Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON)

Front-line clinicians cannot currently test for an individual participant whether symptoms experienced are the pharmacological result of a statin or due to other phenomena. In this trial, participants who have previously ceased statins due to side effects will be offered the opportunity to undergo twelve randomly ordered 1-month periods. There will be four periods of no medication, four periods of placebo and four periods of statin. The placebo and the statin pills will be identical in appearance. Participants will record on a daily basis side-effects experienced. At the end of the study, the one-month sessions are sorted into the order shown above. The participant can then observe directly how much of the increase in symptoms seen with statin is also seen with placebo.

1. Hypothesis 1: that >30% of participants enrolling for the study will complete it.
2. Hypothesis 2: Overall >50% of symptom burden is nocebo rather than pharmacological
3. The investigators will define the Nocebo proportion of side effects.
4. Hypothesis 3: that the majority of participants, at 6 months after completion, will either be taking statins or have declined statins for reasons other than perceived side effects.

Study Overview

• Status: Unknown
• Conditions: Cardiovascular Diseases; Hyperlipidemias; Adverse Effects
• Intervention / Treatment: Drug: Atorvastatin; Other: Placebo

Detailed Description

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 on InForm which will allocate each participant 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 assigned on inform. 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 and thereafter the participants will also receive a monthly reminder on their phone to switch to the next set of HDPE containers each month. 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 participants 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 enrolls 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

3.4 STUDY OUTCOME MEASURES 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. There is an optional daily reminder that can be disabled if intrusive. 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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, W12 0HS
      • Imperial College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 but 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.
• History of statin intolerance to any other drug.
• Pregnant or breast feeding.
• Side effects taking longer than 2 weeks to present.
• In clinical judgement of study doctor, participant should not participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Atorvastatin 20mg Daily; Atorvastatin 20mg daily for 1 month	Drug: Atorvastatin; Atorvastatin 20mg tablets taken orally once daily for one month.; Other Names: HMG CoA reductase inhibitors; Statins
Placebo Comparator: Placebo; Placebo daily for 1 month	Other: Placebo; Placebo tablets taken orally once daily for one month
No Intervention: No Treatment; No Atorvastatin or placebo for 1 month

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Individual Nocebo Proportion	The individual nocebo proportion will be calculated at the end of the 12-months of the trial for each participant. The mean symptom scores for the four months on each arm will be calculated: placebo (mN) , Atorvastatin 20mg OD (mA) and no treatment (mZ). The Nocebo Proportion is (mN-mZ)/(mA-mZ). Let the averages of these standard deviations be respectively sA, sN, sZ. As long as mZ is small compared to mA and mN, and sA is not large in relation to mA, a reasonable approximation to the fractional standard error of the nocebo proportion will be calculated: (mN-mZ)/(mA-mZ) is (sA/mA + sN/mN) /112.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Currently prescribed statins	Following the end of the trial, is the trial participant taking statins or not.	6-months after end of trial
Attribution of adverse symptoms	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.	6-months after end of trial

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: Darrel Francis, MB MD, Imperial College London

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): March 15, 2020
• Study Completion (Anticipated): September 1, 2020

Study Registration Dates

• First Submitted: January 19, 2016
• First Submitted That Met QC Criteria: January 26, 2016
• First Posted (Estimate): January 29, 2016

Study Record Updates

• Last Update Posted (Actual): August 10, 2020
• Last Update Submitted That Met QC Criteria: August 7, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: cardiovascular diseases; hyperlipidemias
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Cardiovascular Diseases; Hyperlipidemias; Hyperlipoproteinemias; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Other Study ID Numbers: 15SM2947; 2015-004109-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No