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
Phase: PHASE4
Conditions: Cardiovascular Disease
Sponsor: London School of Hygiene and Tropical Medicine

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
PROTOCOL NUMBER: ISRCTN30952488 
 
 
 VERSION NUMBER 
DATE 
REASON FOR CHANGE 
1.0 
25 May 2016 
First version  
2.0 
08 August 2016 
Substation Amendment 1: addition of exclusion 
criterion and changes to Adverse Event reporting 
2.1 
28 October 2016 
Non-substantial Amendment 1:  
Correction of typographical errors 
3.0 
27 June 2017 
Substantial Amendment 3.  
i) modifying recruitment pathway description 
ii) modifying Appendix 6 (PIS) and Appendix 7 (ICF)  
iii) including Appendix 6a (PIS, optional genetic study), 
Appendix 7a (ICF, optional genetic study) and 
Appendix 9 (patient recruitment pathway) 
iv) general editing of document 
 
 

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 SUMMARY 
 
FULL TITLE OF STUDY  
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     
SHORT TITLE  
STATIN: WEB-BASED INVESTIGATION OF SIDE EFFECTS 
TRIAL ACRONYM  
STATINWISE 
PROTOCOL /ISRCTN 
NUMBER  
ISRCTN30952488 
EUDRACT NUMBER  
2016-000141-31 
CLINICAL TRIALS.GOV 
NCT02781064 
BACKGROUND: 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. 
AIM: To determine whether statins cause muscle symptoms. 
PRIMARY OUTCOME: Patient reported muscle symptoms (pain, weakness, tenderness, stiffness or 
cramp). 
SECONDARY OUTCOME: Relationship between individual trial result and patient decision whether to 
continue statins long term.  
TRIAL DESIGN: A series of randomised, double-blinded N-of-1 trials.  
DIAGNOSIS AND INCLUSION/EXCLUSION CRITERIA:  
Inclusion criteria: 
 Adults (aged 16 and over) 
 Prescribed statin treatment in the last 3 years  
 Stopped OR considering stopping statin treatment due to muscle symptoms 
 Provided fully informed consent. 
Exclusion criteria: 
 Any previously documented serum alanine aminotransferase (ALT) levels at or above three 
times the upper limit of normal;  

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 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 
 Any contraindications listed in the Summary of Product Characteristics for Atorvastatin 20 
mg (Appendix 8) 
 Should not be using atorvastatin 20mg daily in the opinion of the general practitioner. 
TEST PRODUCT, REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: Once daily oral atorvastatin 20mg 
or placebo for 12 months. 
SETTING: This trial is coordinated from the Clinical Trials Unit at London School of Hygiene & Tropical 
Medicine and conducted in patients registered in General Practice in England and Wales. 
DURATION OF TREATMENT AND PARTICIPATION: Eligible patients should be randomised as soon as possible 
after the screening. Treatment period is for 12 months with a final follow-up within 3 months of the 
end of treatment period. 
CRITERIA FOR EVALUATION: Patients who enter data on muscle symptoms at least once during a 
treatment period with the IMP and at least once during a treatment period with placebo. 
CLINICAL PHASE 
4 
PLANNED TRIAL START 
01/09/2016 
PLANNED DATE OF LAST PATIENT 
ENROLMENT 
01/09/2017 
PLANNED DATE OF LAST PATIENT FINAL 
FOLLOW-UP 
01/10/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS 
 
1. INTRODUCTION...………………………………………………………………………………………………………..……………….………..4 
2. TRIAL DESIGN…………………………………………………………………………………………………………………………………..…….6 
2.1 OVERVIEW ........................................................................................................................................................... 6 
2.2 OPTIONAL GENETIC STUDY ................................................................................................................................. 6 
2.3 NUMBER OF PARTICIPANTS NEEDED ................................................................................................................. 7 
2.4 SAMPLE SIZE ………..………………………………………………………………………………………………………………………….…….8 
2.5 SETTINGS ............................................................................................................................................................. 8 
2.6 RECRUITMENT OF PARTICIPANTS ....................................................................................................................... 9 
2.7 ELIGIBILITY ........................................................................................................................................................... 9 
2.8 RANDOMISATION .............................................................................................................................................. 10 
2.9 TREATMENT....................................................................................................................................................... 10 
2.9.1 DOSE SELECTION ............................................................................................................................................ 11 
2.9.2 DRUG MANUFACTURE, BLINDING AND SUPPLY OF TRIAL MEDICATION ..................................................... 11 
2.9.3 ADMINISTRATION OF TRIAL MEDICATION .................................................................................................... 12 
2.10 DATA COLLECTION .......................................................................................................................................... 12 
2.10.1 BASELINE AND RANDOMISATION DATA...................................................................................................... 13 
2.10.2 TREATMENT PHASE FOLLOW UP DATA ....................................................................................................... 13 
2.10.3 END OF TRIAL DATA ..................................................................................................................................... 13 
2.10.4 PATIENT REPORTING INTOLERABLE SYMPTOMS ………………………………………………………………………..……….14 
2.10.5 EARLY WITHDRAWAL OF PATIENTS FROM THE TRIAL ................................................................................ 15 
2.11 ADVERSE EVENTS ............................................................................................................................................ 16 
2.12 UNBLINDING.................................................................................................................................................... 17 
2.13 OUTCOME MEASURES .................................................................................................................................... 17 
2.14 MONITORING .................................................................................................................................................. 18 
2.15 AUDITS AND INSPECTIONS .............................................................................................................................. 19 
2.16 END OF TRIAL FOR PARTICIPANTS .................................................................................................................. 19 
2.17 ANALYSIS ......................................................................................................................................................... 19 
3. TRIAL ORGANISATION AND RESPONSIBILITIES ……………………………………………………………………………………… 21 
3.1 SPONSORSHIP AND TRIAL MANAGEMENT ....................................................................................................... 21 
3.2 INDEMNITY ........................................................................................................................................................ 21 
3.3 PROTOCOL DEVELOPMENT ............................................................................................................................... 21 
3.4 INDEPENDENT DATA MONITORING COMMITTEE (DMC) ................................................................................ 22 
3.5 TRIAL STEERING COMMITTEE (TSC) .................................................................................................................. 23 
3.6 PRINCIPAL INVESTIGATOR’S’ RESPONSIBILITIES ............................................................................................... 24 
3.7 TRIAL MANAGEMENT GROUP AND CLINICAL TRIALS UNIT RESPONSIBILITIES ............................................... 24 
3.8 CONTACTING THE CTU IN AN EMERGENCY ...................................................................................................... 25 
3.9 PUBLICATION AND DISSEMINATION OF RESULTS ............................................................................................ 25 
3.10 FINANCIAL SUPPORT ....................................................................................................................................... 25 
4. ABBREVIATIONS USED ………………………………………………………………………………………………………………………….. 26 
5. REFERENCES …………………………………………………………………………………………………………………………………………. 27 
6. APPENDICES …………………………………………………………………………………………………………………………………………. 29 
  
          Appendix 1: Trial Assessment Timelines……………………………………………………………….…………………………. 30 
 
          Appendix 2: Baseline Data Form………………………………………………………………………………….………………….. 32 
 
          Appendix 3: End of Trial Form…………………………………………………………………………………………………………. 34 
 
          Appendix 4: Patient Questionnaire…………………………………………………………………………………………………..35 
 
          Appendix 5: VAS Pain Scale Data Form…………………………………………………………………………………….…..…. 38 
 
          Appendix 6: Patient Information Sheet…………………………………………………………………………………………...  40 
 
          Appendix 6a: Patient Information Sheet – Optional Genetic Study…………………………………………………...44 
Appendix 7: Informed Consent Form……………………………………………………………………………………….….......46  
 
          Appendix 7a: Informed Consent Form – Optional Genetic Study…………………………………………………......47 
Appendix 8: Summary of Product Characteristics for Atorvastatin 20 mg…………….…………………………...48 
Appendix 9: Recruiting pathway from advertising….………………………………………………………………………….67 

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1. INTRODUCTION 
 
Statins reduce cardiovascular disease (CVD) risk1 and are recommended as part of the treatment 
strategy for primary and secondary prevention of CVD in the NHS.2   Although statins are the most 
commonly prescribed treatment in the UK,3 there is still uncertainty about adverse effects.4, 5 
 
Severe statin adverse effects are extremely rare (rhabdomyolysis 0.1 and myopathy 0.5 per 1000 
people over 5 years).6 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,7, 8 but 
have not been confirmed in blinded randomised controlled trials (RCTs).9  A major limitation of 
observational studies is lack of blinding: patients taking a medication expect to experience adverse 
effects10 and therefore reporting of symptoms may be higher than in a comparable statin-free 
population. This phenomenon, the “nocebo” effect, can lead to bias in unblinded studies.  
 
In RCTs expectations of adverse effects can lead to inflated reporting in both active and placebo 
groups.  In the Odyssey ALTERNATIVE trial, statin ‘intolerant’ patients initially underwent a double-
blind four week phase where they received placebo.  Interestingly, during this time, 7% dropped out 
due to myalgia.  In the main phase of this three armed trial (alirocumab vs ezetimibe vs atorvastatin), 
rates of adverse events were the same across all groups at roughly 80%, but dropped to 55% among 
alirocumab when unblinded.11 Therefore in some trials of statins, expectation of adverse effects 
among both placebo and active treatment arms may have diluted any true effect of statins on 
muscle symptoms.  A systematic review of randomised trials of statins found that the prevalence of 
myalgia varied from 0% to 30%, but was not different in the active and placebo arms.9   
 
There have also been two other important criticisms of the existing RCT evidence.  First, not all trials 
have collected data on subjective symptoms and recording may be inconsistent due to the 
definitions used. Studies have shown that adverse events are rarely fully presented in journal 
publications.12  Second, while there have been trials among specific vulnerable patient groups,13-15 
there is a perception that trial participants do not reflect populations taking statins in routine care. 
 
We are working closely with the Cholesterol Treatment Trialists’ Collaboration performing a meta-
analysis of statin adverse events reported in RCTs of statins, which will determine using individual 
participant data whether there is an excess of adverse events among those allocated statin 
compared with placebo, and whether to date there has been any bias in the reporting of adverse 
events in statin trials.  However, for the reasons outlined above, re-analysis of the existing evidence 
may not alleviate individual patient concerns. 
 
Despite evidence-based recommendations about the risks and benefits of statin use, many patients 
believe their symptoms are due to statins, leading to discontinuation, and are therefore potentially 

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missing out needlessly on an effective drug intervention. General Practitioners (GPs) are faced with 
the challenge of decision making when patients present with symptoms during statin use as there 
is currently no diagnostic tool allowing clinicians to empirically evaluate whether symptoms 
reported by an individual statin user are caused by the statin itself or by the ‘nocebo’ effect.   
 
N-of-1 trials offer the opportunity for individual patients to discover whether the symptoms that 
they are experiencing are attributable to statins. Each patient acts as their own control, and 
therefore their optimal treatment can be established.16, 17 Importantly, N-of-1 trials offer individual 
patients the opportunity to observe their own response to active and placebo treatments.  We 
anticipate that this knowledge will be an important determinant of subsequent statin use and 
therefore we will follow patients for three months after their blinded treatment period has ended.  
At the end of these three months we will be able to ascertain as to whether they are using statins. 
 
The proposed trial will address some of the criticisms of previous evidence.  The trial will be blinded 
and placebo-controlled to minimise bias and the sequence of statin and placebo treatments will be 
randomised to avoid confounding.  Additionally, the within-patient comparisons of symptoms 
experienced while on placebo and statins will allow us to determine, definitively: (i) whether 
individual patient symptoms are caused by statins and (ii) the extent to which symptoms attributed 
to statins appear to be causally related.   
 
 
 
 

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2. Trial design 
 
2.1 OVERVIEW 
 
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. 
 
Figure 1: Trial overview 
 
2.2 OPTIONAL GENETIC STUDY  
 
A genetic component to statin myopathy (pain accompanied by rises in CK or ALT) has been 
suggested (the SLCO1B1 variant).18 However, it is not clear whether this variant will be found among 
the patients included in our study (who have experienced muscle symptoms while on statins but no 
substantial rises in CK or ALT).  Therefore, as part of the trial, we will ask patients 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.   
Where patients have consented for the genetic blood test, one nine millilitres blood sample will be 
obtained in an EDTA Vacutainer tube, labelled with the genetic study ID number, patient’s gender, 
and the date and time of sample collection. It will then be sent to the genetics laboratory at the 
University of Liverpool via first class post in pre-paid Royal Mail Safeboxes (each containing a 

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maximum of four tubes) as soon as possible after collection. No patient identifiable data will be 
included or separately provided to the University of Liverpool. 
 
2.3 NUMBER OF PARTICIPANTS NEEDED 
 
A feasibility study in the Clinical Practice Research Datalink has indicated that on average 35 patients 
per practice per year will be eligible to take part in the trial.  We anticipate an average uptake of 
15% among primary care patients invited to participate in our trial.  Therefore, we estimate that we 
will need to invite approximately 1300 patients from over 50 general practices to the trial to achieve 
our recruitment target of 200.  
 
