Title: Statin Web-based Investigation of Side Effects Trial (Statin WISE Trial)
Funder: Department of Health and Social Care

Abstract: Aims: To determine whether muscle adverse events attributed to statin use by patients are caused by statins. Design: A series of N-of-1 randomised double blind placebo controlled trials Setting: UK primary care Target population: Patients who have recently stopped using statins or are considering stopping statin use due to perceived adverse effects. Health technologies being assessed: Statin medication (atorvastatin 20mg) will be compared to a placebo control. Participants will receive six two-month treatment blocks of either statin or placebo, with the order of treatments randomly allocated. Measurement of outcomes: Outcomes will be measured on a visual analogue scale (0-100mm) using a bespoke mobile application, pen and paper diary, online submission portal or by patients speaking directly with the Clinical Trial Unit. The primary outcome will be muscle symptoms (pain, weakness, tenderness, stiffness or cramp) and we will include other symptoms as secondary outcomes (joint pain, headache, gastrointestinal symptoms, exercise tolerance, fatigue and sleep disturbance). Measurement of outcomes will be daily during the last 7 days of each treatment period. Secondary outcomes will be collected using a questionnaire at the end of each treatment period and will explore symptoms in more detail, including frequency, intensity and possible causes. Sample size: Our study has recruited the target of 200 participants and is now closed to recruitment (update as of 11th June 2018). Power calculations conducted via Monte Carlo simulation, based on published pilot data for 8 participants,[1] indicate that 200 participants will give in excess of 90% power to detect differences of at least 10mm (the lower confidence limit of the minimum clinically important difference[2]) on the visual analogue scale between statin medication and placebo, after allowing for withdrawal from individual N-of-1 trials. Statistical analysis: Participants will be shown numerical and graphical summaries of their data, in relation to their statin and placebo periods. Data from 200 participants will be aggregated to form a powerful dataset and analysed using linear mixed models with a random participant effect and fixed effects for period and treatment. Residual errors will be modelled using an auto-regressive error structure within each treatment period to account for correlation between the seven daily measurements. Project timetables including recruitment rate: This study is anticipated to be completed within 3.5 years. The first seven months was spent finalising the protocol, gaining ethics and NHS approvals, and piloting all trial logistics, including further piloting of the mobile application and data collection methods. Feasibility calculations show that in an average-sized practice, 35 patients per year would be eligible for the trial, of whom five would be likely to participate. 67 practices have taken part in identifying and recruiting patients, from the Clinical Research Networks Primary Care Specialty. The recruitment target was met in April 2019. Each participant will be randomised to one year of treatment. The final six months of the project will be spent collating and analysing the data, writing the manuscript for publication and disseminating results. Expertise in team: This application was developed by a multi-disciplinary team comprising of senior clinicians, patients, trialists, epidemiologists and statisticians. Specifically, the team includes experts in delivering randomised controlled trials, experts on statins and adverse effects, a GP and primary care research specialists.

Lay abstract: Background: Statins are drugs that lower cholesterol and reduce the risk of heart attacks and strokes. They are the most commonly prescribed treatment in the UK. Recently, updated NICE recommendations increased the number of people eligible to receive statins by over 2 million. Statins are known to cause very rare but serious side effects such as rhabdomyolysis (breakdown of muscle tissue) and its milder form called myopathy. Many patients stop taking statins due to less severe symptoms, such as muscle pain or fatigue. When investigating these less severe symptoms, trials have not found any differences in the numbers of people reporting them between those taking statins and those taking placebo. However, perhaps because people are warned about risk of the rare muscle breakdown, many patients believe that statins cause their muscle symptoms. Given the known effectiveness of statins in reducing heart disease and strokes, accurate data on the cause of symptoms experienced during statin use are needed to inform patients’ and doctors’ treatment choices. The proposed study will address this important uncertainty about statin therapy for patients and the population. Aim: To determine whether symptoms occurring during statin use are caused by statins. Methods: We propose a trial investigating side effects of statins compared to a matching placebo. We have recruited the target population of 200 participants, who have all recently stopped or wish to stop taking statins due to unwanted muscle symptoms. Each participant will be taking study medication for one year, split into six two-month treatment periods. In each period, the participant will be randomly allocated to take statins or matching placebo. This is called an ‘N-of-1’ trial. Two months is sufficient for short-term side effects to emerge, and the trial’s one year duration is brief enough to minimise any adverse impact on cardiovascular outcomes from under-treatment. Participants will be asked to submit outcome data for one week at the end of each treatment period using a specially-designed mobile application, pen and paper diary, online submission portal or by patients speaking directly with the Clinical Trial Unit. Outcomes will be self-reported symptoms using a visual sliding 0-100 scale for muscle pain, weakness, tenderness, stiffness or cramps linked to statins. A questionnaire will explore symptoms in more detail. Non-responders will be prompted by email, text, post or phone. GPs will report serious adverse events to the study team. Participants will be recruited through general practices. At the end of their 12 month follow-up, participants will be given a summary of their own individual study results. This results document will also be given to the patients General Practitioner (GP) or trial nurse to help them understand their data, which we hope will help the patient to decide whether to continue taking statins. We will also combine the results from each participant to perform an analysis and formally assess the extent to which statins cause muscle symptoms at the population level. Patient and public involvement: A panel of patients and the public will be convened to advise on preparation of study documentation and ensure that patient needs are met during the main study phase. They will also take part in the management committee of the study. Dissemination: The results of this study will be published in scientific journals and will be presented to patient and GP groups at formal meetings and in written reports. We will use social media and will target medical correspondents of newspapers and magazines, in this country and overseas, to draw attention to our results.

Research activity codes: 6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR