RATIONALE AND OVERVIEW 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 Trial protocol code: ISRCTN30952488 Version 4, 21 Nov 2017

Background Statins are the most commonly prescribed treatment in the UK NICE guidelines1 recommends statins to all patients >10% ten-year risk of CVD 2m new statins users High prevalence of SAEs (rhabdomyolysis) but many patients stop statins due to less severe effects (muscle pain; fatigue) 1 National Institute for Health and Care Excellence (NICE) Clinical Guideline CG181, September 2016

Statins and muscle pain Research Observational unblinded studies participants expect adverse effects reporting of symptoms may be higher than in a statin-free population, but unrelated to therapy “nocebo” effect1 Severe statin adverse effects are extremely rare (rhabdomyolysis 0.1 and myopathy 0.5 per 1000 people over 5 years). However, there has been widespread reporting of other less well-defined statin-related symptoms in the media, notably muscle pain and weakness. These reports have largely been prompted by data from non-randomised, non-blinded observational studies, but have not been confirmed in blinded randomised controlled trials (RCTs). 1 Barsky et al. Nonspecific medication side effects and the nocebo phenomenon. JAMA 2002; 287(5): 622-7.

cont… Two BMJ articles1,2 in 2013 suggested side effects of statins may outweigh benefits Media coverage grew through early 2014 Internet searches increased3 August ‘17 1 Abramson et al. Should people at low risk of cardiovascular disease take a statin. BMJ 2013;347:f6123 2 Malhotra et al. Saturated fat is not the major issue. BMJ 2013;347:f6340

cont… # of patients starting and stopping statin therapy impacted3 Impact sufficient to lead to an additional 2000 – 6000 heart attacks1 11 % 12 % 1 Mathews et al. Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data. BMJ 2016;353:i3283

Why are we doing this trial? To assess whether atorvastatin 20mg treatment causes more muscle symptoms than placebo

StatinWISE Recruitment 58 GP Practices in England and Wales 200 patients Target recruitment = 5 patients per site No maximum Research cost of paid in quarterly instalments (following first patient recruited) Service Support Cost from CRN (confirm with your CRN)

Data Collection (by Patient) Protocol Overview Patient identification route 1 Research Nurse - database search with GP Clinical eligibility check Research Nurse / site admin  Docmail to patient mail out 0 (Invitation / reply slip & newsletter) mail out 2 (Invitation / reply slip & PIS) mail out 3 (Invitation / reply slip & PIS & newsletter) Patient direct contact with Practice / Research Nurse or CTU (reply slip) CTU to site with reply slip Research Nurse follows up with patient, confirming eligibility Patient identification route 2 Patient Self Referral / Opportunistic e.g. during GP consultation / response to website / Practice adverts / PIS from reception Direct contact to Practice / Research Nurse / CTU or Research Nurse follows up from EOI log at reception CK / ALT bloods Screening visit, consent and randomised Data Collection (by Patient) Confirmation of treatment pack receipt (every two months) Days 50-56 of each treatment period (every two months) Complete one daily symptoms questionnaire per day Day 56 of each treatment period (every two months) Complete one end of treatment period questionnaire Adherence to treatment Serious Adverse Events (SAE) reporting Pain questionnaire Treatment period 1: Statin or placebo 12 months Treatment period 2: Statin or placebo Treatment period 3: Statin or placebo Treatment period 4: Statin or placebo Questions to ask: Role of GP Role of Research nurse Eligibility Treatment period 5: Statin or placebo 1. Telephone with CTU 2. Paper (CTU to post, we remind) 3. Online (link sent, we remind) 4. Mobile phone app (android only) Treatment period 6: Statin or placebo Month 14: Patient receives their own personalised results End Of Trial Individual results disclosed to GP / Research Nurse and Patient (by phone or in person) and decision taken on ongoing statin therapy Month 15: Final contact with patient to learn if patient is continuing to take statins

Identifying patients EMIS database search Eligibility Those stopped statins and [database search], Those considering stopping (waiting room adverts [log at reception] / GP consultation / database search) Issues cant really capture patients considering stopping (opportunistic patients) Questions: Who will run the search How will you manage the Eligibility checking Has this already been sent to you – How many preliminary results came up?