Power calculations: Our power calculation was performed via simulation.19  An initial sample size, 
n, was chosen. The treatment allocation sequence for each of the n patients was drawn by randomly 
allocating the participant to either statin or placebo separately for periods 1, 3, and 5, thereby 
determining the order of the 6 treatment periods. For each participant, a random effect was drawn 
from a normal distribution, with zero mean and variance equal to 302.  Residual errors (6 for each 
participant; one for each period) were drawn from a normal distribution with zero mean and 
variance equal to 252. Then a VAS pain score was simulated for each participant in each period, 
adding a treatment effect of 10 to each statin period, incorporating the patient random effect and 
the participant’s residual error for that period. This simulated dataset was analysed using the 
primary analysis model (as if this were the real data) and the two-sided p-value for the treatment 
effect was stored. After repeating this process a large number of times (e.g. 500), the statistical 
power was estimated by the proportion of simulated datasets in which the P-value was less than 
0.05. If the power was less than 90%, the sample size was increased and the power re-estimated. 
The rationale for the parameters chosen within this model is detailed below. 
  
Minimum clinically significant difference in VAS pain score (10 mm): This value was chosen to 
represent the smallest VAS change in pain which patients would perceive as being beneficial, and 
might therefore change the patient’s decision regarding subsequent statin use. Two studies 
conducted within an Accident and Emergency setting20-23 both concluded that the smallest change 
in VAS pain score corresponding to “a little more” or “a little less” pain was 13mm, with confidence 
intervals (95% CI: 10 to 17mm) and (95% CI: 10 to 16mm). We took the lower limit of the confidence 
interval to represent the smallest change likely to be perceived as being beneficial.   
 
Within and between-participant variability in VAS pain score: (302 and 352, respectively). These 
values were obtained by fitting a mixed model to the data from a pilot series of N-of-1 trials for 
statin adverse effects24 (data obtained by approximation from figures presented therein).  These 
variance components can be poorly estimated, thus we took values from the higher end of the 
confidence intervals, giving conservative estimates of these components. 
 
 
 

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2.4 SAMPLE SIZE 
 
A sample size of 64 participants provides approximately 90% power to detect a treatment effect of 
at least 10mm, assuming a Type I error of 5%. Allowing for loss to follow-up of 40% of participants 
through the trial inflates the required sample size to 107 participants. 
Period effects (changes in underlying VAS pain score due to factors other than randomised 
treatment, e.g. seasonal, activity-related, etc.), variability in individual statin effects across patients, 
and imperfect adherence to the assigned treatment were investigated by further detailed 
simulations. VAS pain scores are not normally distributed, since they are bounded (0-100mm) and 
can display large fluctuations in response. Therefore, further power calculations were performed 
drawing the outcome from a Beta distribution, and from a distribution with normal variance 
components on a logit scale, to assess the robustness of the sample size estimates to the distribution 
chosen. These factors all have the effect of decreasing power, thus increasing the sample size 
required. An approximate 80% increase in the sample size required in the absence of these effects 
provided approximately 90% or more power across a plausible range of these potential effects, thus 
we determined that a final sample size of 200 was required. 
 
Multiple testing: Rather than making formal adjustments for multiple testing, we follow an 
approach advocated by Pocock25 of clearly specifying our primary analysis (which provides a single 
test for treatment effect), while explicitly presenting and interpreting all other tests as secondary 
analyses. 
 
Power for individual N-of-1 trials: In order to increase the statistical power for the analysis of 
individual N-of-1 trials, we will ask participants to report symptoms daily in the last week of each 
period, rather than once per period. Full adherence through the trial will provide between 55 and 
70% power to detect effects of 10mm or greater for individual treatment comparisons. 
 
Estimates of recruitment and retention rates: We anticipate that some patients will not complete 
data in each treatment period, and that some will not complete their 12-month follow-up. By 
designing this study as a series of N-of-1 trials, which offer individual participant benefit in the form 
of an individualised estimate of effect, we hope to minimise this type of dropout. However, we have 
accounted for this in our sample size calculation by allowing for 40% loss to follow-up. 
 
2.5 SETTINGS 
 
GP Practices will be recruited through the Clinical Research Network across England and Wales and 
we will continue to add practices to ensure the sample size is achieved. Suitable collaborating 
practices and investigators will be assessed on their ability to conduct a trial.  In advance of the trial 
starting at a practice, the Principal Investigator (PI) must agree to follow Good Clinical Practice 
Guidelines and all relevant regulations.  All relevant regulatory and ethics approvals must be in place 
prior to practices recruiting their first patient. 
 

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2.6 RECRUITMENT OF PARTICIPANTS 
 
Participants will be recruited directly from GP Practices or by advertising to the public.  
 
Participating practices will recruit eligible patients from two groups as follows: 
1) Patients who are considering discontinuation of their statin due to muscle symptoms:  
These patients will be invited to take part in the trial when they visit the GP to report muscle 
symptoms believed to be associated with statins and where the patient/GP is considering stopping 
statins because of the muscle symptoms. The GP or Research Nurse will approach the patient and 
give the patient information sheet (Appendix 6 and Appendix 6a). If interested, patients will be able 
to consent (Appendix 7 and Appendix 7a) and complete the screening visit with the GP or the 
Research Nurse during this appointment or it can be arranged for another suitable time. 
 
2) Patients who have stopped taking a statin in the last 3 years due to muscle symptoms:   
A search of the practice electronic records will be performed by the Research Nurse on a two-
monthly basis for one year (or until recruitment targets are reached) to identify potentially eligible 
patients.  All screened patients will be documented on a screening log. The list will be reviewed by 
the GP to confirm clinical eligibility before patients are invited to take part.  A letter inviting them 
to attend a screening visit, accompanied with the patient information sheet (Appendix 6 and 
Appendix 6a) for the patient to consider, will be sent by the trial team from their GP practice. 
Contact details of the Research Nurse will be provided should the patient have any questions.  A 
reply slip will be enclosed for the patient to complete if they wish to attend the screening visit, which 
will be returned to the Clinical Trials Unit (CTU), during which the trial will be explained, and they 
will have the opportunity to ask questions. Patients will be sent a letter of invitation to consider 
participation up to a maximum of three times. 
 
3) Patients who contact the CTU from advertising:   
Patients who contact the CTU in response to advertising material will be sent a letter to request 
their GP details on a reply slip. Following receipt of these documents the CTU will contact their GP 
with their consent. The GP will be asked to confirm that the patient is potentially suitable for the 
trial and to provide brief clinical information to allow eligibility to be assessed. This information will 
then be provided to the GP surgery responsible for recruiting the patient.  
Once informed consent has been obtained, eligibility, demographic and medical history data 
(Appendix 1) will be collected directly onto an online trial database. 
 
2.7 ELIGIBILITY 
 
Inclusion criteria: 
 Adults (aged 16 and over) 
 Registered in a participating GP practice 
 Previously prescribed statin treatment in the last 3 years  
 Stopped OR is considering stopping statin treatment due to muscle symptoms 
 Provided fully informed consent. 
 

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Exclusion criteria: 
 Any previously documented serum alanine aminotransferase (ALT) levels at or above three times 
the upper limit of normal  
 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 
 Any contraindications listed in the Summary of Product Characteristics for Atorvastatin 20 mg 
(Appendix 8) 
 Should not participate in the trial in the opinion of the general practitioner. 
 
2.8 RANDOMISATION 
 
Patients eligible for inclusion will be randomised by the Research Nurse/GP practice trial team using 
the online London School of Hygiene & Tropical Medicine (LSHTM) CTU randomisation system to a 
sequence of blinded placebo and atorvastatin treatment periods. There are six paired (statin-
placebo or placebo-statin) treatment periods each of two months’ duration. In practice, this means 
that each individual is randomised (with equal probability) to one of the following eight sequences 
(with P=placebo, S=statin):   
 
 
Treatment Period 
1 
2 
3 
4 
5 
6 
Sequence 1 
S 
P 
S 
P 
S 
P 
Sequence 2 
S 
P 
S 
P 
P 
S 
Sequence 3 
S 
P 
P 
S 
S 
P 
Sequence 4 
S 
P 
P 
S 
P 
S 
Sequence 5 
P 
S 
S 
P 
S 
P 
Sequence 6 
P 
S 
S 
P 
P 
S 
Sequence 7 
P 
S 
P 
S 
S 
P 
Sequence 8 
P 
S 
P 
S 
P 
S 
 
Randomisation codes will be generated and secured by the Information Technology team at LSHTM 
CTU, who has procedures to ensure the trial team remains blinded. The codes will be made available 
to a Good Manufacturing Practice (GMP) certified clinical trial supply company explicitly for the 
treatment packs to be created in accordance with the randomisation list. 
 
2.9 TREATMENT 
 
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. 

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Two months’ supply of allocated treatment will be posted to the patient every 2 months. Treatment 
should start within 4 weeks of randomisation. Patients who have not started by the 3rd week post 
randomisation will be contacted by the CTU. Such patients will therefore have a longer study period. 
 
 
2.9.1 DOSE SELECTION 
 
Atorvastatin is recommended by the current NICE guidelines for lipid modification;2  20mg is the 
recommended dose for primary prevention of cardiovascular disease.  Atorvastatin is also 
recommended by NICE for secondary prevention2 and for patients with a high risk of adverse events 
(our patient population), a dose lower than 80mg is recommended.  The most commonly used dose 
is 20mg. A visually matched placebo has been chosen as an appropriate comparator for two reasons.  
Firstly, patient expectation of symptoms while on statins is likely to affect their experience of 
symptoms.  A placebo control should minimise bias arising from knowledge of allocation. Secondly, 
withholding statin treatment from patients during placebo treatment periods is justified because 
the trial will recruit patients who have recently stopped using statins (and therefore are not 
currently receiving any benefit from statins) and those who wish to discontinue.  If patients in the 
trial tolerate the active treatment periods with few symptoms, then this trial is likely to increase 
their usage of statins in the long term.   
 
2.9.2 DRUG MANUFACTURE, BLINDING AND SUPPLY OF TRIAL MEDICATION 
 
The active trial drug atorvastatin (as atorvastatin calcium trihydrate) will be purchased on the open 
market. Atorvastatin is manufactured by Sharp Clinical Services (UK) Ltd under Marketing 
Authorisation Number 10284. The Marketing Authorisation guarantees that the product has been 
manufactured and released in accordance with the United Kingdom’s Good Manufacturing 
Regulations.  
 
Placebo will be manufactured specially to match the atorvastatin by a GMP certified manufacturer. 
Capsules and packaging will be identical in appearance for both active treatment and placebo. 
DBcaps® capsules which has a unique locking mechanism to help with assuring the integrity of the 
blind will be used for over encapsulation of both active and placebo treatments. Additionally, 
patients will be asked to swallow the capsule whole without chewing or breaking it. The blinding 
process and first stage Qualified Person (QP) release will be done by the designated clinical trial 
supply company. The blinding process will involve encapsulating the active tablet, complete removal 
of the original manufacturer’s label and replacement with the clinical trial label bearing the 
randomisation number which will be used as the pack identification. Other pack label text will be 
identical for both atorvastatin and placebo treatments and will be in compliance with requirements 
for investigational medicinal products.  
 
The designated clinical trial supply company will also be responsible for maintaining the Product 
Specification File (PSF) until final database lock and unblinding of the trial data. The CTU will be 

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responsible for assuring all relevant approvals are available and that the patient is eligible for the 
trial before release of the trial medication to a patient. A separate Manual of Operating Procedures 
(MOP) will detail the drug accountability system. The MOP will also detail labelling of the trial 
treatment and other processes for assuring adherence to Good Manufacturing Practice. 
 
2.9.3 ADMINISTRATION OF TRIAL MEDICATION 
 
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 occurs 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.  
 
2.10 DATA COLLECTION 
 
This trial will be coordinated from the CTU at LSHTM and conducted at GP practices in England and 
Wales.  
Baseline data will be collected at each GP practice by the GP or Research Nurses, and will be entered 
directly online to the trial database provided by the LSHTM CTU. Follow up data will be collected 
directly from each patient at the end of each two-month period.  
Patients will be allowed to choose the method of data collection most suitable for them from the 
following: 
1. Bespoke mobile app which will require patients to use their own smartphone. 
2. Online database using a computer, phone or tablet. 
3. Paper forms which they will receive by post at the same time with their trial treatment and 
which they can complete themselves or they can request a trial team member to contact 
them by phone to help with completing the forms.  
4. Trial staff will telephone the patient on each data collection day and complete the 
questionnaire based on the patient answers. 
 
For patients with a smartphone who choose to submit outcome data using the trial’s bespoke 
mobile app, the Research Nurse will help the patient to install and set-up the app for use. The 
Research Nurse will also give a demonstration to ensure the patient understands how to use it.  Each 
nurse will have access to the internet so that the patient can download the app without using their 
own mobile network (ensuring that download of the app is free of charge to the patient).   
 

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The GP or Research Nurse will also help the patient to complete the symptoms data for the Baseline 
form (Appendix 2) using their preferred method. Any questions can be addressed at this stage.  Once 
baseline procedures have been completed and the patient confirmed as being eligible and 
consented, the patient can then be randomised.  
 
