Plain English Summary
Background and study aims
Cholesterol is essential for the body to work well, but too much ‘bad cholesterol’ (called low-density lipoprotein or LDL) is unhealthy. High levels of ‘bad cholesterol’ in the blood can lead to fatty deposits building up in our arteries. This can increase the risk of developing cardiovascular disease, which includes conditions such as coronary heart disease (leading to angina and heart attack) and stroke. Statins are drugs that are used to reduce the amount of ‘bad cholesterol’ the body makes while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL). Statins are the most commonly prescribed treatment in the UK. Recently, the number of people eligible to receive statins increased by over 2 million due to updated National Institute for Health and Care Excellence recommendations. Statins are known to cause rare but serious side effects such as rhabdomyolysis (breakdown of muscle tissue) but many patients stop taking statins due to less severe symptoms, such as muscle pain or fatigue. Trials have not found any differences between those taking statins and those taking placebo in terms of these less severe muscle symptoms, but some have questioned whether the information collected was adequate. Given that it is known that statins can reduce heart attacks and strokes, it would be helpful to know how frequently the symptoms experienced during statin use are related to the statin and how frequently related to other causes. This will help inform patients’ and doctors’ treatment choices. This study is looking at side effects of atorvastatin compared to a matching placebo (dummy pill).
Who can participate?
Patients who have recently stopped or wish to stop taking statins due to unwanted muscle symptoms.
What does the study involve?
Each participant is initially randomly allocated to either the atorvastatin group or placebo group. They are all recruited into in the study for one year, split into six two-month treatment periods. Each patient is sent their treatment though the post and asked to take it every day for the duration of the study. For the first six months, they receive one treatment. For the second, they receive the other. So, for example, the participants initially in the atorvastatin group will receive the placebo for the second half of the study. This allows them to act as their own control, so at the end of the study, they are able to compare their own level of symptoms between the statin and placebo treatment periods and use this information to help decide the best treatment options. This is called an ‘N-of’1’ study. Two months is enough for short-term side effects to emerge, and the study’s one year duration is brief enough to minimise any adverse impact on cardiovascular outcomes from under-treatment. There is no break between the two treatments (i.e.wash-out period) but symptoms are measured at the end of each treatment period to ensure that they reflect the current treatment. At the end of each two-month period, patients are asked to submit symptom information using a specially-designed mobile app; outcomes are self-reported side effects. If patients are unable to use the mobile app, data can be submitted directly online by the patient or answers to the questions obtained by a researcher through a telephone call. Patients are free to choose a suitable method of follow-up. Patients are reminded to submit symptom information prior to each data collection period. This will be done by email, text, and phone calls. At the end of the trial, patients are shown summaries of their individual results, to help them to decide whether to continue taking statins. Symptom reports are collected 3 months later to assess whether this information impacts subsequent treatment choices and symptom severity.The results are combined from each individual to assess how frequently statins are causing side effects in people who perceive themselves to be intolerant. As part of the study, patients are asked to provide a blood sample for an optional genetic analysis as part of a larger collaborative effort investigating genetic associations with statins effects. Specific results will not be fed back to clinicians or to patients.
What are the possible benefits and risks of participating?
Not provided at time of registration
Where is the study run from?
The Keats Group Practice, London (UK)
When is the study starting and how long is it expected to run for?
April 2016 to April 2019
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
1.Professor Liam Smeeth (scientific)
2. Dr Nabila Youssouf (public)
Prof Liam Smeeth
London School of Hygiene and Tropical Medicine
Dept of Non Communicable Diseases
Dr Nabila Youssouf
Clinical Trials Unit
Faculty of Epidemiology & Public Health
London School of Hygiene & Tropical Medicine
0207 958 8195
A series of randomised controlled N-of 1 trials in patients who have discontinued or are considering discontinuing statin use due to muscle-related symptoms to assess if atorvastatin treatment causes more muscle symptoms than placebo.
Statins are the most commonly prescribed treatment in the UK. Recently updated NICE guidelines have lowered the threshold for statin use to include all patients with a 10% or greater 10-year risk of cardiovascular disease. Previous randomised trials have established the prevalence of serious adverse effects of statins such as rhabdomyolysis, however, many patients discontinue statins due to less severe symptoms, such as muscle pain or fatigue. Randomised trials have shown no differences between those taking statin and placebo in terms of the prevalence of these side effects (approximately 9%), but currently there is no pathway of care for clinicians to empirically and objectively evaluate whether symptoms reported by a statin-user are caused by the statin itself or the so-called ‘nocebo’ effect (symptoms reflecting patient expectation of side effects). Given the effectiveness of statins in preventing cardiovascular disease, accurate data on the cause of symptoms experienced during statin use are needed to reliably inform patient and clinician about continuation of use. The proposed StatinWISE trial will provide definitive answers to this important uncertainty about statin therapy.
