This multi-centre pragmatic randomised controlled non-blinded parallel arm trial assessed the effect of breathing training delivered over three 1 hour-long sessions at weekly intervals, or during a single session in the management of patients with refractory breathlessness due to intrathoracic cancer.
Participants and setting
Patients from eight centres in England, Scotland, and Wales attending hospital respiratory, oncology, palliative care clinics or hospices were screened by the research nurse in conjunction with the patients’ usual clinical team. Adults with intra-thoracic malignancy (primary or secondary tumours) were eligible. Participants could be randomised to trial intervention if they had refractory breathlessness with a self-reported intensity of ≥3/10 on a NRS, where 0 = no breathlessness and 10 = worst imaginable breathlessness, and a clinician-estimated prognosis of at least 3 months. Participants with breathlessness intensity of <3/10 were followed-up at monthly intervals to assess eligibility for randomisation. Refractory breathlessness was defined as persistent breathlessness despite treatment of reversible causes . Patients were excluded if they had intercurrent illness or co-morbidities making completion of the trial unlikely, worsening breathlessness requiring urgent medical intervention, or prior breathing training.
Centres were eligible if clinicians provided breathing training and were willing to deliver the trial intervention. The intervention could be delivered in the hospital, hospice, or a patient’s home according to patient choice.
The protocol, procedures, and trial documentation were approved by the independent UK Integrated Research Approval System via the Sheffield Research Ethics Committee (ref 10/H1308/66). Subsequent Research and Development NHS governance approval was obtained for all sites prior to recruitment. The trial was registered (ISRCTN49387307) and the protocol followed CONSORT recommendations. All participants gave written informed consent.
Intervention and comparator
All participants received training in four techniques (Box 1) during an hour-long session, supported by written and DVD/video reinforcement material and a telephone call from their therapist a week after the last session. Those randomised to the three session arm received two further hour-long clinic sessions at weeks 2 and 3 to reinforce and practice the techniques. Training was provided by the usual therapist providing the service.
The four techniques of breathlessness training were standardised prior to trial commencement, but different centres could provide local additional non-pharmacological therapies such as exercise if this was a usual part of their service. The type of professional (e.g. nurse, physiotherapist, occupational therapist) was not stipulated.
The primary outcome measure, defined by previous feasibility work , was patient-reported intensity of the worst breathlessness over the past 24 hours (‘worst’; 0–10 numerical rating scale [NRS], 0 = no breathlessness; 10 = the worst imaginable breathlessness) [19, 20].
Secondary measures included average intensity of breathlessness over the past 24 hours (‘average’); distress due to breathlessness and 0–10 NRS coping with breathlessness (‘distress’) using NRS 0–10 scales anchored with 0 = none and 10 = worst; ‘coping’ and satisfaction with care of breathlessness (using 0–10 NRS scales anchored with 0 = none and 10 = best outcome); injustice and catastrophizing scale; quality of life Chronic Respiratory Questionnaire - Self-Administered-Survey (CRQ-SAS) ; Hospital Anxiety and Depression Scale (HADS) ; Karnofsky performance scale (KPS), , health status (EQ-5D and EQ-visual analogue scale (EQVAS)) ; coping (BriefCOPE) ; and global impression of change and health service utilisation.
Baseline assessments included demographic data (age, sex, smoking history), KPS, medication and personality aspects (Big Five Inventory (BFI) ; Mental Toughness Questionnaire (MTQ)), and pre-randomisation preference for trial allocation. Follow-up assessments were at weeks 1, 2, 3, 4, and 8 after the first training session. All outcome measures were assessed at baseline, week 4, and week 8 except the Big Five Inventory and Mental Toughness Questionnaire. At weeks 1–3 only NRS scores, EQ-5D and EQVAS were measured. Adverse events were noted at each contact. The primary analysis point was week 4. After week 8 participants had an optional monthly telephone call from the trial nurse to record NRS intensity until withdrawal or death.
Using data from previous feasibility work  to detect a difference of 30 % in area under the curve (AUC) for NRS worst breathlessness (standard deviation (SD), 2.6) at 4 weeks at 80 % power and 5 % two-tailed statistical significance, with a 2:1 randomisation, allowing for 30 % attrition, a sample size of 146 participants was needed. Although week 4 attrition in the feasibility trial was 50 %, a reduction to 30 % was anticipated with earlier consent (consent to trial participation even if their reported breathlessness intensity did not fulfil the criteria for randomisation). AUC was chosen as more indicative of the experience of breathlessness over the trial than change in NRS scores, or comparison of week 4 NRS scores as it includes measures at weekly time points.
Sample size re-calculation
A review of week 4 attrition (June 2013) showed nearly 30 % drop out. In order to reduce the risk of loss of power, a further 10 participants were recruited.
Randomisation and masking
Online 3- or 6-block randomisation (central computer generated sequence) and allocation of consenting participants was performed by the York Trials Unit using a 1:2 ratio (1 three: 2 single). This was done in order to minimise a potential increase in demand on usual services from participating in a trial actively seeking to recruit patients. As this was a pragmatic trial, centres maintained their usual practice other than providing the intervention standard components. To account for site differences in cancer therapies and additional breathlessness measures, participants were stratified by centre. Initially, stratification for site of first intervention (home or clinic) was planned, but as this would not always be known at randomisation, this was not done. Due to the likelihood of participants inadvertently disclosing their allocation arm to the research nurse, allocation was not blinded . Trial assessments were conducted by research nurses.
Baseline characteristics are described and presented in tabular form for all participants and presented by whether they were lost to follow-up or remained in the trial. Mean and SD are presented for quantitative data and number and percentage for categorical data. Summary statistics over time are also reported for the repeated outcome measures as are missing data.
For the primary analysis of AUC at 4 weeks (worst breathlessness), we used a two-sample t-test to compare the two arms. Multiple regression was used to estimate the effect of three sessions compared to one adjusting for baseline characteristics (age, sex, baseline breathlessness intensity, and smoking status). To account for missing data we i) utilised multiple imputation method for the primary outcome and ii) used complete cases for all secondary measures. Variation resulting from different practices at different sites was accounted for in the analysis by the stratification . Management of missing data for the cost-effectiveness analysis is described below.
The cost-effectiveness of three sessions versus one was compared. Costs were estimated for both arms and included the cost of the intervention and other health-related resource use costs. The effectiveness measure for this analysis was the Quality Adjusted Life Year (QALY) generated from responses to the EQ5D. A sensitivity analysis using multiple imputation to account for missing data was performed.