A screening log will be used to record all patients who were identified as potentially eligible using 
the GP practice database, including those who were ineligible and those who declined participation. 
The Screening Log will remain at the relevant GP practice and only anonymised information 
regarding number of screened patients and number and reasons for screen failure will be shared 
with the CTU. 
Only data outlined on the baseline, follow up, end of trial and adverse events data forms will be 
collected as part of the trial database. 
 
2.10.1 BASELINE AND RANDOMISATION DATA  
 
Baseline data will be collected by the GP or Research Nurse performing the assessment at the 
Screening Visit (Appendix 2).  Baseline data will be collected via a bespoke online trial database, to 
which each GP and Research Nurse will have a unique log-in ID and password. Eligible patients will 
then be randomised and data about the randomisation (date, time and randomisation number) is 
generated.  
 
2.10.2 TREATMENT PHASE FOLLOW UP DATA   
 
In the seventh week of each treatment period, patients will receive reminders (format agreed at 
baseline) to alert them that follow-up data collection is approaching. During the 8th week of each 
treatment period, the Patient Questionnaire and VAS Pain Scale forms (Appendices 4 and 5) will be 
completed by the patient. Patients can choose to receive daily reminders on each day their data is 
due to be collected. Non-responders will automatically receive a reminder after 24 hours of due 
date by the trial team.  
 
2.10.3 END OF TRIAL DATA 
 
During the seventh week of treatment period 6, 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 a 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. 

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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. 
 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. 
 Where treatment with an interacting drug is needed for longer than one month, the patient 
will be asked to withdraw from study treatment completely. 
When the patient is randomised, a temporary Read code indicating StatinWISE participation will be 
recorded in their primary care record, the code will be removed at the end of the trial.  
 
Patients will also be given an alert card that identifies them as a StatinWISE patient.  Patients will be 
asked to present this card to anyone providing medical care outside of their usual general practice.  
This card will have a link to the trial website and a trial contact number.  
 
2.10.4 PATIENTS REPORTING INTOLERABLE SYMPTOMS 
 
The GP will remain as the first point of contact for patients during the trial for their care. Intolerable 
muscle symptoms should be reported to the GP who will provide clinical care as directed by the 
appropriate NICE guidelines.  Where a patient reports intolerable symptoms, Figure 2 shows the 
decision making pathway for the GP and the patient. 
For patients who experienced intolerable muscle symptoms, and who do not want to be 
withdrawn early from the trial, the GP will be asked to confirm that the patient still meets the trial 
eligibility criteria.  Patients who continue to meet the eligibility criteria can be offered the 
following options by the GP, depending on their clinical judgement: 
i. 
continue with their current treatment 
ii. 
reduce the frequency of tablet use to every other day rather than daily  
iii. 
stop for that treatment period and resume at the start of the next period 

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Figure 2: Intolerable symptoms pathway 
 
Patients who withdraw from treatment temporarily or permanently will be asked to inform the 
study team and report symptoms at the time of stopping, and continue to submit outcome data for 
their current treatment period.    
 
2.10.5 EARLY WITHDRAWAL OF PATIENTS FROM THE TRIAL 
A patient is free to change their minds about participation at any time. We would advise that the 
patient see their GP to discuss future routine care. A GP can withdraw a patient at any time if clinical 

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concerns arise or if the patient presents with any reason to stop atorvastatin as described in the 
Summary of Product Characteristics for Atorvastatin 20 mg (Appendix 8). In each case, an end of 
trial form (Appendix 3) should be completed. 
 
2.11 ADVERSE EVENTS 
 
Reporting of Adverse Events for this trial: Atorvastatin is not a new drug and has a well-
documented safety profile. Furthermore, this trial is being conducted in a population in which statin 
use is clinically indicated.  It is anticipated that patients in this trial are at higher risk of cardiovascular 
diseases because of underlying clinical conditions requiring statin use. Additionally, as participation 
is for 15 months it is likely that they will have common medical problems (e.g. colds, coughs, fevers 
etc). On the basis that patients: (1) would have had prior exposure the trial treatment, (2) the trial 
treatment is clinically indicated for their medical condition, and (3) the known safety profile of the 
trial treatment, we will limit adverse events to be reported to those events that fulfill the Serious 
Adverse Event (SAE) criteria as described below.   
 
Patient Self-report: In the two-monthly questionnaire, patients will be asked to self-report any 
event which resulted in unplanned hospital admissions. Where a patient indicates that there was 
an unplanned admission, the GP/Research Nurse will be asked to submit a brief report to the CTU.  
 
General Practitioner report: Participating GPs will report any event to the  CTU that fulfill the 
Serious Adverse Event (SAE) criteria as described below  within 24 hours of becoming aware of the 
event.  To minimize the risk of unreported events, at two-monthly intervals, the Research Nurse/GP 
will conduct a search of their database for any StatinWISE patients who have been recorded as 
having died.  
 
Definitions:  
Adverse Event (AE): 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.  
Serious Adverse Event (SAE): A serious adverse event (experience) is an adverse event (as defined 
above) 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 
 
Adverse Reaction (AR): An AE when there is at least a possibility that it is causally linked to a trial 
drug or intervention. 
Serious Adverse Reaction (SAR): SAE that is thought to be causally linked to a trial drug or 
intervention. 

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Suspected Unexpected Serious Adverse Reaction (SUSAR): An unexpected occurrence of a SAR that 
is inconsistent with the list of expected events in the Summary of Product Characteristics for 
atorvastatin 20 mg dated 02/09/2015 (Appendix 8); there need only be an index of suspicion that 
the event is a previously unreported reaction to a trial drug or a previously reported but exaggerated 
or unexpectedly frequent adverse drug reaction. 
All SAEs assigned by the PI or delegate as both suspected to be related to IMP-treatment and 
unexpected will be classified as SUSARs and will be subject to expedited reporting to the Medicines 
and Healthcare Products Regulatory Agency (MHRA).  The Sponsor (or delegate) will inform the 
MHRA, and the ethics committee of UK-relevant SUSARs within the required expedited reporting 
timescales (no later than 7 days after the Sponsor was first made aware for fatal/life threatening 
reactions; no later than 15 days for other reactions). 
As this is a blinded trial, all SUSARs must be reported to the Sponsor (or delegate) assuming the 
active compound is involved.  All expedited reports submitted to the regulatory authorities will be 
unblinded. 
 
2.12 UNBLINDING 
In general, there should be no need to unblind the allocated treatment during the treatment phase.  
If some contraindication to statins develops after randomisation, the trial treatment can be stopped 
and all usual standard care given. Unblinding should be done only in those rare cases where the 
clinician believes that clinical management depends importantly upon knowledge of whether the 
patient is receiving statin or placebo.  In those few cases when urgent unblinding is considered 
necessary, a 24-hour telephone service will be provided by the CTU and details provided in the 
Investigator’s Study File and the Patient Alert Card.  The caller will be told whether the patient is 
receiving statin or placebo.  An unblinding report form will be completed by the person requesting 
the unblinding. Participation will not restart once unblinding has occurred. 
In this trial, it is important that the CTU is contacted for unblinding as any request is likely to 
originate from emergency departments or hospital clinics needing to know the treatment allocation 
urgently. As most GPs and research surgery staff do not provide a 24-hour cover, for patient safety 
reasons, the CTU will provide a 24 hour on-call unblinding service. 
 
2.13 OUTCOME MEASURES 
Primary outcome: The primary outcome is self-reported ‘muscle symptoms’, defined as pain, 
weakness, tenderness, stiffness or cramp to the body of any intensity, recorded where the 
participant believes they are associated with the study medication; these are the symptoms most 
commonly reported by patients and are often the reasons for discontinuation. The primary outcome 
will be assessed by the mean difference in VAS scores (range 0 to 100) between treatment periods 
with the trial treatment and treatment periods with placebo, estimated via a linear mixed model. 
 
Secondary outcomes: Secondary outcomes relating to participant belief about the cause of their 
muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant 
and information about any other symptoms will be collected on the last day of each two-month 
treatment period, using a questionnaire (Appendix 5). The other secondary outcomes are adherence 

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to medication, the participant’s decision about statin treatment following the trial, and whether 
they found their own trial result helpful. 
Specifically, secondary outcomes will be: 
1. The proportion of patients with muscle symptoms during each two-month period who report 
that they believe their symptoms were caused by the study medication, comparing periods 
of IMP treatment with placebo. 
2. Site of muscle symptoms (single or multiple; head and neck/upper limbs/lower limbs/trunk). 
3. Among patients reporting muscle symptoms, the difference in mean VAS scores (range 0 to 
100) for the following, comparing periods of IMP treatment with placebo: 
a. General activity 
b. Mood 
c. Walking ability 
d. Normal work (includes both work outside the home and housework) 
e. Relations with other people 
f. Sleep 
g. Enjoyment of life 
4. Other symptoms that the patient believes can be attributed to the study medication 
(grouped: musculoskeletal; gastrointestinal; respiratory; neurological; psychological; other). 
5. Adherence to study medication as assessed by: (a) self-report and (b) counting pills 
remaining in returned packages, and the relationship between adherence and muscle 
symptoms. 
6. Participant decision regarding future statin use and the relationship to their primary 
outcome. 
7. Whether patients found their own trial result helpful in making the decision about future 
statin use. 
 
2.14 MONITORING 
 
GCP section 5.18.3 states in regard to monitoring, “The determination of the extent and nature of 
monitoring should be based on considerations such as the objective, purpose, design, complexity, 
blinding, size and endpoints of the trial. In general, there is a need for on-site monitoring, before, 
during, and after the trial; however, in exceptional circumstances the sponsor may determine that 
central monitoring in conjunction with procedures such as investigators training and meetings, and 
extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. 
Statistically controlled sampling may be an acceptable method for selecting the data to be verified.” 
 
StatinWISE is a pragmatic, randomised placebo controlled trial. The intervention (atorvastatin) has 
marketing authorisation in the United Kingdom and has been in clinical use for decades. The trial 
will collect data on SAEs which may be associated with this product and other clinical conditions 
which will be common in this population. These events will be reviewed routinely by the trial 
Medical Advisor and will be reported routinely to the Trial Steering Committee. The trial involves 
getting consent, giving the trial drug in the usual way and collecting information regarding muscle 
symptoms directly from the patients. There are no extra tests or procedures unless patients agree 

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to take part in the genetic study, for which 9 ml of blood is required. Apart from the trial drug, any 
other medication will be issued as per usual practice under the care of the GP. For these reasons, 
we believe that the risk of harm or injury (whether physical, psychological, social or economic) to 
trial patients is low. We will use central monitoring along with investigators’ training and meetings, 
and extensive written guidance to make sure the trial is carried out properly. Statistically controlled 
sampling will be used to select data to be verified at GP practices. We plan to carry out on-site 
monitoring where central statistical monitoring show abnormality. Consent forms will be monitored 
centrally at the CTU. 
Investigators/practices are required to provide direct access to source data/documents for trial-
related monitoring, audits, ethics committee review and regulatory inspection. Source data will be 
low as the majority of patients will enter data using the mobile application method directly. All trial-
related and source documents must be kept for ten years after the end of the trial.  
 
2.15 AUDITS AND INSPECTIONS  
 
The trial may be subject to audit by the London School of Hygiene & Tropical Medicine under their 
remit as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence 
to GCP. 
 
2.16 END OF TRIAL FOR PARTICIPANTS 
 
The follow-up period ends 15 months after the first treatment day with a final contact (telephone 
or face-to-face) with the Research Nurse as described above. This will be considered as the end of 
trial for patients.  
 
2.17 ANALYSIS 
Individual N-of-1 trials: The purpose of these analyses is to inform the individual patient of the 
effect of the IMP on their VAS muscle symptom score. The analysis and presentation of individual 
level results will be developed in collaboration with the Patient and Public Involvement (PPI) group. 
We will examine a range of graphical summaries and statistical analyses in order to identify the most 
informative presentation of individual results. As a result of this process, at the end of each 
individual trial the participant will be shown numerical and graphical summaries of their individual 
data, in relation to their IMP and placebo periods.  
 
Combined analysis of N-of-1 trials  
Primary analysis: To estimate the population average estimate of the trial treatment n VAS muscle 
symptom score, data from each N-of-1 trial will be aggregated to form a powerful dataset. We will 
adopt an intention-to-treat approach. Patients who enter data on muscle symptoms at least once 
during a treatment period with the IMP and at least once during a treatment period with placebo 
will be included in the primary analysis. 
The primary analysis will be a linear mixed model for VAS muscle symptom score with random 
effects for participant and treatment and fixed period effects. Residual errors will be modelled using 

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a first-order auto-regressive error structure within each treatment period to account for correlation 
between the 7 daily measurements, with robust standard errors to account for non-normality of the 
VAS scores. Although VAS muscle symptom scores are unlikely to be exactly normally distributed, 
analysing such data using normal-based methods is likely to be a sufficiently robust approach.26 All 
tests will be two-sided. p <0.05 will be considered statistically significant.  
 
