Self-Assessment Method for Statin Side-effects Or Nocebo

Participants: 50 participants will be recruited to the trial.

Method: At baseline each participant will have a detailed interview with the study doctor to assess past medical history and previous symptoms attributed to statins and assess if they are eligible to be enrolled. Eligible participants will be enrolled and allocated a random predefined order to take the study interventions in. These random codes will be generated by the trials unit statistician and supplied to the production pharmacy. The participant will be dispensed High Density Polyethylene (HDPE) containers which are in this pre-specified order. Each participant will receive 12 sets of HDPE containers pre-labelled. 4 sets of HDPE containers will contain no medication, 4 will contain 1-month supply of matched placebo and 4 will contain 1-month supply of atorvastatin 20mg. At the start of the next calendar month after the screening visit the participants will commence the trial intervention. The research nurse will call the participant to remind them to start on the 1st day of the next month after screening. Each day participants will rate their daily symptom on a phone application and will also complete 3 additional questionnaires on a monthly basis. The study nurse will call the participant at the end of each month to assess their progress in the trial. Each participant will return their boxes at dispensing visits (if applicable) and at the study end in order for a pill count to be undertaken to assess medication adherence. The placebo and atorvastatin pills will be visually identical.

The study enrols participants not intending to re-start clinical use of statins. Participants' other medications will continue to be managed as normal by their own physicians, with no restriction on starting, stopping or changing doses. For safety reasons the participant's own physician will be asked to consult the investigators prior to consideration of starting, or amending the dose of, any other lipid lowering medication.

For the trial, each participant will receive a smartphone, or if preferred, can have the application downloaded to their existing phone to allow real-time daily documentation of symptoms experienced on a visual analogue scale of 0-100. Participants will receive training on the simple touch-screen interface and a leaflet with further information will also be provided. Participants will rate symptoms every day, with the daily scores aggregated into a monthly score. This is preferable over scoring only once a month, because participants may struggle to remember and aggregate their symptom burden especially if it varies between days.

Each month participants will fill out two validated questionnaires on the impact of their side-effects on their quality of life. These are EuroQol (EQ-5D-3L), a well-validated measure of health related quality of life, and the Treatment Satisfaction Questionnaire for Medicine (TSQM) questionnaire, a validated treatment satisfaction questionnaire. EQ-5D-3L assesses five domains of health and overall self-rated health using a visual analogue scale. EQ-5D-3L is conventional for assessing efficacy of medication on quality of life but may not be sufficient for assessing side effects, therefore the TSQM questionnaire will also be used. Use of both a health related quality of life questionnaire and a treatment satisfaction questionnaire will allow assessment of participants' multiple health states, overall self-rated health status and treatment satisfaction, and provide a test of both convergent validity and measurement invariance for the monthly aggregate symptom burden score.

The investigators will also ask participants to fill in a short questionnaire detailing any potentially their own physicians, with no restriction on starting, stopping or changing doses For safety reasons the participant's own physician will be asked to consult the investigators prior to consideration of starting, or amending the dose of, any other lipid lowering medication.

• Atorvastatin (Drug), also known as HMG CoA reductase inhibitors, Statins: Atorvastatin 20mg tablets taken orally once daily for one month.
• Placebo (Other): Placebo tablets taken orally once daily for one month

Primary outcomes

• Mean Symptom Scores Across Statin, Placebo and no Treatment Periods [12 months]: The full scale name would be "daily symptom score" measuring patient-reported symptoms on a scale from 0 (no symptoms) to 100 (worst imaginable symptoms). The unit of measurement would be "scores on a scale". The mean symptom scores for the four months on each arm will be calculated: placebo, Atorvastatin 20mg and no treatment. Mean symptom scores across statin, placebo and no treatment periods is calculated. There are no subscales/subranges.

Secondary outcomes

• Number of Participants Currently Being Prescribed Statins [At 6-months after the end of trial up to 7-months]: Following the end of the trial, is the trial participant taking statins or not.
• Attribution of Adverse Symptoms [6-months after end of trial]: Following the end of the trial, whether individual trial participants currently believe that most of the side-effects previously attributed to the statin, were indeed a pharmacological effect of the statin.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Aged 18 years or older
* Previously taken one or more statins
* Withdrawn from statins because of perceived side effects
* Developed side effects within 2 weeks of initiation
* Clinical indication for statins for primary or secondary prevention of cardiovascular disease or dyslipidaemia, on either no medication or non-statin lipid lowering therapy (e.g, ezetimibe)

Exclusion Criteria:

* History of neuropathy
* Regularly taking prescribed analgesia
* History of a chronic pain condition
* History of severe mental illness (as their experience of symptoms may already be altered)
* Current use of fibrates (because of the risk of interaction with statins; will not exclude participants taking ezetimibe).
* Severe previous reaction or reaction considered immunological, such as anaphylaxis, facial swelling, severe rash, muscle ache with rise in serum creatine kinase, inflammatory myopathy, rhabdomyolysis or liver function abnormalities (aspartate transaminase (AST) or alanine transaminase (ALT) greater than 3 times upper limit or normal).
* Side-effects taking longer than 2 weeks to develop (because in such participants much longer blocks of treatment would be required; if the present study is positive such studies will be planned for the future).
* History of statin intolerance with drug interaction to antiretroviral drugs.
* Currently taking antiretrovirals with known interaction to statins
* Currently taking any drug other than antiretrovirals with known interaction to statins
* Side effects taking longer than 2 weeks to present.
* In clinical judgement of study doctor, participant should not participate.

Participant flow

Outcome results

• Mean Symptom Scores Across Statin, Placebo and no Treatment Periods (Primary), Mean, units on a scale: Atorvastatin 20mg Daily 16.3 (13.0 to 19.6); Placebo 15.4 (12.1 to 18.7); No Treatment 8.0 (4.7 to 11.3)
• Number of Participants Currently Being Prescribed Statins (Secondary), Count of participants, Participants: Atorvastatin 20mg Daily 30; Placebo 0; No Treatment 0
• Attribution of Adverse Symptoms (Secondary), Number, participants: Attribution of Side Effects 6-months After End of Trial 22

Adverse events

Time frame: 12-months of the trial and for six-months post-trial until the participant had completed their end of study plus six-month visit.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: To be eligible for the trail, patients' previous perceived side effects whilst taking statins must have arisen within 2 weeks of commencing the drug. This is to ensure the 1 month long blocks are long enough that symptoms would be expected to arise. Patients whose symptoms take longer than 2 weeks to arise were not eligible for this study.

• Results publication: Howard JP, Wood FA, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, Rajkumar CA, Connolly S, Cegla J, Stride C, Sever P, Norton C, Thom SAM, Shun-Shin MJ, Francis DP. Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. J Am Coll Cardiol. 2021 Sep 21;78(12):1210-1222. doi: 10.1016/j.jacc.2021.07.022. PMID 34531021

• Study Protocol (PDF, 2020-04-10)
• Statistical Analysis Plan (PDF, 2020-01-14)

• Darrel P Francis, MB MD, Principal investigator, Imperial College London

NIH grants: 2015