Study setting {9}
GP practices in the South East of England.
Eligibility criteria {10}
Patients aged 18+ with Stage 1 Hypertension who are not yet on anti-hypertensive medication and without any significant medical condition that would contraindicate their participation.
Exclusion criteria
Patients who are taking anti-hypertensive medication; have white coat hypertension (as evidenced by averaged home systolic BP <135 mmHg); are unable to undertake the study intervention (isometric exercise); have a previous history of diabetes mellitus (Type 1 or type 2), known or suspected ischaemic heart disease (including myocardial infarction and/or angina and/or coronary revascularization procedure), moderate or severe stenotic or regurgitant heart valve disease, atrial or ventricular arrhythmia, stroke or transient ischaemic attack, aortic aneurysm and/or peripheral arterial disease, uncorrected congenital or inherited heart condition; have an estimated glomerular filtration rate <45 ml/min (calculated using CKD-EPI or MDRD formulae, and taking most recent documented results); have a documented left ventricular ejection fraction <45% and/or left ventricular hypertrophy (by either echocardiography or standard ECG criteria e.g. Sokolow-Lyon); have a documented urine albumin:creatinine ratio >3.5 mg/mmol; are unable to provide informed consent; are enrolled in another Clinical Trial of an Interventional Medicinal Product or Medical Device or other interventional study; and if female, are pregnant or currently breast feeding. Then finally, any medical condition that, in the opinion of the investigator, would make the participant unsuitable for the study.
Who will take informed consent? {26a}
Trained healthcare professionals will be obtaining informed consent via discussion on video call and completion via online software or hardcopy.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable
Interventions
Explanation for the choice of comparators {6b}
Not applicable
Intervention description {11a}
Standard care lifestyle advice (Arm 1 – control) or isometric wall squat exercise training as previously described by Wiles et al37 with standard care lifestyle advice (Arm 2). Figure 2 shows flow-chart of selection of participants and interventions.
Criteria for discontinuing or modifying allocated interventions {11b}
Modification of the isometric exercise prescription will be made if appropriate, after the participant’s first week of exercise training, as part of a fidelity check.
Strategies to improve adherence to interventions {11c}
Participants will receive reminder text or email messages to help adherence to standard care advice, collecting home blood pressure measurements and isometric exercise training (for Arm 2 participants).
Relevant concomitant care permitted or prohibited during the trial {11d}
Exclusion criteria states the participants should not be taking anti-hypertensive medications whilst taking part in the trial.
Provisions for post-trial care {30}
The participants in the control Arm will be offered an Isometric exercise intervention after they have completed their time in the study. The GP practice will oversee participant’s general care throughout the trial and participants will be returned to the care of their GP after the trial.
Outcomes {12}
Primary:
1. Feasibility of isometric exercise prescription assessed using qualitative data from healthcare professional focus groups at month 11/12 of the study
2. Feasibility of isometric exercise intervention and study assessed using qualitative data from participants at month 7 and 11 of the study
3. Variance of blood pressure changes from baseline using participant blood pressure data at week 4, months 3 and 6
4. Sample size for a definitive randomised controlled trial, calculated using evidence of effect on participant systolic blood pressure change at week 1, months 3 and 6
Secondary:
1. Fidelity of the isometric exercise prescription measured using prescription competency assessment data at month 3
2. Fidelity of the isometric exercise prescription measured using observation data from the first Incremental Isometric Exercise Test (IIET) delivered from month 3 to month 5
3. Fidelity of the isometric exercise prescription defined by participant heart rate data within HR reference intervals at Day 7-10
4. Short and medium-term adherence rates recorded as those adhering to isometric exercise intervention at week 4, month 3 and month 6
5. Recruitment and attrition rates from data collected at sites at month 10 and month 15
6. GPs and healthcare professionals’ attitudes to isometric exercise as a treatment option for patients, measured using remote focus groups and telephone interviews at month 11/12
7. Cost and cost-utility of the isometric exercise intervention using healthcare resource use data and quality-adjusted life years (QALYs) at month 15 (or last patient follow up)
8. Participant experiences of undertaking isometric exercise using participant isometric exercise experience surveys at week 4
9. Effect of COVID-19 on recruitment rates and participation using participant focus groups or telephone calls at month 7 and 11 of the study
10. Feasibility of using observed home blood pressure readings for remote blood pressure monitoring, using participant blood pressure data and observations from the measures at day 1, week 4, month 3 and month 6
Participant timeline {13}
Sample size {14}
Review of current literature revealed few IE studies in a hypertensive population. These studies were small (n<25), conducted under different conditions to the proposed study, and showed low precision and large variability in estimates of the standard deviation (SD). A sample size of 100 participants, 50 per arm, will be used in the study. Allowing for 20% attrition and 6.5% incomplete data, 74 participants (37 in each arm) will have completed change measures at 4 weeks. This is in line with the recommended sample size of 70 to estimate key parameters from external pilot RCTs (38). A sample size of 74 produces a two-sided 95% confidence interval with a width of 1.33 when the standard deviation is 4. This estimate of 4 has been taken from a previous study (N=24) (19). The sample size confidence interval has been calculated using Pass11 software (PASS 11. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com).