Secondary analyses: Secondary outcomes relating to the impact of the IMP on other aspects of life 
will be analysed in a similar manner to the primary outcome, omitting the auto-regressive 
correlation structure since these secondary outcomes are measured once per treatment period. 
We will investigate whether the excess muscle symptoms, if any, experienced during treatment 
periods with the IMP appears to be concentrated in multiple sites. 
Descriptive statistics will be used to summarise the measures of adherence to randomised 
treatment, and their relationship to the IMP and placebo periods. We will use the measures of 
adherence to randomised treatment to perform an efficacy analysis based around an instrumental 
variables approach.27 Because these analyses require much stronger assumptions than the 
intention-to-treat analysis above, the results of the efficacy analysis will be presented and 
interpreted as a secondary analysis. The secondary outcomes include a single binary measure of 
whether the participant reports having muscle symptoms during that treatment period or not. This 
will be combined with the follow-up question pertaining to attribution, to obtain a single binary 
measure of whether the participant reports having muscle symptoms that they attribute to the 
study medication or not. These two binary outcome measures will be assessed using a logistic mixed 
model with random participant and treatment effects and fixed period effects. 
We will relate the patients’ decision regarding future statin use, and whether or not the participant 
found their own result helpful in making their subsequent treatment decisions, to their individual 
estimated effect of the IMP. 
 
Subgroup analyses: There are no priori subgroup analyses planned. If an overall population-level 
effect is detected, we may investigate whether the effect varies within subgroups defined by 
measured baseline characteristics. These analyses will be regarded and interpreted as being 
exploratory.  
 
 
 
 
 
 
 
 
 

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3. Trial Organisation and Responsibilities 
 
3.1 SPONSORSHIP AND TRIAL MANAGEMENT  
 
The StatinWISE trial is sponsored by the LSHTM and its responsibilities coordinated by the CTU. The 
CTU may delegate responsibilities to third parties which will be outlined in relevant agreements. 
The responsibilities of the CTU will be overseen by the Trial Management Group (TMG). 
 
3.2 INDEMNITY 
 
LSHTM accepts responsibility attached to its sponsorship of the trial and, as such, would be 
responsible for claims for any non-negligent harm suffered by anyone as a result of participating in 
this trial. The indemnity is renewed on an annual basis and LSHTM assures that it will continue 
renewal of the indemnity for the duration of this trial.  
 
3.3 PROTOCOL DEVELOPMENT 
 
The Protocol Committee consists of the following investigators who will be responsible for the 
development of and agreeing to the final protocol. Subsequent changes to the final Protocol will 
require the agreement of the Trial Steering Committee (TSC). 
 
NAME 
AFFILIATION 
Jane Armitage 
University of Oxford,  UK 
Danielle Beaumont 
LSHTM, London, UK 
Elizabeth Crellin 
LSHTM, London, UK 
Ben Goldacre 
LSHTM, London, UK 
Emily Herrett 
LSHTM, London, UK 
Ian Roberts 
LSHTM, London, UK 
Haleema Shakur 
LSHTM, London, UK 
Liam Smeeth 
LSHTM, London, UK (Chair) 
Tjeerd van Staa 
University of Manchester, UK 
Elizabeth Williamson 
LSHTM, London, UK 
Nabila Youssouf 
LSHTM, London, UK 

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3.4 INDEPENDENT DATA MONITORING COMMITTEE (DMC) 
 
MEMBERSHIP  
NAME 
AFFILIATION 
EXPERTISE 
Professor John Norrie 
Chair of Medical Statistics and Trial 
Methodology.  
Director of Edinburgh Clinical Trials Unit 
(ECTU), University of Edinburgh 
Chair – Senior Statistician & 
Trialist 
Professor Nicholas L Mills 
Chair of Cardiology and Consultant 
Cardiologist, 
BHF 
Senior 
Clinical 
Research Fellow 
Clinical Expert 
Dr Hannah Castro 
Freelance  
Medical Statistician 
 
To provide protection for study participants, an independent DMC has been appointed for this trial 
to oversee the safety monitoring. The DMC will review on a regular basis accumulating data from 
the ongoing trial and advise the TSC regarding the continuing safety of current participants and 
those yet to be recruited, as well as reviewing the validity and scientific merit of the trial. 
 
The DMC composition, name, title and address of the chairman and of each member, will be given 
in the DMC Charter which will be in line with that proposed by the DAMOCLES Study Group 
(DAMOCLES Study Group 2005). Membership includes expertise in the relevant field of study, 
statistics and research study design. An independent statistician will be appointed to provide the 
analysis service required by the DMC. 
The DMC Charter includes, but is not limited to, defining: 
 the schedule and format of the DMC meetings 
 the format for presentation of data 
 the method and timing of providing interim reports  
 stopping rules 
 
STANDARD OPERATING PROCEDURES 
 
The DMC has the responsibility for deciding whether, while randomisation is in progress, the 
unblinded results (or the unblinded results for a particular subgroup), should be revealed to the TSC. 
The DMC Charter states that they will do this if, and only if, the following two conditions are 
satisfied: (1) the results provide proof beyond reasonable doubt that treatment is on balance either 
definitely harmful or definitely favorable for all, or for a particular category of participants in terms 
of the major outcome; and (2) the results, if revealed, would be expected to substantially change 
the prescribing patterns of clinicians who are already familiar with any other trial results that exist. 
Exact criteria for “proof beyond reasonable doubt” are not, and cannot be, specified by a purely 
mathematical stopping rule, but they are strongly influenced by such rules. The DMC Charter is in 
agreement with the Peto-Haybittle stopping rule whereby an interim analysis of a major endpoint 
would generally need to involve a difference between treatment and control of at least three 
standard errors to justify premature disclosure (Haybittle 1971; Peto 1977). An interim subgroup 
analysis would, of course, have to be even more extreme to justify disclosure. This rule has the 
advantage that the exact number and timing of interim analyses need not be pre-specified. In 

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summary, the stopping rules require extreme differences to justify premature disclosure and involve 
an appropriate combination of mathematical stopping rules and scientific judgment. 
  
3.5 TRIAL STEERING COMMITTEE (TSC) 
 
The composition of the TSC is provided in the table below:  
 
NAME 
AFFILIATION 
EXPERTISE 
Michael Moore 
University of Southampton 
Independent Chair 
Professor of Primary Healthcare Research 
and General Practitioner 
Brian Mac Kenna 
Chief Pharmaceutical Office 
Medical Directorate, NHS England 
Independent member 2 
Pharmacist 
Irwin Nazareth 
University College London and Keat’s 
GP Practice, Hampstead 
Independent member 3  
Professor of Primary Care and General 
Practitioner 
Maurice Hoffman 
StatinWISE PPI Group 
Independent member 4  
Patient Representative 
David Symes 
StatinWISE PPI Group 
Independent member 5  
Patient Representative 
Rebecca Harmston 
StatinWISE PPI Group 
Independent member 6  
Patient Representative 
Haleema Shakur 
LSHTM 
Trials Expert 
Senior Lecturer 
Liam Smeeth 
LSHTM 
Chief Investigator  
Professor of Clinical Epidemiology and  
General Practitioner 
 
The role of the TSC is to provide overall supervision of the trial. In particular, the TSC will concentrate 
on the progress of the trial, adherence to the protocol, patient safety and consideration of new 
information. The TSC must be in agreement with the final protocol and, throughout the trial, will 
take responsibility for: 
 ensuring relevant regulatory approvals are in place 
 major decisions such as a need to change the protocol for any reason 
 monitoring and supervising the progress of the trial 
 reviewing relevant information from other sources 
 informing and advising the TMG on all aspects of the trial 
 
Face-to-face meetings or teleconferences will be held at regular intervals determined by need, but 
no less than once a year. A TSC Charter, which will detail how it will conduct its business, will be 
agreed at the first meeting. 
 
 
 
 
 
 

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3.6 PRINCIPAL INVESTIGATOR’S’ RESPONSIBILITIES 
 
Coordination within each participating general practice will be through a local PI whose 
responsibility will be detailed in an agreement in advance of starting the trial and will include:  
 ensure all necessary regulatory approvals are in place prior to starting the trial 
 delegate trial related responsibilities only to suitably trained and qualified personnel 
 train relevant medical and nursing staff who see patients and ensure that they remain aware 
of the state of the current knowledge, the trial and its procedures (there are wall charts, 
pocket summaries and PowerPoint presentations to assist with this)  
 agree to comply with the final trial Protocol and any relevant amendments 
 ensure that all patients who meet the eligibility criteria are considered promptly for the trial 
 ensure consent is obtained in line with local approved procedures 
 ensure that the patient baseline data are completed and transmitted to the CTU in a timely 
manner 
 ensure the Investigator’s Study File is up-to-date and complete 
 ensure all adverse events are reported promptly to the CTU 
 ensure the trial is conducted in accordance with ICH GCP and fulfils all national and local 
regulatory requirements 
 allow access to source data for monitoring, audit and inspection 
 be responsible for archiving all original trial documents including data forms for five years after 
the end of the trial 
 
3.7 TRIAL MANAGEMENT GROUP AND CLINICAL TRIALS UNIT RESPONSIBILITIES  
 
The TMG will consist of the Protocol Committee members (Section 3.3) plus trial manager(s), data 
manager and other key trial staff as required.  
 
The CTU will act on behalf of the Sponsor and will be responsible to the TMG to ensure that all of 
the Sponsor’s responsibilities are carried out. The responsibilities include (but are not limited to): 
 report to the TSC 
 maintain the Trial Master File 
 identify trial sites 
 confirm all approvals are in place before release of the trial treatment and the start of the 
trial at a site  
 provide training about the trial 
 provide study materials 
 data management centre 
 Investigational Medicinal Product management 
 24-hour advice and unblinding service 
 give collaborators and patients regular information about the progress of the study 
 respond to any questions (e.g. from collaborators and patients) about the trial 
 ensure data security and quality and observe data protection laws 

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 safety reporting 
 ensure trial is conducted in accordance with the ICH GCP including trial monitoring 
 statistical analysis 
 publication of trial results 
 
3.8 CONTACTING THE CTU IN AN EMERGENCY  
 
For urgent enquiries, adverse event reporting and unblinding queries investigators and patients can 
contact the 24-hour telephone service provided by the CTU. This number is given in the 
Investigator’s Study File and the Patient Alert Card. 
 
3.9 PUBLICATION AND DISSEMINATION OF RESULTS 
 
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 
(statinwise.Lshtm.ac.uk) 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.  
 
3.10 FINANCIAL SUPPORT 
 
The StatinWISE trial is funded by the NIHR Health Technology Assessment programme. Funding for 
this trial covers trial materials, meetings and central organisational costs. The design and 
management of the study are entirely independent of the manufacturers of atorvastatin, which is 
not a new product. 
 
 

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4. ABBREVIATIONS USED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AR 
Adverse Reaction 
CK 
Creatinine Kinase 
CONSORT 
Consolidated Standards Of Reporting Trials 
CRF 
Case Report Form 
CTU 
Clinical Trials Unit 
CVD 
Cardiovascular Disease 
DMC 
Data Monitoring Committee 
GP  
General Practitioner 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICH GCP 
International Conference on Harmonisation of Good Clinical Practice 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
LSHTM 
London School of Hygiene & Tropical Medicine 
mg 
milligram 
MOP 
Manual of Operating Procedures 
NICE 
National Institute for Health and Care Excellence 
PI 
Principal Investigator 
PSF 
Product Specification File 
QP 
Qualified Person 
RCT 
Randomised Controlled Trial 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
VAS  
Visual Analogue Scale 

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5. REFERENCES 
 
 
1. 
Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive
 lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised 
trials. Lancet 2010; 376(9753): 1670-81. 
2. 
National Institute for Health and Care Excellence (NICE). Lipid modification: cardiovascular risk 
assessment and the modification of blood lipids for the primary and secondary prevention of 
cardiovascular disease.  NICE clinical guideline 181. London, 2014. 
3. 
Scholes S, Faulding S, Mindell J. Chapter 5: Use of Prescribed Medicines, Health Survey for England 
2013. 2014. 
4. 
Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side 
effects in patients taking statins are genuinely caused by the drug? Systematic review of 
randomized placebo-controlled trials to aid individual patient choice. European journal of 
preventive cardiology 2014; 21(4): 464-74. 
5. 
Maningat P, Breslow JL. Needed: pragmatic clinical trials for statin-intolerant patients. The New 
England journal of medicine 2011; 365(24): 2250-1. 
6. 
Armitage J. The safety of statins in clinical practice. Lancet 2007; 370(9601): 1781-90. 
7. 
Garavalia L, Garavalia B, Spertus JA, Decker C. Exploring patients' reasons for discontinuance of 
heart medications. The Journal of cardiovascular nursing 2009; 24(5): 371-9. 
8. 
Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort 
study. Annals of internal medicine 2013; 158(7): 526-34. 
9. 
Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview 
of randomized clinical trials. Circulation 2006; 114(25): 2788-97. 
10. 
Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo 
phenomenon. Jama 2002; 287(5): 622-7. 
11. 
Moriarty PM. ODYSSEY ALTERNATIVE demonstrates complexity of statin-intolerant patients. AHA 
2014; 2014. 
12. 
Wieseler B, Wolfram N, McGauran N, et al. Completeness of reporting of patient-relevant clinical 
trial outcomes: comparison of unpublished clinical study reports with publicly available data. PLoS 
medicine 2013; 10(10): e1001526. 
13. 
Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. The 
New England journal of medicine 2007; 357(22): 2248-61. 
14. 
Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering 
with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 
2002; 360(9326): 7-22. 
15. 
Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus 
ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a 
randomised placebo-controlled trial. Lancet 2011; 377(9784): 2181-92. 
16. 
Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized 
controlled trial: clinical usefulness. Our three-year experience. Annals of internal medicine 1990; 
112(4): 293-9. 
17. 
Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical trial: the ultimate 
strategy for individualizing medicine? Personalized medicine 2011; 8(2): 161-73. 
18. 
Search Collaborative Group, Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy-
-a genomewide study. The New England journal of medicine 2008; 359(8): 789-99. 
19. 
Sakaeda T, Kadoyama K, Okuno Y. Statin-associated muscular and renal adverse events: data 
mining of the public version of the FDA adverse event reporting system. PLoS One 2011; 6(12): 
e28124. 
20. 
Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog 
pain scores. Academic emergency medicine : official journal of the Society for Academic Emergency 
Medicine 1996; 3(2): 142-6. 