Using Docmail to Invite Patients Once list of potentially eligible patients is given final approval by StatinWISE practice PI, site trial staff will send “mail outs” to patients, with 2-3 weeks in between each mailing: Scheduled Mail outs: Mail out “0” Invitation & newsletter & reply slip/prepaid envelope to CTU Mail out “2” Invitation & PIS & reply slip/prepaid envelope to CTU Mail out “3” Invitation & PIS & newsletter & reply slip/prepaid envelope to CTU Detailed Instructions on how to use Docmail are provided in Folder 1, Section 6 of the ISF Mail out “0a” is just the PIS and brief letter with reply slip and envelope when site trial staff just need to send the PIS to a particular patient Questions Do you use Docmail - Log in will be confirmed once we receive your delegation log Who should we sent EOI’s to?

Docmail: scheduled mailings Instructions – Folder 1, Section 6 of the ISF mail out 2 (Invitation / PISs & reply slip) mail out 0 (Invitation / newsletter & reply slip ) mail out 3 (Invitation / PIS / newsletter & reply slip) Questions Do you use Docmail - Log in will be confirmed once we receive your delegation log Who should we sent EOI’s to? All mailpacks contain reply slip and return envelope to CTU

Docmail: mailing 0a to send out PISs when needed mail out 0a (Invitation / PISs) Questions Do you use Docmail - Log in will be confirmed once we receive your delegation log Who should we sent EOI’s to?

“Opportunistic recruitment” Waiting room adverts “Opportunistic recruitment” Adverts in Study File Have pdf / PowerPoint / free text Key for each practice inform reception staff of study keep copies of PIS at reception catalogue EOI’s for RN to follow Question Do you think these will work Who will look after keep track of the EOI log?

“Opportunistic recruitment” GP reminders “Opportunistic recruitment” Extra's ‘Read’ code in practice system To alert GPs of trial participation Cover changes in drug prescription e.g. antibiotics Highlight statin user for GP - prompt to discuss StatinWISE Identify clinically eligible patients from search list

Data Collection (by Patient) Protocol Overview Patient identification route 1 Research Nurse - database search with GP Clinical eligibility check Research Nurse / site admin  Docmail to patient mail out 0 (Invitation / reply slip & newsletter) mail out 2 (Invitation / reply slip & PIS) mail out 3 (Invitation / reply slip & PIS & newsletter) Patient direct contact to Practice / Research Nurse or CTU (reply slip) CTU to site with reply slip Research Nurse follows up Patient identification route 2 Patient Self Referral / Opportunistic e.g. from website / Practice adverts / PIS from reception Direct contact to Practice / Research Nurse / CTU or Research Nurse follows up from EOI log at reception CK / ALT bloods Baseline visit, consent and randomised Data Collection (by Patient) 7 symptoms questionnaires every two months one per day on days 50-56 of each treatment period Once – one day 56 of each treatment period Adherence to treatment Serious Adverse Events (SAE) reporting Pain questionnaire Confirmation of treatment pack receipt Treatment period 1: Statin or placebo 12 months Treatment period 2: Statin or placebo Treatment period 3: Statin or placebo Treatment period 4: Statin or placebo Treatment period 5: Statin or placebo 1. Telephone with CTU 2. Paper (CTU to post, we remind) 3. Online (link sent, we remind) 4. Mobile phone app (android only) Treatment period 6: Statin or placebo End Of Trial Individual results disclosed to GP / Research Nurse and Patient (by phone or in person) and decision taken on ongoing statin therapy Within 3 months Trial results presented to patient Final decision recorded on End of Trial form

Baseline visit * Confirming eligibility * Patient attends the site for the Baseline visit with Nurse/GP Nurse/GP goes through PIS, re-explains the trial and answers any questions Informed consent must be recorded on Informed Consent form provided in Section 13 of the Investigator Site File Baseline data is recorded on the database Patient meets all eligibility criteria Patient is randomised Complete the Screening / Randomisation logs Patient changes their mind Patient does not meet all eligibility criteria Patient is not randomised Complete the Screening log * If patient consents to participating in the optional genetic study (separate ICF), a single blood sample is taken and posted using the Safebox provided (see separate presentation & slide 28) A separate presentation for taking informed consent is available. Question – Who will perform this – are there any questions? Please remember that patients do not have to consent to the genetic study: the consent form is in 2 parts. They can simply consent to the main StatinWISE study only A separate presentation explaining the optional genetic study and its procedure is available. A separate presentation for access to the trial database and how to enter data is available. General Medical Information and re-checking eligibility The trial treatment is posted to patients by the CTU

