Design

A parallel two-group randomised controlled pilot trial with individual participant allocation to the intervention or control group with a nested mixed methods feasibility evaluation and mechanistic substudy. Participants will be individually randomised to either the intervention group (REACH-HF intervention plus usual care) or the control (usual care alone) group. The design is depicted in figure 1.

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Figure 1

Consort flow chart.

Setting

The study will be conducted in a single investigator centre in one Scottish Health Board. In order to achieve adequate participant enrolment to sample size, the site can recruit via a number of secondary care pathways: HF disease/research registers; outpatient cardiology, HF and cardiovascular risk clinics: medicine for the elderly clinics; or CR services. Recruitment performance will be formally reviewed periodically by the central trial management team. Follow-up procedures will usually be conducted on NHS premises. Conduct of the study will be led by a local principal investigator (supported by a coinvestigator), research nurse/fellow and a research assistant (for qualitative elements); all of whom are trained in Good Clinical Practice and in the requirements of the study protocol. The site is responsible for the recruitment and scheduled follow-up visits of participants.

Study population

The study population includes patients and their caregivers. Participating patients will be aged 18 years or older and have a confirmed diagnosis of HFpEF on echocardiography (preferable), radionuclide ventriculography or angiography (ie, left ventricular ejection fraction ≥45% within the last 6 months prior to randomisation). Patients who have undertaken CR within 6 months prior to enrolment will be excluded, as will patients with a contraindication to exercise testing or exercise training (with consideration of adapted European Society of Cardiology guidelines for HF).23 The full list of patient inclusion and exclusion criteria is listed in box 1.

Participating caregivers will be aged 18 years or older and provide unpaid support to participating patients who could otherwise not manage without such support. Unpaid support includes emotional support, prompting with taking medications, observing for signs and symptoms of HF, getting prescriptions, encouraging participation in social events and physical activity, helping with household tasks or providing physical care.

A patient may still participate if s/he does not have an identified caregiver, or if the patient's caregiver is not willing to participate.

Participants are free to withdraw from the study at any time, without any negative impact to their ongoing care. If a participant chooses to withdraw, their reason for withdrawal will be noted where possible. Any data collected on participants prior to withdrawal will be retained for analysis.

Randomisation

Participants will be randomly allocated in a 1:1 ratio to either intervention or control group arms without stratification or minimisation. Randomisation numbers will be computer generated and assigned in strict sequence. At the point of randomisation, participants will be assigned the next randomisation number in the sequence. To maintain concealment and minimise selection bias, randomisation will be performed after the baseline visit by a member of Peninsula Clinical Trials Unit (CTU), independent from investigator teams, using a secure, web-based randomisation system.

Intervention

The REACH-HF intervention is grounded in the support needs and priorities of people living with HF and the services that provide care for them. A systematic, six-step intervention mapping framework guided intervention development,24 drawing on research evidence, national and international guidelines and stakeholder consultations with patients, caregivers and health professionals to identify ‘targets for change’. In line with intervention mapping, regulatory processes underpinning target behaviour patterns and evidence-based change techniques were matched to each behaviour-change target.25 A key element of the intervention development process was an active patient and public involvement (PPI) group consisting of six people with a range of experiences with HF and three caregivers of people with HF. The intervention development process is described in detail elsewhere.26 Development of a facilitated self-care and rehabilitation intervention for people with HF and their care givers; Rehabilitation Enablement in Chronic Heart Failure (REACH-HF). Submitted for publication, November 2015).

The REACH-HF intervention is a comprehensive self-care support programme comprising the ‘Heart Failure Manual’ (REACH-HF manual), with a choice of two exercise programmes for patients, a ‘Family and Friends Resource’ for caregivers, a ‘Progress Tracker’ tool for patients and a 3-day training course for intervention facilitators.

Participating patients and caregivers will work through the REACH-HF manual over a 12-week period with facilitation by a specially trained intervention facilitator (cardiac nurse by background), who will help to build the patient's and caregiver's understanding of how to manage HF. The REACH-HF manual includes information and interactive elements covering a wide range of topics relating to living with/adapting to living with HF and includes four core elements:

1. an exercise training programme, tailored according to initial fitness assessments, delivered as a walking programme or a chair-based exercise DVD, or a combination of the two (as selected by the patient);

2. managing stress /breathlessness /anxiety;

3. heart failure symptom monitoring (and associated help-seeking);

4. understanding HF and taking medications.