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21. 
Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain 
severity measured on a visual analog scale. Annals of emergency medicine 2001; 38(6): 633-8. 
22. 
Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in 
Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. 
Journal of clinical lipidology 2012; 6(3): 208-15. 
23. 
Keech A, Collins R, MacMahon S, et al. Three-year follow-up of the Oxford Cholesterol Study: 
assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. 
European heart journal 1994; 15(2): 255-69. 
24. 
Breivik H, Borchgrevink PC, Allen SM, et al. Assessment of pain. British journal of anaesthesia 2008; 
101(1): 17-24. 
25. 
Arnold BF, Hogan DR, Colford JM, Jr., Hubbard AE. Simulation methods to estimate design power: 
an overview for applied research. BMC medical research methodology 2011; 11: 94. 
26.            Dexter F, Chestnut DH. Analysis of statistical tests to compare visual analog scale measurements     
                  among groups. Anesthesiology, 1995, 82:896-902 
27.             White IR, Kalaitzakib E, Thompson SG. Allowing for missing outcome data and incomplete uptake  
                   of randomised interventions, with application to an Internet-based alcohol trial. Statistics in     
                  Medicine, 2011, 30: 3192–3207 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6. Appendices 
 
Appendix 1: Trial assessment timelines 
Appendix 2: Baseline data form  
Appendix 3: End of Trial data form 
Appendix 4: Patient questionnaire 
Appendix 5: VAS Pain Scale data form 
Appendix 6: Patient Information Sheet 
Appendix 6a: Patient Information Sheet, Optional Genetic Study 
Appendix 7: Informed Consent Form 
Appendix 7a: Informed Consent Form, Optional Genetic Study 
Appendix 8: Summary of Product Characteristics for Atorvastatin 20 mg tablets 
Appendix 9: Recruiting pathway 
 

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StatinWise Trial Assessment timelines, Version 1.1, 27/06/2017 
Appendix 1 StatinWISE Trial assessment timelines  
 
 
  
Database 
search   
PIS posted 
to eligible 
patients 
Baseline 
Visit  
TP1          
(month 1-2) 
TP2           
(month 3-4) 
TP3           
(month 5-6)  
TP4          
(month 7-8)  
TP5       
(month 9-10)  
TP6  
(month 11-
12)  
Follow-up 
Visit 
(F2F/Phone) 
Secondary 
outcome 
data 
capture 
SCREENING 
  
  
  
  
  
  
  
  
  
  
  
Trial team performs GP practice 
patients' list screening to identify 
potentially eligible patients 
x 
  
  
  
  
  
  
  
  
  
  
GP reviews screening list and 
confirms patients are clinically 
eligible  
  
x 
  
  
  
  
  
  
  
  
  
Trial team posts PIS with reply 
slip 
  
x 
  
  
  
  
  
  
  
  
  
Patients contact trial team to 
arrange Baseline visit 
  
x 
  
  
  
  
  
  
  
  
  
ENROLMENT 
  
  
  
  
  
  
  
  
  
  
  
Patients attend enrolment visit 
with Research Nurse and sign 
consent form 
  
  
x 
  
  
  
  
  
  
  
  
Research Nurse completes the 
Baseline Form on electronic trial 
database. Baseline data will 
include:   
- Personal Details 
- Demographic data 
- Eligibility assessment  
- General medical history which 
may include blood test to 
measure total non-fasting 
cholesterol if none available in 
notes 
- Randomisation data  
  
  
x 
  
  
  
  
  
  
  
  

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Database 
search   
PIS posted 
to eligible 
patients 
Baseline 
Visit  
TP1          
(month 1-2)  
TP2           
(month 3-4)  
TP3           
(month 5-6)  
TP4          
(month 7-8)  
TP5       
(month 9-10)  
TP6           
(month 11-
12)  
Follow-up 
Visit 
(F2F/Phone) 
Secondary 
outcome 
data 
capture 
ENROLMENT 
  
  
  
  
  
  
  
  
  
  
  
Patients are randomised and 
trained on data entry tool of their 
choice 
  
  
x 
  
  
  
  
  
  
  
  
TREATMENT PERIOD 
  
  
  
  
  
  
  
  
  
  
  
IMP posted to patients' address 
  
  
 
 x 
x  
x  
x  
x  
 x 
  
  
Patients confirm receipt of IMP  
  
  
  
x 
x 
x 
x 
x 
x 
x 
  
Patients take study medication 
orally once daily 
  
  
  
x 
x 
x 
x 
x 
x 
x 
  
Reminder to submit outcome 
data 
  
  
  
x 
x 
x 
x 
x 
x 
x 
  
Patients enter outcome data and 
report any adverse events 
  
  
  
x 
x 
x 
x 
x 
x 
x 
  
Patients post unused IMP to 
Pharmacy 
  
  
  
x 
x 
x 
x 
x 
x 
x 
  
IMP accountability by Pharmacy 
  
  
  
x 
x 
x 
x 
x 
x 
x 
  
Trial newsletter sent to patients 
  
  
  
  
  
x 
  
  
x 
  
x 
FOLLOW-UP 
  
  
  
  
  
  
  
  
  
  
  
Individual results ready to 
disclose 
  
  
  
  
  
  
  
  
  
x 
  
Appointment (face-to-face or 
telephone call) with Research 
Nurse to discuss individual results 
  
  
  
  
  
  
  
  
  
x 
  
END OF TRIAL 
  
  
  
  
  
  
  
  
  
  
  
Research Nurse telephones 
patients to record outcome data  
  
  
  
  
  
  
  
  
  
  
x 

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StatinWISE Baseline data form, Version 3.1, 28/10/2016 
Appendix 2: StatinWISE Baseline data form 
 
 
 
ELIGIBILITY ASSESSMENT  (Circling any RED box means patient is NOT eligible)   
Eligibility 
Please circle 
8. Written informed consent obtained?  
YES 
NO* 
9. Is the patient aged 16 and over? 
YES 
NO* 
10. Patient has a clinical reason for treatment with atorvastatin 20mg daily? 
YES 
NO* 
11. Used statin within the last 3 years? 
YES 
NO* 
12. Is patient considering discontinuation of their statin due to muscle related 
adverse effects  
OR 
Has patient stopped taking a statin due to muscle related adverse effects? 
YES 
NO* 
13. Can atorvastatin 20mg daily be started or continued in the GP’s opinion? 
YES 
NO* 
14. Has patient had previously documented ALT levels at or above three times 
the upper limit of normal (ULN)?  
Test date: dd/mm/yyyy                    Result:  
(must be within 3 months of visit) 
    
 
 
iU/L 
YES* 
NO 
15. Does the patient 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? 
Test date: dd/mm/yyyy                            
(must be within 3 months of visit)                            Result: 
    
 
 
 U/L 
YES* 
NO 
                                                                                                                               *if circled, patient is NOT eligible 
1. Patient 
Initials 
 
 
 
2. Patient 
Screening ID 
 
 
 
 
- 
 
 
 
3. Site ID 
 
 
 
4. Visit date 
dd/mm/yyyy 
5. Gender 
 
6. Ethnicity 
a. White: (i) British (ii) Irish (iii) Traveller (iv) Other  
b. Black: (i) African (ii) Caribbean (iii) Black British (iv) Other 
c. 
Asian: (i) Asian British (ii) Indian (iii) Pakistani (iv) Chinese (v) Other 
d. Mixed 
e. Other: (describe)_________________ 
Circle main group and sub-
group  
7. Age                         
                                      Years            
Patient Personal Details:  The following information is needed for trial management purposes (sending trial 
medication and reminders) only and will not be collected as part of the trial database. 
A. Full name 
 
First name 
 
Last name 
B. Postal address 
 
 
House number/Name 
 
 Street name 
 
 
Town/City 
 
 
  
Postcode 
 
C. Email (primary) 
 
 
 
D. Email  (secondary) 
 
E. Home Telephone 
 
F. Mobile number 
 

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This data should be collected directly onto the online trial database (detail in your study file). If you are unable to enter this data, call 0207 299 
4684 
PATIENT GENERAL MEDICAL HISTORY 
16. Symptoms experienced during statin use that the patient believed were caused by the statin:  
(a) Muscle pain                     YES/NO                                              (f)  Sore throat                 YES/NO 
(b) Joint pain                         YES/NO                                              (g) Digestive problems   YES/NO 
(c) Muscle weakness           YES/NO                                              (h) Headache                    YES/NO 
(d) Tiredness/fatigue           YES/NO                                              (i)  Feeling sick                 YES/NO  
(e) Nosebleeds                     YES/NO                                        
17.  Does the patient think something other than statin may have caused their muscle pain?  YES/NO 
17(a)  If YES to Question 17, please describe: 
18. Does the patient have any history of cardiovascular disease?   YES/NO 
18a. If YES to Question 18, please indicate all that apply : 
(a) Angina or diagnosed coronary heart disease    YES/NO           (c) Previous ischaemic stroke       YES/NO 
(b) Previous myocardial infarction                            YES/NO           (d) Peripheral vascular disease     YES/NO 
(e) Other                                                                        YES/NO  (If yes, describe)_________________________________ 
19. Current use of high blood pressure medication? YES/NO 
 
 
 
 
 
 
 
20. Blood pressure measurement (mmHg):  
 
                                                                                                  a.  Systolic                 b.   Diastolic 
21. Diabetes? YES /NO 
22. Smoking status: (a) non-smoker  (b) ex-smoker (c) current smoker             
23. Total cholesterol measurement 
[mmol/L] (within last 3 years):  
          
 
If no reading, in line with NICE guidelines, organise 
non-fasting blood test for total cholesterol  
24. 
a. Height:  
cm 
 
b. Weight:  
Kg 
 
25. QRISK2 score: 
26. Record all current medication: 
Name of drug (generic) 
Total daily dose and unit 
1. 
 
27. Consent to participate in genetic study?  YES/NO 
27a. Blood sample taken?  YES/NO 
27b. Blood shipment reference: 
RANDOMISATION DATA 
28. Is patient fully eligible?   YES/NO 
29a. Date of Randomisation?  
  
 
 
 
 
 
 
 
 
 
 
 DD                             MM                               YYYY 
29b. Time of Randomisation? (24 hour clock) 
                                                                               
 
 
 
 
 
  HOUR                       MINS 
         
                                                                    
30. Randomisation Number: 
 
 
 
 
 
 
 
 
 
31. Method of data collection chosen?  
 
(a) Online system    (b) Mobile application 
(c) Phone call           (d) Paper CRFs           
31a. App successfully installed?  
 
YES/NO 
 
32. Training provided on 
method chosen? 
YES/NO 
 
33. Form completed by:  
34. Date: 
 

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StatinWISE End of Trial Form (Month 15) / Early Withdrawal, Version 1.0, 23/05/2016 
Appendix 3: StatinWISE End of Trial data form  
 
 
 
End of Trial Form (Month 15) / Early Withdrawal 
1. Did the patient complete 6 Treatment Periods?  
 