Baseline visit – guidance Folder 1, Section 6

Data Collection (by Patient) Protocol Overview Patient identification route 1 Research Nurse - database search with GP Clinical eligibility check Research Nurse / site admin  Docmail to patient mail out 0 (Invitation / reply slip & newsletter) mail out 2 (Invitation / reply slip & PIS) mail out 3 (Invitation / reply slip & PIS & newsletter) Patient direct contact with Practice / Research Nurse or CTU (reply slip) CTU to site with reply slip Research Nurse follows up with patient, confirming eligibility Patient identification route 2 Patient Self Referral / Opportunistic e.g. during GP consultation / response to website / Practice adverts / PIS from reception Direct contact to Practice / Research Nurse / CTU or Research Nurse follows up from EOI log at reception CK / ALT bloods Screening visit, consent and randomised Data Collection (by Patient) Confirmation of treatment pack receipt every two months Days 50-56 of each treatment period (every two months) Complete one daily symptoms questionnaire per day Day 56 of each treatment period (every two months) Complete one end of treatment period questionnaire Adherence to treatment Serious Adverse Events (SAE) reporting Pain questionnaire Treatment period 1: Statin or placebo 12 months Treatment period 2: Statin or placebo Treatment period 3: Statin or placebo Treatment period 4: Statin or placebo Questions to ask: Role of GP Role of Research nurse Eligibility Treatment period 5: Statin or placebo 1. Telephone with CTU 2. Paper (CTU to post, we remind) 3. Online (link sent, we remind) 4. Mobile phone app (android only) Treatment period 6: Statin or placebo Month 14: Patient receives their own personalised results End Of Trial Individual results disclosed to GP / Research Nurse and Patient (by phone or in person) and decision taken on ongoing statin therapy Month 15: Final contact with patient to learn if patient is continuing to take statins

Statinwise Treatment Atorvastatin 20 mg and matched placebo capsule to swallowed whole anytime once daily double blind 3x 2 months taking statins and 3x 2 months on placebo predetermined random order Treatment will be posted to patients by CTU in 2-months treatment packs – triggered by CTU data base The treatment packs fit through a standard letterbox. A self-addressed envelope is enclosed with each treatment packs for patients to return their used treatment packs at the end of each treatment period

Data Collection (by Patient) Protocol Overview Patient identification route 1 Research Nurse - database search with GP Clinical eligibility check Research Nurse / site admin  Docmail to patient mail out 0 (Invitation / reply slip & newsletter) mail out 2 (Invitation / reply slip & PIS) mail out 3 (Invitation / reply slip & PIS & newsletter) Patient direct contact with Practice / Research Nurse or CTU (reply slip) CTU to site with reply slip Research Nurse follows up with patient, confirming eligibility Patient identification route 2 Patient Self Referral / Opportunistic e.g. during GP consultation / response to website / Practice adverts / PIS from reception Direct contact to Practice / Research Nurse / CTU or Research Nurse follows up from EOI log at reception CK / ALT bloods Screening visit, consent and randomised Data Collection (by Patient) Confirmation of treatment pack receipt every two months Days 50-56 of each treatment period (every two months) Complete one daily symptoms questionnaire per day Day 56 of each treatment period (every two months) Complete one end of treatment period questionnaire Adherence to treatment Serious Adverse Events (SAE) reporting Pain questionnaire Treatment period 1: Statin or placebo 12 months Treatment period 2: Statin or placebo Treatment period 3: Statin or placebo Treatment period 4: Statin or placebo Questions to ask: Role of GP Role of Research nurse Eligibility Treatment period 5: Statin or placebo 1. Telephone with CTU 2. Paper (CTU to post, we remind) 3. Online (link sent, we remind) 4. Mobile phone app (android only) Treatment period 6: Statin or placebo Month 14: Patient receives their own personalised results End Of Trial Individual results disclosed to GP / Research Nurse and Patient (by phone or in person) and decision taken on ongoing statin therapy Month 15: Final contact with patient to learn if patient is continuing to take statins