Recruitment {15}
Participants will be identified opportunistically through patient database searches and invited to participate. The study will also be advertised with ethically approved advertising materials, in participating GP practices, with electronic adverts on their websites, social media and newsletters as well as by text message to potential participants.
Assignment of interventions: allocation
Sequence generation {16a}
Random permuted blocks will be used within stratification (of site and age), ensuring that treatments are balanced at the end of every strata block.
Concealment mechanism {16b}
Participants will be allocated to either the control or isometric exercise arm using a third-party supplier of randomisation services (39). This internet-based service allows investigators to randomise patients from anywhere in the world through a web browser.
Implementation {16c}
The investigators will implement the allocation created by the online randomisation software (39).
Assignment of interventions: Blinding
Who will be blinded {17a}
Not applicable.
Procedure for unblinding if needed {17b}
Not applicable.
Data collection and management
Plans for assessment and collection of outcomes {18a}
The success of intervention delivery by health care professionals in a primary NHS healthcare settings will be determined using both qualitative data (remote) and the heart rate data recorded by the participants at the end of each isometric wall squat bout x4 per session over the 3 sessions completed in the first week using a wireless heart rate monitor and chest strap (Sigma PC 15.11, Neustadt /Weinstraße, Germany). The average HR calculated from the first 3 sessions will then be compared against the individuals’ target training HR (calculated as 95% of HR peak measured during the individuals incremental isometric exercise test IIET) with an acceptable target heart rate range (THRR) of 76-111% of heart rate peak37. Perceptions of intervention delivery by healthcare professionals will be explored in qualitative focus groups (remote).
Any change in BP following the IE intervention will be determined using the home blood pressure data (measured using an automatic upper arm blood pressure monitor [Omron M3 Intellisense, Kyoto, Japan] at weeks 4, 12 and 24) recorded in the participants diaries and comparing this against their observed baseline (recorded at day 1). This data will also be used to estimate BP variance by calculating the difference in systolic BP change from baseline at each endpoint between the isometric exercise and control group with 80% and 95% confidence intervals.
Accuracy of IE protocol delivery will be determined using data from three fidelity assessments; the first being healthcare professional competency checks administered during their isometric exercise prescription training; the second being expert observation /evaluation of at least the first IIET delivered by each HCP; and then finally, by third party examination of the first week of heart rate data recorded in the study diaries of each HCP’s specific participants, with average HR calculated from the first 3 sessions being compared against the individuals target training HR as described above.
Execution of the IE training protocol in the home will be assessed for each individual participant at the end of the first week by checking to see if their mean training heart rate per week falls within target heart rate range / reference interval (76-111%) data for weeks 4, 12 and 24 will now be assessed at the end of the 6-month training period. An estimate of the short- (4-week) and medium-term (3- and 6-month) adherence rates to IE training will be based upon the data collected from participant diaries to calculate the proportion of participants completing ≥two thirds of all IE sessions (12, 36 and 72) at each time point respectively. Patient recruitment and participant attrition rates will be calculated based upon the average number of participants recruited per week over the 7-month recruitment period and the number of withdrawals from the study once the last follow-up call to the last participant has been made.
Participant experiences of IE will be assessed through a quantitative online survey conducted at week 4. All participants receiving the IE intervention will be invited to take part in one of two focus groups (remote) to draw out respondents’ attitudes, feelings, beliefs and experiences regarding the intervention (40). This will also be used as an opportunity to explore possible negative effects of COVID-19 on recruitment rates and participation. These groups will be held at month 4 and month 8 of the recruitment period with 6-8 participants in each group. One focus group will also be undertaken with healthcare professionals involved in the intervention delivery at the end of the recruitment period to explore views and experiences of the IE intervention. Lay and professional members of the research team will co-produce the topic guide and co-facilitate the focus groups. The focus groups are proposed to last for between 60-90 minutes. The groups will be digitally recorded and transcribed. Telephone interviews (n=5-10) will be conducted with stakeholders from GP practices which are not recruitment sites and not involved in the intervention delivery to explore the willingness of GPs and primary care healthcare professionals to consider IE as a viable treatment option for patients, including barriers and facilitators for delivering and integrating this within an NHS care pathway for hypertension.