 
 
 
  
C.1.This form was completed by:___________________________    Date: dd/mm/yyyy 
NO 
B.1. Please tick reason why the patient did not complete 6 
treatment periods:  
 
 Lost to follow-up 
 Early withdrawal 
 Death  
B.2. Lost to follow-up:  
Date of last contact with patient? _________________ 
Dd/mm/yyyy 
B.3. If Early withdrawal, give reason: 
a. withdrawal of informed consent 
b. intolerable muscle symptoms* 
c. 
clinical concern* 
d. other* 
 
*: please enter details here: _____________________ 
____________________________________________ 
B.4. Has the patient contacted their GP to discuss reason 
for withdrawal?  
(i)  YES   
(ia)Date seen: :_____________ dd/mm/yyyy  
(ii) NO – (advise patient to contact GP).  
B.5. Has the Research Nurse/GP spoken to the patient to 
discuss their individual results?   
(i)  YES   
(ia)Date seen: :_____________ dd/mm/yyyy  
(ii) NO – (please arrange an appointment).  
(iia) Date of appointment:_______ dd/mm/yyyy 
 
B.6. Death ( SAE report form must be completed) 
 
B.6.a. Date of death: _____________ dd/mm/yyyy 
B.6.b Cause of death (either autopsy report or clinical 
judgement if autopsy not available): 
_______________________________ 
B.6.c. Date SAE form completed: ________dd/mm/yyyy 
 
YES 
A.1. Has the Research Nurse/GP spoken to the patient to 
discuss their individual results?   
(i)  YES   
(ia)Date seen: :_____________ dd/mm/yyyy  
(ii) NO – (please arrange an appointment).  
(iia) Date of appointment:_______ dd/mm/yyyy 
 
A.2. Has the patient seen his/her GP since end of 
Treatment Period 6? 
(i) YES 
(ii) NO (please remind the patient to book an appointment) 
(iia) Date reminder done:  _______ dd/mm/yyyy 
 
A.3. Has the patient been given a statin prescription in the 
4 weeks since Treatment Period 6 ended? 
(i) YES 
(ia) Name of Statin:____________ 
(ib) Dose of statin:_____________ 
(ii) NO  
 
A.4. Has the patient found their own trial results helpful to 
reach the decision as to whether to continue statin use?   
YES/NO 

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StatinWISE Patient questionnaire, Version 2.1, 28/10/2016 
Appendix 4: StatinWISE Patient questionnaire  
 
 
 
PART 1: ADHERENCE TO MEDICATION 
Step 1 (all participants): 
Q1. How would you best describe your use of study medication in the past two months? (Please choose one of the 
following options) 
 I didn’t take my study medication at all 
 
 I took my study medication on some days 
 
 I took my study medication on most days, but missed an occasional dose 
 
 I took my study medications every day 
 
 
Step 2 (appears if the participant chooses “I didn’t take my study medication at all“, or “I took my study medication on 
some days”): 
Q2. What was the reason that you didn’t take your study medication every day in the past two months? (please tick 
all that apply) 
 I forgot to take my study medication 
Ticking the above will prompt the following option, if ticked, the trial team will action:  
 Would you like a daily reminder sent to you via email/push notification 
 
 I was prescribed another medication and my doctor told me to stop taking my study medication 
Ticking the above will prompt an alert for the trial team to contact surgery for details and consider withdrawal 
from study  
 
 My doctor recommended that I stop taking study medication because of muscle symptoms 
Ticking the above will prompt an alert for the trial team to contact surgery for details  
 
 I decided to stop taking study medication because of muscle symptoms 
Ticking the above will prompt an alert for the patient to contact the GP for advice  
  
 I didn’t want to take my study medication 
Ticking the above will prompt the following option, if ticked NO, the trial team will arrange for end of trial: 
Do you still wish to participate in the trial: □ Yes □ No  
 Other (please specify) 
(free text) 
 
 
 
INSTRUCTIONS 
This questionnaire is to be filled out once every two months (on day 56).  We will remind you one day 
before it is due. Please answer all questions.  If you need any help to complete the form. Please call our 
Freephone number 08000 147410 or email the study team: statinwise@lshtm.ac.uk.  
 

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PART 2: EXPLORING SYMPTOMS IN THE PAST TWO MONTHS 
 
1. (all participants): In the last two months, have you experienced muscle symptoms, e.g. muscle pain or weakness?  
 Yes 
 
 No 
 
 
2. (appears if the participant ticks yes for Question 1): Do you think these muscle symptoms are related to your study 
medication? 
 
 Yes 
 
 No 
 Don’t know 
 
 
3. (appears if the participant ticks no for Question 2): What do you think may have caused these muscle symptoms? 
 (free text) 
 
 Don’t know 
 
 
 
4. (appears if the participant ticks yes for Question 1): Indicate with a cross ()  on the scale  the number that 
describes how, during the last two months, pain has interfered with your: 
a. General activity 
b. Mood 
c. 
Walking ability 
d. Normal work (includes both work outside the home and housework) 
e. Relations with other people 
f. 
Sleep 
g. 
Enjoyment of life 
For each of (a) to (g),  the following scale will appear:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5. (appears if the participant ticks yes for Question 1): On the diagram, tap to highlight the area that hurts the most. 
(Paper form will read: ‘On the diagram, put an X on the area that hurts the most.’) 
 
 
 
 
 
 
 
 
 More than one area 
 
The body will be divided into the following locations and answers should be categorized depending where the participant 
taps. For paper forms, the location given by X marked on the body will be entered into the web or app version at data 
entry. Locations: head and neck/upper limbs/lower limbs/trunk. 
 
 
 
 
6. (All participants): In the last two months, have you experienced any other symptom that you think is associated 
with your study medication?  
 Yes (please specify) 
 
(free text) 
 No 
 Don’t know 
 
PART 3: ADVERSE EVENTS 
1.  (All participants): Have you been admitted to hospital in the last two months? 
 Yes 
 
 No 
 
2. (Appears if the participant ticks yes for Question 1): What was the reason for your admission to hospital? 
 
(free text) 
 
 
 
      FRONT                                          BACK 
      Right                                   Left        Left                                    Right 

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StatinWISE VAS Pain Scale data form, Version 1.0, 23/05/2016 
Appendix 5: StatinWISE VAS Pain Scale data form  
 
You will be asked to complete this form each day during the last seven days of each two-month treatment period.  
Day 
                    Daily symptoms report 
 
 
1 
 
1. Did you take study medication yesterday? 
 
 
  
2. Did you experience muscle symptoms 
today? 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 
2 
 
1. Did you take study medication yesterday? 
 
 
  
2. Did you experience muscle symptoms 
today? 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 
3 
 
1. Did you take study medication yesterday? 
 
 
  
2. Did you experience muscle symptoms 
today? 
 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 

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4 
 
1. Did you take study medication yesterday? 
 
 
  
2. Did you experience muscle symptoms 
today? 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 
5 
 
1. Did you take study medication yesterday? 
 
 
  
2. Did you experience muscle symptoms 
today? 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 
6 
 
1. Did you take study medication yesterday? 
 
 
  
2. Did you experience muscle symptoms 
today? 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 
7 
 
1. Did you take study medication yesterday? 
 
 
If yes: 
2. Did you experience muscle symptoms 
today? 
 
 
No               Yes 
 
 
 
No               Yes 
If yes: 
 
 
  3: Please indicate severity of muscle symptoms you experienced today.  
 
 

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StatinWISE Patient Information Sheet, Version 2.0, 27/06/2017 
Appendix 6: StatinWISE Patient Information Sheet 
IRAS project ID: 197990 
 
 
 
 
Site contact info and logo 
 
StatinWISE: Investigation of STATIN Side Effects 
INFORMATION FOR PATIENTS  
 
We invite you to take part in a research study  
called StatinWISE 
 
 Before you decide whether to take part, it is 
important for you to understand why the research is 
being done, and what it will involve 
 Please take time to read this information carefully 
and discuss it with friends or relatives if you wish 
 You are encouraged to ask any questions you wish, 
before, during or after the study 
 You are entirely free to decide whether or not to take 
part in this trial. If you choose not to take part, the 
care you are given by your GP will not be affected 
 If there is anything that is not clear, or if you would 
like more information, please telephone the 
StatinWISE Research Nurse on [insert details]  
 
Important things that you need to know 
 
 We want to find out whether statins are the cause of 
muscle symptoms 
 There will be only one visit to your GP practice as the 
study is done by phone or by the web 
 The study treatment is posted directly to you and will 
fit through your letterbox 
 At the end of the study, you will get personalised 
results so you can see if your own muscle symptoms 
are caused by statins 
 You can stop taking part in the study at any time 
 Support will be given to you throughout the study 
  
Contents 
 
1. 
Why are we doing this study? 
 
2. 
Why have I been asked to take part? 
 
3. 
What will happen if I take part?  
 
4. 
What are the possible benefits of 
taking part in the study? 
 
5. 
What are the possible risks of taking 
part in the study? 
 
6. 
What if I don’t want to be part of this 
study anymore? 
 
7. 
What happens if I experience side 
effects? 
 
8. 
Will my participation in the study be 
kept private?  
 
9. 
Who can I contact to join the trial, ask 
questions or contact if I have a 
problem? 
 
10. What else do you need to know? 
 

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1. Why are we doing this study? 
Statins reduce the risk of heart attacks and strokes, however many patients stop taking statins 
because they get aches and pains in their muscles. The link between taking statins and aches and 
pains is not fully understood. Aches and pains are really common among people who don’t take 
statins, and this means when someone taking a statin develops pain, it is really difficult to know 
whether the pain is caused by their statin. This means it is very difficult for patients and doctors to 
know whether to stop the statin or to continue. This is an important decision, because by not taking 
a statin, a patient’s risk of a heart attack or stroke goes up by about one third. This study aims to 
determine whether statins cause muscle pain, thus allowing patients to make well-informed 
decisions whether to stop them or not.  
 
2. Why have I been asked to take part? 
You have been invited to take part because you have been prescribed a statin which you have either 
stopped taking within the last 3 years, or you are considering stopping, due to muscle related side-
effects. Your GP thinks you are eligible and has invited you to take part. It is up to you to decide if 
you wish to take part or not.  
 
3. What will happen if I take part?  
Everyone taking part will have agreed to do so voluntarily, knowing the study involves: 
 Most people will need a blood test, but this will only be once. 
 One main visit to your GP Practice. The Research Nurse will explain everything about the study, 
including what to do if you have queries. You can ask any questions that you may have.  
 If you decide to go ahead, you will have your weight, height and blood pressure recorded and 
sign a consent form.  
 Taking atorvastatin or placebo (dummy treatment) daily for 1 year in 2-months sequences, 
switching between them in a random order. Neither you, nor your doctor, will know which you 
are taking in each 2-month period, except in an emergency. 
 Completing 6 short questionnaires on your muscle symptoms every 2 months. There are a few 
ways in which you can choose to complete the questionnaires; via the web, verbally over the 
phone, mobile phone app or conventional paper form. 
 At the end of 12 months, there will be one phone call or face-to-face appointment with your GP 
or Research Nurse to discuss your own results based on the information you provided in your 
questionnaires. You can also discuss the results with your GP and make a decision about whether 
you want to continue taking a statin or not.  
 Three months after you stopped the study treatment, the study team will contact you to ask if 
you continued taking statins or not. 
 
 
 
Take your 
treatment 
everyday 
for a year 
Appointment 
with your GP 
practice to 
enrol in the 
study 
Complete a short 
questionnaire on 
your muscle 
symptoms for only 
7 days 
Get your own 
personalised 
results
1 - 12 Months 
Every 2 months 
Month 14 
Study 
treatment 
posted 
directly to 
you 
Phone call from 
study team to 
find out if you 
continued taking 
statins 
Month 15 
Have your 
routine 
blood test 
(if needed) 
Study Timeline: 

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4. What are the possible benefits of taking part in the study? 
This study will allow you and your GP to find out if any muscle symptoms you experience happen 
more when you are taking statins. This may help you to decide with your GP whether to take statins 
to reduce your risk of cardiovascular disease after the end of the study. 
 
5. What are the possible risks of taking part in the study? 
The study team do not know if statins cause milder muscle symptoms such as pain, which is why we 
are doing the study. Statins sometimes cause a very rare but serious muscle problem, but in less 
than 2 in 10,000 people.  
 
6. What if I don’t want to be part of this study anymore? 
You can withdraw from the study at any time. We hope that you will let us use the information we 
have collected up to that point, but if you do not want us to use it please tell the Research Nurse or 
your GP.  
 
7. What happens if I experience side effects? 
You will be given an alert card when you join the study. If you experience any bad side effects, and 
wish to stop the medications, you should tell your GP. Your GP will continue to give you the best 
available care if there are any problems. If your GP decides you should not take part in the study for 
any reason, s/he can also withdraw you from the study.  
 
8. Will my participation in the study be kept private?  
The only people who are allowed to look at the information will be the team responsible for the 
study at the London School of Hygiene & Tropical Medicine and regulatory authorities who check 
that the study is being carried out properly. The GP Practice will need to share your personal 
information (name, address, phone number and email address) with the London School of Hygiene 
& Tropical Medicine so that they can send you the study treatment and help you with completing 
the questionnaires. All information collected about you will be kept private and used in strict 
confidence by the people working on the study.  
 
We will publish the study results in a medical journal so that other doctors can benefit from the 
knowledge. Your personal information will not be included in the study report and there is no way 
that you can be identified. The study data, without any personal information, will be made available 
to researchers worldwide so that it can be used to improve medical knowledge and patient care. 
 
9. Who can I contact to join the trial, ask questions or contact if I have a problem? 
If you would like to join the study, you can complete the reply slip enclosed and return it in the 
freepost envelope provided. The Research Nurse at your GP Practice will then contact you to arrange 
an appointment. Otherwise you can call your GP Practice on [insert details] to arrange an 
appointment.  
 
If you have any questions or concerns about the study, you should ask to speak with the study 
doctors or Research Nurses who will do their best to answer your questions. Your GP and Research 
Nurse can be contacted as follows: 
 
Name 
Personalise for each site 
Address 
 
Phone Number 
 
Email 
 
 

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10. What else do you need to know? 
 The study is organised by the London School of Hygiene & Tropical Medicine and is funded by the 
Department of Health.  
 The lead study doctor is a GP Professor Liam Smeeth at the London School of Hygiene and 
Tropical Medicine. 
 In the unlikely event of you being harmed as a result of taking part in the study, the London 
School of Hygiene & Tropical Medicine would be responsible for claims for any non-negligent 
harm suffered as a result of participating in the study. You would retain the same rights of care 
as any other patient treated in the National Health Service. 
 If you have any complaints about the StatinWISE study, please contact your GP Practice Manager. 
 To protect your rights and well-being, all research conducted in the NHS is reviewed by an 
independent group of people called a Research Ethics Committee. Southampton Research Ethics 
Committee have given favorable ethical opinion for the study. The study has been reviewed, and 
approved, by the Medicines and Healthcare products Regulatory Agency who regulate clinical 
trials in the UK. 
 If you would like to have a summary of the results of this study when it has ended, please let the 
Research Nurse know. 
 