The REACH-HF manual was originally designed for patients with HFrEF (ejection fraction <45%). There was limited evidence to guide the development of the REACH-HF manual for HFpEF patients; it has been adapted for this pilot study to allow evaluation in patients with HFpEF (ejection fraction ≥45%). The section on medications has been revised to make it relevant to HFpEF patients, and an additional section has been added on the nature of causes and treatment of HFpEF. The majority of the self-care advice in all other sections of the REACH-HF manual is relevant to all patients with HF and corresponds to national HF guidelines.27 ,28

Patients will be advised to use the Progress Tracker, which is designed to encourage patients to monitor their own condition over the period of the intervention and to make associations between improvements in self-care and improvements in symptoms/well-being. It includes sections in which patients can record changes in physical and mental state, intensity of exercise and self-reported walking speed, physical activity, engagement in enjoyable activities, frequency of self-weighing (to monitor fluid build-up) and frequency of use of stress-management techniques. The Family and Friends Resource, a manual for use by caregivers, includes advice on providing support for a person with heart failure, becoming a caregiver, managing the caregiver's own health and well-being and getting help.

Intervention delivery may be discontinued at any time at the request of a participant or by the intervention facilitator if the intervention is no longer deemed appropriate, for example, altered clinical condition.

Adherence by facilitators to the intervention protocols will be measured through fidelity assessment.

Usual care

In accord with findings of our national survey,29 HF patients typically do not receive CR, despite national recommendations.28 The choice of a usual care (no CR) comparator in this therefore reflects of the current situation for the vast majority of HF patients in UK. Intervention and control group patients will receive usual medical management for HF according to national and local guidelines. Data related to health service usage and medication use will be captured at each follow-up through participants' completion of healthcare resource use questionnaires and by collection of concomitant medication usage as reported by participants.

Outcome measures

Outcome data will be collected at 4 and 6 months postrandomisation (table 1). The 4-month time point coincides with the planned end of the 3-month intervention delivery period for participants in the intervention arm. This allows a 1-month period after the baseline visit for completion of randomisation and referral processes.

Sample size

We aim to recruit 50 patient participants (25 intervention: 25 control). This number will allow us to achieve the feasibility aims and objectives of this study, that is, an estimate of attrition (mean 20%, 95% CI of 23%), estimates of the SD of the primary and secondary outcome measures and sufficient numbers of patients to undertake qualitative interviews to assess feasibility and acceptability of study design and intervention. It is estimated that a total of 216 patients would be needed for a definitive trial to detect a clinically meaningful between group difference in the primary outcome of MLHFQ (for details of this sample size calculation, see ref. 12). No sample size calculation has been applied to the caregiver participants. A previous RCT in CR indicates a ratio of caregivers to patients of 0.6–0.7:1.0,40 therefore it is expected that between 30 and 35 caregivers will be recruited in this pilot.

Trial data collection

Trial data are collected from trial participants (patients and caregivers) during three clinic visits (at baseline, 4 and 6 months). In order to encourage participant retention and completeness of data, participants may claim travel expenses associated with clinic visits and are provided with postage-paid envelopes to return questionnaires by post. Participants who are unwilling or unable to travel to research assessments or accommodate home visits are excluded at the point of consent.

At the baseline clinic visit, after written informed consent has been obtained by the principal investigator or authorised delegate, the following information will be collected:

• medical history (including comorbidities (number and severity scored with Charlson comorbidity index), New York Heart Association class, HF aetiology, concomitant HF medication and presence of implantable HF devices);

• healthcare resource usage over the prior 6 months;

• sociodemographic information (ie, date of birth, ethnicity, weight, employment status, education level, smoking status).

Participating patients will be asked to:

• complete a booklet comprising the primary and secondary outcome questionnaires;

• perform an incremental shuttle walking test;

• undergo echocardiography examination at rest;

• provide two blood samples (∼4 mL blood sample for measurement of NT pro-BNP level and ∼4 mL for the analysis of bloodborne biomarkers);

• wear a wrist-worn accelerometer for 8 days.

Participating caregivers will also be asked to provide sociodemographic information (ie, age (date of birth), ethnicity, weight, employment status, education level, smoking status) and to complete a booklet comprising the caregiver outcome questionnaires.

At the 4-month and 6-month clinic visits investigators will record details of any changes to patients' HF medication or implantable cardiac devices, details of any hospitalisations and healthcare resource usage since the previous visit. Investigators will also check that participating patients have not developed contraindications to exercise testing before conducting the incremental shuttle walking tests. The echocardiography examinations at rest will be conducted at baseline and 6 months, unless an appropriate echocardiography examination has been conducted within 2 weeks prior to the clinic visit, and the patient agrees to the data being used for the study. Echocardiographic measurements will include diastolic and systolic parameters. Blood samples collected for determination of NT pro-BNP levels) will be dispatched to a central laboratory (Royal Cornwall Hospital NHS Trust). Blood samples collected for the analysis of bloodborne biomarkers will be analysed at the recruiting site. Biomarkers of distinct mechanisms that contribute to the pathophysiology of HF will be measured (growth differentiation factor 15 (GDF15); ventricular remodelling (soluble ST2); myonecrosis (highly sensitive troponin T (hsTnT)) and wall stress (NT-pro-BNP)).41 Accelerometer devices will be worn for 8 days then returned by participants using postage-paid to the CTU for data extraction. Participant safety will be monitored through recording, reporting and review of all serious adverse events collected from baseline until final follow-up visit.