Data Collection: Day 50-56 Daily Symptoms Questionnaire

Data Collection: Day 56 End of Treatment Period Questionnaire

Data Collection (by Patient) Protocol Overview Patient identification route 1 Research Nurse - database search with GP Clinical eligibility check Research Nurse / site admin  Docmail to patient mail out 0 (Invitation / reply slip & newsletter) mail out 2 (Invitation / reply slip & PIS) mail out 3 (Invitation / reply slip & PIS & newsletter) Patient direct contact to Practice / Research Nurse or CTU (reply slip) CTU to site with reply slip Research Nurse follows up Patient identification route 2 Patient Self Referral / Opportunistic e.g. from website / Practice adverts / PIS from reception Direct contact to Practice / Research Nurse / CTU or Research Nurse follows up from EOI log at reception CK / ALT bloods Baseline visit, consent and randomised Data Collection (by Patient) 7 symptoms questionnaires every two months one per day on days 50-56 of each treatment period Once – one day 56 of each treatment period Adherence to treatment Serious Adverse Events (SAE) reporting Pain questionnaire Confirmation of treatment pack receipt Treatment period 1: Statin or placebo 12 months Treatment period 2: Statin or placebo Treatment period 3: Statin or placebo Treatment period 4: Statin or placebo Treatment period 5: Statin or placebo 1. Telephone with CTU 2. Paper (CTU to post, we remind) 3. Online (link sent, we remind) 4. Mobile phone app (android only) Treatment period 6: Statin or placebo End Of Trial Individual results disclosed to GP / Research Nurse and Patient (by phone or in person) and decision taken on ongoing statin therapy Within 3 months Trial results presented to patient Final decision recorded on End of Trial form

End of trial – Documentation Month 14: Individual results disclosed to patient Month 15: Final contact with patient to ask if they decided to continue taking statins

Early withdrawal - Intolerable muscle pain Page 15 of Protocol Page 10 of Protocol First two treatment periods always cover statin and placebo

Serious Adverse Events Guidance in Folder 1, Section 7 Only SAEs are reported in StatinWISE An SAE in StatinWISE is: Any untoward medical occurrence not listed in the investigational medicinal product dossier (IMPD) and/or Summary of Product Characteristics (SmPC) affecting a trial participant during the course of a clinical trial, which, at any dose: Results in death Is life threatening Requires inpatient hospitalisation or prolongation of existing hospitalisation; or Results in persistent or significant disability / incapacity Is a congenital anomaly/birth defect (unlikely for StatinWISE) Patients will self-report SAEs via their End of Treatment Period Questionnaire Site trial staff are to check medical records for death of patients at two-monthly intervals (we will contact site) SAEs must be reported by site trial staff within 24 hours of becoming aware of the SAE. The Adverse Event Form must be completed using the online database. If trial site staff don’t have access to the database in that time period, a paper form may be submitted If in doubt contact us Unblinding – Emergency number: 07768 707 500 (on alert card)

Alert card – Folder 2, Section 13 Front and back Inside Labels – in Folder 2, Section 13

Optional Genetic Study A genetic component to statin myopathy identified: SLCO1B1 variant Patients will be invited to participate Separate PIS & ICF Single blood sample Biobank resource Sample taken at Baseline Anonymised Tube/Butterfly and Safebox provided Samples should be sent to University of Liverpool (UoL) Monday – Thursday only Please label envelope with StatinWISE Notify us so we can email UoL Results will not be available to GPs or patients Guidance in separate training presentation (# 14) is on the portable storage device in Folder 1

Logs to be maintained Site Responsibility Delegation Log (Folder 2, Section 17) – needed post training, will trigger database entry Screening log (Folder 2, Section 14) - Recently changed to: All patients expressing an interest in the StatinWISE trial, confirmation of eligibility by PI EOI log at reception Screening log (Folder 2, Section 14) - Important for local Research nurse to follow up with patients Randomisation log Screening log (Folder 2, Section 14) – patients who are randomised Site visit log (Folder 1, Section 12) – for any site visits related to the StatinWISE trial Final Study Results Requested By Patients (Folder 2, Section 18)

Trial Materials BEFORE YOU START THE TRIAL YOU WILL RECEIVE: an investigator study file (ISF) compiled specifically for your site, containing contact details, further information, guidance, spare consent and AE forms and filing space for completed forms CD with study materials and PowerPoint presentations TRAINING AND PRESENTATIONS Please contact the CTU if you need more training materials for staff sessions you are presenting the trial at meetings or conferences