To contact the Clinical Trials Unit at London School of Hygiene & Tropical Medicine: 
e-mail: statinwise@lshtm.ac.uk 
Freephone: 0800 014 7410 
Post: StatinWISE study, LSHTM, Room 180, Keppel Street, London WC1E 7HT.  
 
 
 
 
 
 

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StatinWISE Patient Information Sheet, Optional Genetic Study, Version 1.0, 27/06/2017 
 
 
Site contact info and logo 
 
Appendix 6A: StatinWISE Patient Information Sheet – Optional Genetic Study  
IRAS Project ID: 197990 
 
 
   
Web-based Investigation of STATIN Side Effects 
 
INVITATION TO TAKE PART IN AN OPTIONAL 
GENETIC STUDY FOR StatinWISE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A randomised clinical trial to assess if atorvastatin treatment 
causes more muscle symptoms than placebo  
Thank you for taking part in StatinWISE 
 
Before you decide whether to take part in this optional genetic study, it is 
important for you to understand why the research is being done and what 
is involved. Please take time to read the information carefully and discuss it 
with friends or relatives if you wish. You are entirely free to decide whether 
or not to take part in this optional blood sample study. There are no extra 
visits to take part in this study. If you choose not to take part, the care you 
are given by your GP will not be affected. 
 
If anything is unclear, or if you would like more information, please 
telephone the StatinWISE Research Nurse on [insert details]  
 
StatinWISE is coordinated by the London School of Hygiene & Tropical Medicine Clinical Trials Unit and funded by the 
National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme 

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Web-based Investigation of STATIN Side Effects 
 
1. Why are we doing this optional genetic study 
The link between taking statins and aches and pains is not fully understood, but may be linked to 
underlying genetic markers. This study aims to determine whether muscle pain considered to be 
due to statins is associated with genetic markers. Knowing this association may direct future medical 
management of using statins. 
 
2.  Why have I been asked to take part? 
You have been asked to participate because you are taking part on StatinWISE. It is up to you to 
decide if you wish to participate or not. If you do not want to take part, your participation on 
StatinWISE will not change, neither will your future medical care be affected.   
 
3. What will happen if I take part?  
 Your GP practice research nurse will take one small (9mls, 2 teaspoons) blood sample 
 Your sample will be labelled only with a trial identification number and sent to a laboratory 
at the University of Liverpool for analysis without any of your personal information. 
 
4. What are the possible benefits of taking part in the study? 
This optional study will allow scientists to understand if muscle symptoms experienced with statins 
are influenced by people’s genes. The blood sample you give can be used also for other research 
studies. This may help direct future medical management of the use of statins. 
 
5. What are the possible risks of taking part in the study? 
It is very rare for a blood test to result in any serious complications. Risks associated with this test 
are no different to any regular blood test that you will have as part of routine clinical care.  You may 
experience bruising as a result of taking the blood. 
 
6. Will my participation in the study be kept private?  
The only people who are allowed to look at your personal information will be the team responsible 
for the study at the London School of Hygiene & Tropical Medicine and regulatory authorities who 
check that the study is being carried out properly. The GP Practice will not share your personal 
information with the genetics laboratory. The results of the genetic analysis will not be shared with 
you, your GP or the StatinWISE team.  
 
To contact the Clinical Trials Unit at London School of Hygiene & Tropical Medicine: 
e-mail: statinwise@lshtm.ac.uk 
Freephone: 0800 014 7410 
Post: StatinWISE study, LSHTM, Room 180, Keppel Street, London WC1E 7HT.   
 
 
  
 
 

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StatinWISE Informed Consent Form, Version 2.0, 27/06/2017 
IRAS project ID: 197990 
Appendix 7: StatinWISE Informed Consent Form  
 
Name of Principal Investigator: 
 
 
  
 
 
 
       Printed name of participant 
 
         Signature of participant                                      Date  
I confirm that I have explained the study information accurately to, and was understood to the best of my 
knowledge by, the participant and that he/she has freely given their consent to participate. 
 
 
 
 
   Printed name of person obtaining consent 
        Signature of person obtaining consent 
 Date 
1 copy of participant, 1 for investigator file and 1 for medical notes. 
 
 
1. Patient Initials 
 
 
 
2. Patient 
Screening ID 
 
 
 
 
- 
 
 
 
3. Site ID 
 
 
 
Statement  
Please  initial 
each box 
I confirm that I have read the information sheet dated………………….(version…….) for the above named 
study and given a copy to keep.  I have had the opportunity to consider the information, ask questions 
and have these answered satisfactorily. 
 
I understand that my participation is voluntary and that I am free to withdraw at any time without 
giving any reason, and without my medical care or legal rights being affected. 
 
I understand that relevant sections of my medical notes and data collected during the study may be 
looked at by individuals from the sponsor of the trial (London School of Hygiene & Tropical Medicine) 
and responsible persons authorised by the sponsor, from ethics and regulatory authorities, or from 
the NHS Trust, where it is relevant to my taking part in this research. I give permission for these 
individuals to have access to my records.  
 
I understand that my personal details will be kept separately and I give permission for those details to 
be available to LSHTM Clinical Trial Unit staff to post the study treatment to my address. 
 
I understand that the information collected about me (with my personal information removed) will be 
used to support other research in the future, and I agree that data collected during this study can be 
used in future ethically approved research projects.  
 
I give permission for a copy of this consent form, which contains my personal information, to be made 
available to the LSHTM Clinical trials Unit. 
 
I agree to take part in the StatinWISE study. 
 

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StatinWISE Informed Consent Form, Optional Genetic Study, Version 1.0, 27 /06/2017 
IRAS project ID: 197990 
Appendix 7A StatinWISE Informed Consent Form – Optional Genetic 
Study  
 
Name of Principal Investigator: 
 
 
 
 
  
 
 
 
    Printed name of participant  
 
       Signature of participant 
                                   Date  
  
I confirm that I have explained the study information accurately to, and was understood to the best of my knowledge by, the 
participant and that he/she has freely given their consent to participate. 
 
 
 
 
     Printed name of person obtaining consent 
       Signature of person obtaining consent 
      Date 
 
1 copy of participant, 1 for investigator file and 1 for medical notes. 
 
 
1. Patient Initials 
 
 
 
2. Patient 
Screening ID 
 
 
 
 
- 
 
 
 
3. Site ID 
 
 
 
Statement - Optional blood sample 
Please  initial 
each box 
I understand that my blood sample will not contain any of my personal information and will be stored 
at the University of Liverpool. 
 
I give permission for my blood sample to be used in the future ethically approved research projects. 
 
I agree to have a blood sample taken for genetic analysis.  
 

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Appendix 8: Summary of Product Characteristics for Atorvastatin 20 mg tablets 
 
1       NAME OF THE MEDICINAL PRODUCT  
Atorvastatin 20 mg Film-coated Tablets  
  
  
  
2       QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
Each film coated tablet contains 20 mg atorvastatin (as atorvastatin calcium)  
  
For a full list of excipients, see section 6.1.  
  
  
 
3       PHARMACEUTICAL FORM  
Film-coated tablet.  
  
White to off-white, elliptic, biconvex and smooth film-coated tablets. The dimensions of each tablet are 
approximately 12.5 mm x 6.6 mm.  
  
  
 
4      CLINICAL PARTICULARS  
  
4.1       THERAPEUTIC INDICATIONS  
  
Hypercholesterolaemia  
Atorvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-
cholesterol (LDL-C), apolipoprotein B and triglycerides in adults, adolescents and children aged 10 years or 
older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or 
combined (mixed) hyperlipidaemia (corresponding to Types IIa and IIb of the Fredrickson classification) when 
response to diet and other non pharmacological measures is inadequate.  
  
Atorvastatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial 
hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such 
treatments are unavailable.  
  
Prevention of cardiovascular disease  
Prevention of cardiovascular events in patients estimated to have a high risk for a first cardiovascular event 
(see section 5.1), as an adjunct to correction of other risk factors.  
  
 
 
 
 

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4.2       POSOLOGY AND METHOD OF ADMINISTRATION  
  
Posology  
The patient should be placed on a standard cholesterol-lowering diet before receiving atorvastatin and should 
continue on this diet during treatment with atorvastatin.  
  
The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient 
response.  
  
The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or 
more. The maximum dose is 80 mg once a day.  
  
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia The majority of patients are 
controlled with atorvastatin 10 mg once a day. A therapeutic response is evident within 2 weeks, and 
the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained 
during chronic therapy.  
  
Heterozygous familial hypercholesterolaemia  
Patients should be started with atorvastatin 10 mg daily. Doses should be individualised and adjusted every 4 
weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid 
sequestrant may be combined with 40 mg atorvastatin once daily.  
  
Homozygous familial hypercholesterolaemia  
Only limited data are available (see section 5.1).   
  
The dose of atorvastatin in patients with homozygous familial hypercholesterolaemia is 10 to 80 mg daily (see 
section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) 
in these patients or if such treatments are unavailable.   
  
Prevention of cardiovascular disease  
In the primary prevention trials the dose was 10 mg/day. Higher dosages may be necessary in order to attain 
(LDL-) cholesterol levels according to current guidelines.  
  
Renal impairment  
No adjustment of dose is required (see section 4.4).  
  
Hepatic impairment  
Atorvastatin should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). 
Atorvastatin is contraindicated in patients with active liver disease (see section 4.3).  
  
Use in the elderly  
Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general 
population.  
  
Paediatric use  
Hypercholesterolaemia:  
Paediatric use should only be carried out by physicians experienced in the treatment of paediatric 
hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.  
  
For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day with 
titration up to 20 mg per day.  Titration should be conducted according to the individual response and 
tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, 
corresponding to about 0.5 mg/kg, is limited.  

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There is limited experience in children between 6-10 years of age (see section 5.1).  Atorvastatin is not 
indicated in the treatment of patients below the age of 10 years.  
  
Other pharmaceutical forms/strengths may be more appropriate for this population.  
  
Method of administration  
  
Atorvastatin is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at 
any time of day with or without food.  
  
4.3       CONTRAINDICATIONS  
  
              Atorvastatin is contraindicated in patients:  
 
with hypersensitivity to the active substance or to any of the excipients of this medicinal product  
 
with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 
times the upper limit of normal  
 
during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate 
contraceptive measures (see section 4.6).  
  
  
4.4        SPECIAL WARNINGS AND PRECAUTIONS FOR USE  
 
Liver effects  
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients 
who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. 
Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve. 
Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction 
of dose or withdrawal of atorvastatin is recommended (see section 4.8).  
  
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have 
a history of liver disease.   
  
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In a post-hoc analysis of stroke 
subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack 
(TIA) there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin 80 mg compared 
to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar 
infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and 
benefits of atorvastatin 80 mg is uncertain, and the potential risk of haemorrhagic stroke should be carefully 
considered before initiating treatment (see section 5.1). Immune-mediated necrotizing myopathy (IMNM)  
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after 
treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and 
elevated serum creatine kinase, which persist despite discontinuation of statin treatment.  
  
Skeletal muscle effects  
Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and 
cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening 
condition characterised by markedly elevated creatine kinase (CK) levels (>10 times ULN), myoglobinaemia 
and myoglobinuria which may lead to renal failure.  
  
Before the treatment  
Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabomyolysis. A CK 
level should be measured before starting statin treatment in the following situations:  
− Renal impairment  

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− Hypothyroidism  
− Personal or familial history of hereditary muscular disorders  
− Previous history of muscular toxicity with a statin or fibrate  
− Previous history of liver disease and/or where substantial quantities of alcohol are consumed  
− In the elderly (age >70 years), the necessity of such measurement should be considered, according to the 
presence of other pre-disposing factors for rhabdomyolysis.  
− Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and 
special populations including genetic subpopulations (see section 5.2)  
  
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical 
monitoring is recommended.  
  
If CK levels are significantly elevated (>5 times ULN) at baseline, treatment should not be started.  
  
Creatine kinase measurement  
Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible 
alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly 
elevated at baseline (>5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the 
results.  
  
Whilst on treatment  
− Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied 
by malaise or fever.  
− If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should 
be measured. If these levels are found to be significantly elevated (>5 times ULN), treatment should 
be stopped.  
− If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤5 x 
ULN, treatment discontinuation should be considered.  
− If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction 
of an alternative statin may be considered at the lowest dose and with close monitoring.  
− Atorvastatin must be discontinued if clinically significant elevation of CK levels (>10 x ULN) occur, or 
if rhabdomyolysis is diagnosed or suspected.  
  
Concomitant treatment with other medicinal products  
Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal 
products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or 
transport proteins (e.g.  
ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, 
posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). 
The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid 
derivates, erythromycin, niacin and ezetimibe. If possible, alternative (noninteracting) therapies should be 
considered instead of these medicinal products.   
  
In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the 
risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products 
that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. 
In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered 
and appropriate clinical monitoring of these patients is recommended (see section 4.5).  
  