Data collected at clinic visits will be recorded on study-specific case report forms (CRFs) by the research team at each site. Completed CRFs will be checked and signed at the research sites by a member of the research team before being sent to the CTU. Original CRF pages and completed questionnaire booklets will be posted to the CTU at agreed time points for double-data entry in to the study database. Accelerometer data will be imported directly into the study database. All forms and data will be tracked using a web-based trial management system. Double-entered data will be compared for discrepancies according to a data management plan held in CTU. Discrepant data will be verified using the original paper data sheets.

Separate participant contact details will be retained for the purpose of managing intervention delivery and follow-up interviews. Investigators will ensure that the participants' anonymity is maintained on all other documents. Within the CTU, anonymised and identifiable study data will be stored separately, to prevent the identification of participants from research records, in locked filing cabinets within a locked office. Data will be collected and stored in accordance with the Data Protection Act 1998. Electronic records will be stored by the CTU in a secure and Secure Sockets Layer (SSL) encrypted web-based database maintained by the University of Plymouth with daily back up. Direct access to the trial data will be restricted to members of the research team and the CTU, with access granted to the sponsor on request and overseen by the CTU data manager and trial manager.

Process evaluation

Alongside the main patient and carer follow-up, a process evaluation will be completed using a nested mixed methods design to assess the following elements of the intervention.

Economic evaluation

In this pilot study, we will estimate the additional resource use and related costs, associated with the delivery of the intervention, and assess the methods used to collect participant level data on healthcare services used and other related resource use. Data on these areas of resource use will be collected within trial, using reported input by intervention facilitators, and self-report (interviewer administered) participant resource use questionnaires (eg, primary and community healthcare, hospital-based healthcare). In any future economic evaluation, alongside a full trial, the primary perspective of the evaluation is expected to be that of factors related to collecting clinical and resource-use data within the trial will be evaluated. The primary perspective will be that of the UK NHS and personal social services (consistent with the reference case approach used in the UK by NICE),45 with a broader perspective, addressing partial patient and societal resource use, explored in sensitivity analyses. That will therefore be the guiding perspective for data collection in the current pilot study perspective. Informed by CRFs, methods for estimating the resource use and costs associated with delivery of the intervention will be developed and tested. Alongside the data collection on resource use, consideration will be given to outcomes, including the anticipated primary economic end point of the EQ-5D-5L35 and to the development of the framework for future within trial and longer term cost-effectiveness analyses.

Data analysis

All analyses, quantitative and qualitative, will be conducted according to best practise and reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting of clinical trials and appropriate guidelines for reporting process evaluations and qualitative research.46–48

Data monitoring and quality assurance

The site principal investigators (CCL, KS) or authorised delegate(s) will check completed CRFs for missing data or obvious errors before the forms are sent to the CTU. Data will be monitored centrally for quality and completeness by the CTU, and every effort will be made to recover data from incomplete forms where possible.

The CTU data manager will oversee data tracking and data entry and initiate processes to resolve data queries where necessary. The CTU trial manager(s) (CH and VE) will devise a monitoring plan specific to the study which will include central monitoring strategies and study site visits as appropriate. The participating site will be required to permit the CTU trial manager or deputy, or representative of the sponsor, to undertake study-related monitoring to ensure compliance with the approved study protocol and applicable standard operating procedures (SOPs), providing direct access to source data and documents as requested. All study procedures will be conducted in compliance with the protocol and according to the principles of the International Conference on Harmonisation Good Clinical Practice (ICH GCP). Procedures specifically conducted by the CTU team (eg, data management, study management and study monitoring) will be conducted in compliance with CTU SOPs.

Trial management and independent committees

Team members directly involved with the day-to-day running of the trial at site will meet regularly to discuss trial progress, teleconferencing with external members of the REACH-HF management team on a monthly basis with email and telephone exchange as necessary between. The Programme Management Group including health economics, statistics, process evaluation and patient and public representation will meet on a quarterly basis to review status of the overall programme, including trial progress.

The REACH-HF Programme Steering Committee (Chair: Professor Martin Cowie and four other independent members including a patient and public involvement representative) have formally agreed to adopt the role of Trial Steering Committee and will oversee the conduct of the trial with safety and ethics review by a fully independent Data Monitoring Committee (Chair: Dr Ann-Dorthe Zwisler and two other independent members). Evidence for treatment differences in the main efficacy outcome measures will not be monitored through review of accumulating outcome data, and no interim data analyses will be conducted.

The Trial Steering Committee and Data Monitoring Committee meet one to two times per year. Detailed descriptions of the remit and function of the oversight committees are documented in specific charters held in the Trial Master File by CTU.

The Independent Adjudication Committee (Professor Ian Squire (Chair), De Sern Lim and Dr Francisco Levya) will independently assess all hospitalisations and deaths of patient participants during the study for their relatedness to HF in accordance with the study-specific procedure.