Trial Overview and Guidance Materials

Statinwise Flow: Training Enrolment [Part 1] Site Training Practice staff conduct database search to identify potentially eligible patients (repeated every 1-2 months to identify new patients) Posters placed in surgery reception and GP reminders in rooms Statinwise Flow: Training Enrolment [Part 1] List of potentially eligible patients is given final approval by StatinWISE practice PI Practice staff use Docmail to send “mail outs” to patients, with 2-3 weeks between each mailing: Personalise Docmail letters with practice letterhead and contact details Mail out 0 (letter of invitation, reply slip, newsletter and pre-paid envelope) Mail out 2 (letter of invitation, reply slip, PIS and pre-paid envelope) Mail out 3: (letter of invitation, reply slip, PIS, newsletter and pre-paid envelope) Patients return reply slips in mail to CTU Or ……………………………………….…………………………………………….. Patients contact practice / research nurse directly Patient identified opportunistically in clinic CTU provides practice with scans of reply slips “EOIs” Research Nurse calls/speaks with patient to discuss trial Key points: Patient has used statins in last 3 years Patient stopped statins due to muscle symptoms or Patient is considering stopping statins due to muscle symptoms StatinWISE trial lasts for 12 months, during which patient has periods of taking statins and periods of taking placebo During the last week of each 2 month period, patient will report their muscle symptoms, adherence, and serious adverse events At month 14 patient will receive their personalised results At month 15 there is a final contact to learn if patient chose to continue taking statins Patient not interested. STOP Patient interested. CONTINUE StatinWISE Flow Guide Version 1.0; 25AUG17

Statinwise Flow: Training Enrolment [Part 2] Patient Interested On same phone call/discussion, once participant has expressed interest in joining: As part of clinical care, CK + ALT must be checked If no CK + ALT results within 3 months of anticipated baseline visit: Research Nurse gives instructions on how to get blood test form and blood test for CK + ALT Statinwise Flow: Training Enrolment [Part 2] Patient gets blood test Blood test results are available Research Nurse checks blood test results for CK + ALT If CK >990 U/L and/or ALT >165 U/L then patient is INELIGIBLE. STOP If both CK <990 U/L + ALT <165 U/L, then patient is ELIGIBLE Research Nurse calls patient to book Baseline visit Baseline Visit Key elements: Screening (pre-consent, confirmation of eligibility) Patient has used statins in last 3 years Patient stopped statins due to muscle symptoms or Patient is considering stopping statins due to muscle symptoms StatinWISE trial lasts for 12 months, during which patient has periods of taking statins and periods of taking placebo Patient will report their muscle symptoms, adherence and SAEs during the last week of each 2 month period At month 14 patient will receive their personalised results At month 15 there will be a final contact Patient signs informed consent form …………………………Consent Signing……………………. Enrolment (post-consent, study processes) Research Nurse enters information in StatinWISE Database and randomises patient Research Nurse provides instructions on taking study drug Patient chooses data reporting method, Research Nurse provides training on that method Research Nurse provides patient with StatinWISE Alert Card Research Nurse and patient discuss optional genetic study If patient agrees: sign consent form, take blood, mail blood StatinWISE Flow Guide Version 1.0; 25AUG17

Statinwise Flow: Enrolment End of Trial From GP Practice Point of View Patient enrols: CTU manages study drugs Participant provides self-report of data directly to CTU Every 2 months: GP Practice searches for death of participants At any point during trial: Statinwise Flow: Enrolment End of Trial From GP Practice Point of View In case of SAE: when GP Practice becomes aware of a SAE, complete form and report within 24 hours of becoming aware of SAE In case of intolerable symptoms: refer participant to GP and follow intolerable symptoms pathway in protocol In case of death, lost to follow up, or participant withdraws consent/GP withdraws participant: complete Early Withdrawal Form During 7th week of treatment period 6: Research Nurse contacts participant to thank them for participation and schedule a “month 14” visit to receive their individualised results with their GP Month 14: Individualised results visit is conducted (in person or over the phone) Month 15: “End of Trial” contact is conducted to find out if patient decided to continue taking statins. Complete End of Trial Form StatinWISE Flow Guide Version 1.0; 25AUG17

Trial Team Liam Smeeth – CI and trial Medical Advisor Haleema Shakur – Project Director Emily Herrett – Research Fellow Fizz Williamson – Statistician Kieran Brack – Trial Manager **main contact** Danielle Beaumont – Trial Manager Danielle Prowse – Trial Data Manager Lori Miller – Recruitment Support Andrew Thayne – Data Assistant Collette Barrow – Trial Administrator PPI, DMC and TSC in place ** please email statinwise@lshtm.ac.uk and ‘cc kieran.brack@lshtm.ac.uk any time after 4.30pm

public health patients care GPs Practices StatinWISE aims to: Answer an important question for public health Answer the question for individual patients Bring together research and care As little work as possible for GPs Practices

CONTACT US London School of Hygiene & Tropical Medicine Room 180, Keppel Street, London WC1E 7HT Tel +44(0)20 7299 4684 Fax +44(0)20 7299 4663 Email: statinwise@Lshtm.ac.uk