures. Data were collected as part of a double blind randomised feasibility trial of mirtazapine for chronic breathlessness (ISRCTN registration 33236160). Participants were studied over 35 days with contacts at baseline, and days 7, 14, 21, 28 and 35. Qualitative interviews were conducted at the end of the trial and included questions about; experience of recruitment to the trial, experience of being in the trial, whether participants had perceived any change during the trial period, and if so what had changed.
The quantitative data was analysed using descriptive statistics to provide measurements of feasibility and included: screening and recruitment data, number of adverse events, number of participants who discontinued the intervention, and the proportion of missing data in the trial- based questionnaires.
The qualitative interviews were analysed for themes relating to recruitment and retention using thematic analysis, and then considered in relation to the core elements of person- centred care (PCC). Qualitative interviews were also analysed for themes relating to change in experience of breathlessness during the trial and considered within the domains of ‘total breathlessness’. The outcome measure data was analysed quantitatively to derive a change score according to available guidance. The qualitative and quantitative data relating to change was then integrated and where change was seen in the qualitative data evidence of change was looked for in the quantitative data and vice versa.
Results: The trial was open to recruitment at three centres between 17th August 2016 and 30th November 2017. Each centre was open for 12 months, during which time 409 patients were screened, of whom 150 were eligible, and 64 randomised. The screening to recruitment ratio was 6.4:1. The intervention was well tolerated during with trial with few adverse effects reported. There was only one adverse event (grade 3) which was reported in the placebo arm.
In total 12 serious adverse events were reported, 7 in the mirtazapine arm and 5 in the placebo arm. Twelve patients (six per arm) discontinued treatment prematurely. There was 100% completion of questionnaires at baseline and few missing data throughout the trial.
Paired data were available for 22 of 64 participants who participated in the trial. 11 had a diagnosis of COPD, 8 ILD, 2 CHF and 1 cancer. Median age was 71 (56-84) years. 16 were male. 20 had completed the trial, 2 withdrew due to adverse effects. Prioritisation of the relationship between the patient and professional; person-centred processes including home visits, assistance with questionnaires, and involvement of the carer; and enabling people to participate by having processes in line with individual capabilities appeared to support recruitment and retention in the trial. Themes were considered in relation to PCC and a model of the person-centred trial was developed. Participants described change in experience across all domains of ‘total breathlessness’ during the trial. Changes in the qualitative data were commonly captured in the NRS (worst and average) and CRQ. However, agreement was highest with the NRS worst, which despite being a single item measure appeared to capture changes across multiple domains.
Conclusions: In this feasibility trial recruitment targets were met, and attrition levels were low. Aspects of the person-centred approach were viewed positively by trial participants and appeared to support high rates of recruitment and retention. Future work should aim to evaluate the application of a person-centred approach to clinical trials in different settings. A single item outcome measure, the NRS worst, appeared to best capture important changes in the experience of breathlessness across multiple domains. It may therefore be a candidate primary outcome measure for this and other drug effectiveness trials. However, future work should ensure the validity of this specific format of question.
| Date of Award | 1 Jun 2020 |
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| Original language | English |
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| Supervisor | Irene Higginson (Supervisor), Matthew Maddocks (Supervisor) & Sabrina Bajwah (Supervisor) |