Not provided at time of registration
A series of randomised, double-blinded N of 1 trials.
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet. StatinWISE Study Team Tel: 0207 299 4684 Email: Statinwise@lshtm.ac.uk
Statinwise is a randomised, double blind, placebo controlled N-of-1 trial taking place in a primary care setting, to quantify the occurrence of self-reported muscle symptoms whilst taking daily atorvastatin. A total of 200 patients who fulfil the eligibility criteria will be recruited. The trial treatment consists of once daily oral administration of Atorvastatin (20mg) capsules, which will be compared with matching placebo (Microcrystalline Cellulose). The treatment phase of the trial will be one year in duration for each patient. A blinded placebo, identical in size, colour, smell and packaging to the active statin, has been chosen to prevent knowledge of treatment from affecting symptom scores.
Patients will receive their allocated trial medications through the post and they will be asked to take the study medication daily through the six two-month treatment periods. Ideally there should be no break between treatment periods. However, if for any reason there is a break; patients can simply restart taking the trial medication as soon as possible.
Patients will be asked to take one capsule orally once daily at a time of day convenient to them. Capsules should be swallowed whole. Patients will be given written instructions on how to take the study medication. At the start of each two month treatment period, patients will be asked to inform the trial team about their first date of study medication use using the trial’s mobile application (app), email, text message, Freephone telephone service or a pre-paid postage reply slip, whichever is easier to ensure data collection occur on the correct days. A Freephone telephone number will be provided for patients to call if they have any questions. Adherence to the study medication will be collected on the same days as other data as part of the outcome data collection.
During the last week of treatment period, the Research Nurse will contact patients to thank them for their participation so far, inform them that this is the last treatment period, and that they, together with their GP, will receive their individual results at the beginning of month 14. The Research Nurse and patient will arrange a telephone or face to face appointment to discuss the individual results during month 14. The Research Nurse will also inform patients that if they want to continue taking statin without a break, to arrange a separate clinical appointment with their GP prior to the end of the treatment period.
At month 15, trial staff will email/telephone the patient to document their decision on future statin use and whether their results helped reach this decision. This will be the last data collection point of the trial.
Throughout the trial, continued patient care will be at the discretion of their GP. In primary care, the patient will be recorded as having an ongoing statin prescription.
1. Where treatment with an interacting drug is needed that will be for less than one-month duration, the patient will be asked to stop the trial treatment for that period.
2. Where treatment with an interacting drug is needed for longer than one month, the patient will be asked to withdraw from study treatment completely.
This will be the last data collection point for the study.
Primary outcome measures
Muscle symptoms (pain, weakness, tenderness, stiffness or cramp) reported every 7-week during treatment, measured using the Visual Analogue Score (VAS) score
Secondary outcome measures
Relationship between individual trial result and patient decision whether to continue statins long term at month 15, measured by checking if a statin prescription was issued by the General Practitioner.
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Adults (aged 16 and over)
2. Prescribed statin treatment in the last 3 years
3. Stopped OR considering stopping statin treatment due to muscle symptoms
4. Provided fully informed consent
Target number of participants
Participant exclusion criteria
1. Any previously documented serum alanine aminotransferase (ALT) levels at or above three times the upper limit of normal
2. Have persistent, generalised, unexplained muscle pain (whether associated or not with statin use) and have creatinine kinase (CK) levels greater than 5 times the upper limit of normal
3. Should not be using atorvastatin 20mg daily in the opinion of the general practitioner
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
The Keats Group Practice
1B Downshire Hill
National Institute for Health Research
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
The trial protocol and results will be published in peer-reviewed journals. All publications will follow the CONSORT statement.21 Links to the publication will be provided in all applicable trial registers. Dissemination of results to patients will take place via the media, trial website and relevant patient organisations. Collaborating investigators will play a vital role in disseminating the results to colleagues and patients.
The success of the trial depends entirely upon the collaboration of nurses and doctors in the participating practices and those who hold key responsibility for the trial. Hence, credit for the study will be assigned to the key collaborator(s) from a participating site as it is crucial that those taking credit for the work have actually carried it out. The results of the trial will be reported first to trial collaborators.
Intention to publish date
Participant level data
To be made available at a later date
Results - basic reporting