The economic evaluation of delivering the IE intervention will be calculated once the last follow-up call has been made to the last participant and will be estimated from Healthcare resource use data and quality-adjusted life years (QALYs). Since QALYs are the primary outcome of the economic evaluation, utility values will be obtained from patients’ responses to each of the EQ-5D-5L at the beginning of the intervention and at week 4, and months 3 and 6 after the intervention (41-42).
New insight into the accuracy of home BP measurements to monitor changes in BP will be based upon the BP data (observed and home readings) recorded (at Baseline Assessment - Day 1, Assessment 2 - Week 4, Assessment 3 - Month 3 and Assessment 4 - Month 6) in the participant diaries; along with expert evaluation of the participants ability to carry out the measure.
Plans to promote participant retention and complete follow-up {18b}
Participant adherence will be measured as outcome data including the number of IE sessions completed. Completion of at least 8 of 12 sessions between baseline and the 4-week timepoint will be deemed adherence to the intervention. The percentage of completed IE sessions that meet the required target HR threshold will be calculated. The percentage of participants that deviate from protocol will be recorded to assess fidelity to the IE programme. The rate of healthcare professionals that pass the competency assessment after the half-day training session will be calculated.
Data management {19}
Data entered directly into paper case report forms is considered as source data, additional source documentation includes participant study diaries, online questionnaires and focus group/ interview audio recordings and transcripts. Data from case report forms and participant diaries will be entered manually into the database allowing for data monitoring and cleansing. Questionnaire data will be received and directly accessible online by only research team members who have the appropriate access. Case report forms will be shared with the coordinating center via password secured email and a copy retained securely at site. A unique code will be produced for each participant and used on all corresponding documentation and files, to ensure anonymity.
Confidentiality {27}
Only anonymised data will be shared with the coordinating centre for analysis. Electronic files with personal information will be password protected and stored on the university partner networks in folders that can only be accessed by the research team. Access to the data collected during the project (including any participant personal data) will be restricted to the research team, and data will not be shared with anyone else. Personal information that may enable the service user to be identified will be removed from interview and focus group transcripts.
Any personal data will be destroyed on completion of the project. The coded data will be stored for five years following the completion of the study, when it will be destroyed.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Quantitative data analysis
Descriptive statistics will be used to assess primary and secondary process outcomes such as recruitment rates, adherence rates and completeness of data. Exercise adherence will be compared with outcomes to inform compliance criteria in the full study. In a definitive study, the primary outcome – change from baseline in systolic BP – will be analysed using analysis of covariance (ANCOVA), with a fixed treatment effect allowing adjustments for baseline values, centre, sex and age. This model will be used to estimate differences between the arms and confidence intervals from the feasibility study. 80% and 95% confidence intervals will be calculated. Data from the IE experience questionnaires will be transferred to SPSS (v24) and analysed using descriptive statistics.
Qualitative data analysis
Thematic analysis of focus group/interview transcripts will be carried out using Braun and Clarke’s (2013) six stage model using NVIVO v11 (43). Drawing on Sweeney et al.’s (44) notion that the service user researcher unique perspective should be preserved rather than subsumed, the process will involve multiple members (including public co-applicants) of the project team. Inductive thematic analysis of focus group/interview transcripts will be carried out using NVIVO 11. The process will involve reading and re-reading the transcripts and noting down initial ideas. Then the transcripts will be coded. Data extracts will be collated within each code and then codes ordered into potential themes. Subsequently, these themes will then be reviewed and refined. Ongoing analysis will refine the specifics of each theme and identify any themes which have not previously been recognised. Deviant case analysis will be used to ensure that perspectives that diverged from dominant trends are not overlooked.
Interim analyses {21b}
Not applicable
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not applicable
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Baseline observation carried forward will be used in the secondary analysis of intention to treat.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Anonymised data will be made available to researchers at universities, NHS organisations or other healthcare providers where the sharing of data has a clear defined purpose and its use will be of benefit to wider society.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Delivery of the project is a collaboration between the Section of Sport, Exercise & Rehabilitation Sciences, Canterbury Christ Church University (CCCU), the Centre for Health Services Studies, University of Kent (UKC) and East Kent Hospitals University Foundation Trust (EKHUFT).
Two groups were established to provide appropriate oversight of the study and ensure this is maintained from various perspectives, the Study Steering Committee (SSC) and the Project Management Group (PMG).
The SSC is comprised of at least 75% independent members and includes the project co-leads, an independent statistician, a health economist, a clinician with expertise in hypertension/clinical trials/primary care, an exercise specialist and two independent lay members. The SSC meets tri-monthly to: critically oversee progress, outputs, deliverables and governance of the project; have oversight of delivery of the study on behalf of the funder to ensure achievement of study objectives within agreed timelines; ensure the protection of rights and safety of study participants; regularly review of ongoing project data; periodically review of safety data to ensure patient safety throughout (45). In doing so, the SSC reports directly to the funder. The SSC will consider the need for any interim analysis based on reports received and may consider dat emerging from other related studies and make recommendations for this study based on these. The SSC will also consider whether further time or funding is required for any aspect of the study and advise where best this may be obtained.
The PMG is comprised of 2 co-chief investigators, 4 co-applicants (including the project manager), 1 statistician, 1 health economist, 2 public co-applicants, 1 research facilitator and 1 study coordinator (45). The members of PMG were responsible for the elaboration of this protocol and meets fortnightly with the purpose of: maintaining clear oversight of study delivery according to the protocol, original grant application and subsequent changes; assessing the progress of the study and identifying any barriers to completion; agreeing mitigation plans and actions for any barriers to study completion e.g. the current Covid-19 pandemic; providing advice to the Chief Investigators; ensuring the protection of rights and safety of study participants; and reporting on study progress to the SSC and funder.
The organizational study chart will include the sponsor EKHUFT, the SSC, the PMG, the two research units; UKC as lead on Qualitative data (health economics, focus group, interviews, patient participant involvement etc.) and CCCU as lead on quantitative data (intervention delivery, fidelity and patient outcomes etc.), the clinical research lead and the investigators at each primary care recruitment sites in SE England.
Composition of the data monitoring committee, its role and reporting structure {21a}
A data monitoring committee is not needed for this study because the intervention is non-invasive with minimal risk of harm.
Adverse event reporting and harms {22}
Only adverse events (AE) resulting (definitely or probably) from study procedures or the intervention will be collected by the research team and recorded in the participant’s medical records. All serious adverse events (SAEs) will be recorded within 24 hours of knowledge of the event. The Chief investigator will report all SAEs to the Sponsor and the Research Ethics Committee within the conditions of ethical approval. The Study Steering Committee will periodically review safety data to ensure patient safety throughout.
Frequency and plans for auditing trial conduct {23}
Regular monitoring will be performed by the Study Coordinator to evaluate compliance with the protocol. Monitoring will verify that the study is conducted, and data are generated, documented and reported in compliance with the protocol and the applicable regulatory and national policy requirements (45). Any data issues will be addressed by raising data queries for GP sites to resolve where possible, following this on-site monitoring will be undertaken. Direct access will be granted to authorised representatives from the Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits and inspections- in line with participant consent.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any substantial amendments to the protocol or other study documents may require review and approval by the REC before the changes can be implemented to the study. Where amendments are required, NHS HRA and REC procedures will be followed.
Dissemination plans {31a}
Results will be presented at national and international conferences (e.g. UKactive Summit) and findings published in high-impact, open access peer-reviewed journals in the field where the project team’s previous work has been well received (e.g. Hypertension, Journal of Human Hypertension, Journal of Hypertension, Journal of Applied Physiology, PLOS Medicine, British Medical Journal).
Study participants will receive a personalised report of their own results and a summary of study findings will also be sent to GP practices and local organisations (E.g. Canterbury and Costal Clinical Commissioning Group, EKHUFT, Kent and Medway STP, Kent AHSN and NIHR CRN:KSS). The study final report will be submitted and a lay summary disseminated to a wider audience to create national impact by engaging with policy and national governing body organisations (e.g., Public Health England, The National Institute for Health and Care Excellence, National Centre for Sport & Exercise Medicine), third sector organisations (e.g. British Heart Foundation, British Hypertension Society) with the aim of understanding the evidence required to influence current hypertension treatment guidelines with respect to offering lifestyle interventions like IE as standard care and a tangible product that can be marketed in the NHS.