The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of 
atorvastatin may be considered during fusidic acid therapy (see section 4.5).  
  
Interstitial lung disease  
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term 
therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in 
general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung 
disease, statin therapy should be discontinued.  

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Diabetes Mellitus  
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future 
diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, 
however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for 
stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised 
triglycerides, hypertension) should be monitored both clinically and biochemically according to national 
guidelines.  
  
Paediatric use   
Developmental safety in the paediatric population has not been established (see section 4.8).  
  
4.5        INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF 
INTERACTION  
  
Effect of co-administered medicinal products on atorvastatin  
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate to transport proteins e.g. 
the hepatic uptake transporter OATP1B1. Concomitant administration of medicinal products that are inhibitors 
of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased 
risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other 
medicinal products that have a potential to induce myopathy, such as fibric acid derivates and ezetimibe (see 
section 4.4).  
  
CYP3A4 inhibitors  
Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see 
Table 1 and specific information below). Coadministration of potent CYP3A4 inhibitors (e.g. ciclosporin, 
telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole 
and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be 
avoided if possible. In cases where coadministration of these medicinal products with atorvastatin cannot be 
avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical 
monitoring of the patient is recommended (see Table 1).  
  
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma 
concentrations of atorvastatin (see Table 1).. An increased risk of myopathy has been observed with the use of 
erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil 
on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 
activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a 
lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is 
recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is 
recommended after initiation or following dose adjustments of the inhibitor.  
  
CYP3A4 inducers  
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz, rifampin, St. 
John’s Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual 
interaction mechanism of rifampin, (cytochrome P450 3A induction and inhibition of hepatocyte uptake 
transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as 
delayed administration of atorvastatin after administration of rifampin has been associated with a significant 
reduction in atorvastatin plasma concentrations. The effect of rifampin on atorvastatin concentrations in 
hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be 
carefully monitored for efficacy.  
  
Transport protein inhibitors  
Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 
1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is 
unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for 
efficacy is recommended (see Table 1).  
 

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Gemfibrozil / fibric acid derivatives  
The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The 
risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If 
concomitant administration cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic 
objective should be used and the patients should be appropriately monitored (see section 4.4).  
 
Ezetimibe  
The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of 
these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate 
clinical monitoring of these patients is recommended.  
  
Colestipol  
Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when colestipol 
was co-administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol 
were co-administered than when either medicinal product was given alone.  
  
Fusidic acid  
Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle 
related events, including rhabdomyolysis, have been reported in post-marketing experience with atorvastatin 
and fusidic acid given concurrently. The mechanism of this interaction is not known. Patients should be closely 
monitored and temporary suspension of atorvastatin treatment may be appropriate.  
  
Effect of atorvastatin on co-administered medicinal products  
Digoxin  
When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steadystate digoxin 
concentrations increased slightly. Patients taking digoxin should be monitored appropriately.  
 
 
Oral contraceptives  
Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of 
norethindrone and ethinyl oestradiol.   
  
Warfarin  
In a clinical study in patients receiving chronic warfarin therapy, coadministration of atorvastatin 80 mg daily 
with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of 
dosing which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of 
clinically significant anticoagulant interactions have been reported, prothrombin time should be determined 
before starting atorvastatin in patients taking coumarin anticoagulants and frequently enough during early 
therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has 
been documented, prothrombin times can be monitored at the intervals usually recommended for patients on 
coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be 
repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in 
patients not taking anticoagulants.   
  
Paediatric population  
Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric 
population is not known.  The above mentioned interactions for adults and the warnings in section 4.4 should 
be taken into account for the paediatric population.  
  
 
 
 
 
 

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Table 1: Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin  
  
Co- 
administered 
medicinal 
product and 
dosing regimen  
Atorvastatin  
 
 
Dose (mg)  
Change in AUC*  
Clinical  
Recommendation**  
Tipranavir 
500 
mg BID/  
Ritonavir 200 
mg BID, 8 days 
(days 14 to 21)  
40 mg on day 1,  
10 mg on day 20  
↑ 9.4 fold  
In cases where 
coadministration with 
atorvastatin is necessary, 
do not exceed 10 mg 
atorvastatin daily. 
Clinical monitoring of 
these patients is 
recommended  
Ciclosporin 5.2 
mg/kg/day, 
stable dose  
10 mg OD for 28 
days  
↑ 8.7 fold  
Lopinavir 400 
mg BID/  
Ritonavir 100 
mg BID, 14 days  
20 mg OD for 4 days  ↑ 5.9 fold  
In cases where 
coadministration with 
atorvastatin is necessary, 
lower maintenance doses 
of atorvastatin are 
recommended. At 
atorvastatin doses 
exceeding 20 mg, clinical 
monitoring of these 
patients is recommended.  
Clarithromycin 
500 mg BID, 9 
days  
80 mg OD for 8 days  ↑ 4.4 fold  
Saquinavir 
400 
mg BID/  
Ritonavir (300 
mg BID from 
days 5-7, 
increased to 400 
mg BID on day 
8), days 5-18, 30 
min  
after atorvastatin 
dosing  
40 mg OD for 4 days  ↑ 3.9 fold  
In cases where 
coadministration with 
atorvastatin is necessary, 
lower maintenance doses 
of atorvastatin are 
recommended. At 
atorvastatin doses 
exceeding 40 mg, clinical 
monitoring of these 
patients is recommended.  
Darunavir 300 
mg BID/ 
Ritonavir 100 
mg BID, 9 days  
10 mg OD for 4 days  ↑ 3.3 fold  
Itraconazole  
200 mg OD, 4 
days  
40 mg SD  
↑ 3.3 fold  
Fosamprenavir  
700 mg BID/ 
Ritonavir 100 
mg BID, 14 days  
10 mg OD for 4 days  ↑ 2.5 fold  
Fosamprenavir  
1400 mg BID,  
14 days  
10 mg OD for 4 days  ↑ 2.3 fold  

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Nelfinavir  
1250 mg BID,  
14 days  
10 mg OD for 28 
days  
↑ 1.7 fold***  
No specific 
recommendation  
Grapefruit  
Juice, 240 mL  
OD ****  
40 mg, SD  
↑ 37%  
Concomitant intake of 
large quantities of 
grapefruit juice and 
atorvastatin is not 
recommended.  
Diltiazem 240 
mg 
OD, 
28 
days  
40 mg, SD  
↑ 51%  
After initiation or 
following dose 
adjustments of diltiazem, 
appropriate clinical 
monitoring of these 
patients is recommended.  
Erythromycin 
500 mg QID, 7 
days  
10 mg, SD  
↑ 33%***  
Lower maximum dose  
and clinical monitoring 
of these patients is 
recommended.  
Amlodipine 10 
mg, single dose  
80 mg, SD  
↑ 18%  
No specific 
recommendation.   
Cimetidine 300 
mg QID, 2 
weeks  
10 mg OD for 4 
weeks  
↓ less than 1%***  
No specific 
recommendation.  
Antacid 
suspension of 
magnesium and 
aluminium 
hydroxides, 30 
mL QID, 2 
weeks  
10 mg OD for 4 
weeks  
↓ 35%***  
No specific 
recommendation.  
Efavirenz 600 
mg OD, 14 days  
10 mg for 3 days  
↓ 41%  
No specific 
recommendation.  
Rifampin 600 
mg OD, 7 days  
(coadministered)  
40 mg SD  
↑ 30%  
If co-administration 
cannot be avoided, 
simultaneous 
coadministration of 
atorvastatin with rifampin 
is recommended, with 
clinical monitoring.  
Rifampin 600 
mg OD, 5 days  
(doses separated)  
40 mg SD  
↓ 80%  
Gemfibrozil 600 
mg BID, 7 days  
40mg SD  
↑ 35%  
Lower starting dose and 
clinical monitoring of 
these patients is 
recommended.  
Fenofibrate 160 
mg OD, 7 days  
40mg SD  
↑ 3%  
Lower starting dose and 
clinical monitoring of 
these patients is 
recommended.  
* Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 
1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = 
no change).  
** See sections 4.4 and 4.5 for clinical significance.  
*** Total atorvastatin equivalent activity  
**** Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of 
medicinal products metabolized by CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a 
decreased AUC of 20.4% for the active orthohydroxy metabolite. Large quantities of grapefruit juice (over 1.2 
l daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites).  
Increase is indicated as “↑”, decrease as “↓”  

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OD = once daily; SD = single dose; BID = twice daily; QID = four times daily  
  
Table 2: Effect of atorvastatin on the pharmacokinetics of co-administered medicinal products  
  
Atorvastatin and 
dosing regimen  
Co-administered medicinal product 
 
Medicinal product/Dose 
(mg)  
Change in AUC*  
Clinical  
Recommendation  
80 mg OD for 10 
days  
Digoxin 0.25 mg OD, 
20 days  
↑ 15%  
Patients taking digoxin 
should be monitored 
appropriately.  
40 mg OD for 22 
days  
Oral contraceptive OD, 
2 months  
- norethindrone 1 mg -
ethinyl estradiol 35 μg  
↑ 28%  
↑ 19%  
No specific 
recommendation.  
80 mg OD for 15 
days  
** Phenazone, 600 mg 
SD  
↑ 3%  
No specific 
recommendation.  
* Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change)  
** Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in 
the clearance of phenazone.  
Increase is indicated as “↑”, decrease as “↓”  
OD = once daily; SD = single dose  
  
4.6       PREGNANCY AND LACTATION  
 
Women of childbearing potential  
Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 
4.3).  
  
Pregnancy  
Atorvastatin is contraindicated during pregnancy (see section 4.3). Safety in pregnancy woman has not been 
established (see section 4.3). No controlled clinical trials with atorvastatin have been conducted in pregnant 
women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase 
inhibitors have been received. Animal studies have shown toxicity to reproduction (see section 5.3).  
  
Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of 
cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering 
medicinal products during pregnancy should have little impact on the long-term risk associated with primary 
hypercholesterolaemia.  
  
For these reasons, atorvastatin should not be used in women who are pregnant, trying to become pregnant or 
suspect they are pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or 
until it has been determined that the woman is not pregnant (see section 4.3.)  
  
Breastfeeding  
It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma 
concentrations of atorvastatin and its active metabolites are similar to those in milk (see section 5.3). Because 
of the potential for serious adverse reactions, women taking atorvastatin should not breast-feed their infants 
(see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).  
  
Fertility   
In animal studies atorvastatin had no effect on male or female fertility (see section 5.3).  

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4.7        EFFECTS ON ABILITY TO DRIVE AND USE MACHINES  
Atorvastatin has negligible influence on the ability to drive and use machines.  
 
4.8        UNDESIRABLE EFFECTS  
  
In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Lipitor vs. 7311 placebo) patients 
treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions 
compared to 4.0% of the patients on placebo.  
  
Based on data from clinical studies and extensive post-marketing experience, the following table presents the 
adverse reaction profile for atorvastatin.  
 
Estimated frequencies of reactions are ranked according to the following convention: common (≥1/100, 
<1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (≤1/10,000), not known (cannot 
be estimated from the available data).  
  
Infections and infestations  
Common:   
nasopharyngitis. 
Blood and lymphatic system disorders  
Rare:    
thrombocytopenia. 
Immune system disorders  
Common: 
  
Very rare: 
allergic reactions  
anaphylaxis 
Metabolism and nutrition disorders  
Common:  
Uncommon:  
hyperglycaemia  
hypoglycaemia, weight gain, anorexia  
Psychiatric disorders 
Uncommon: 
nightmare, insomnia 
Nervous system disorders  
Common:  
 
Uncommon:    
Rare:  
headache  
dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia  
peripheral neuropathy   
Eye disorders  
Uncommon:  
Rare: 
vision blurred   
visual disturbance 
Ear and labyrinth disorders  
Uncommon:  
Very rare: 
tinnitus  
hearing loss 
Respiratory, thoracic and mediastinal disorders  
Common:   
pharyngolaryngeal pain, epistaxis 
Gastrointestinal disorders  
Common:  
Uncommon:  
constipation, flatulence, dyspepsia, nausea, diarrhoea  
vomiting, abdominal pain upper and lower, eructation, pancreatitis 
Hepatobiliary disorders  
Uncommon:  
Rare:  
Very rare:  
Hepatitis 
cholestasis  
hepatic failure 
Skin and subcutaneous tissue disorders  
Uncommon: 
Rare: 
urticaria, skin rash, pruritus, alopecia  
angioneurotic oedema, dermatitis, bullous including erythema multiforme, 
Stevens-Johnson syndrome and toxic epidermal necrolysis                                      
Musculoskeletal and connective tissue disorders  
Common: 
Uncommon:  
myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain  
neck pain, muscle fatigue  

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Rare: 
 
Not known: 
myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by 
rupture  
immune-mediated necrotizing myopathy (see section 4.4) 
Reproductive system and breast disorders 
Very Rare: 
gynaecomastia 
General disorders and administration site conditions  
Uncommon: 
malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.   
Investigations  
Common: 
Uncommon: 
liver function test abnormal, blood creatine kinase increased  
white blood cells urine positive  
As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients 
receiving atorvastatin. These changes were usually mild, transient, and did not require interruption of 
treatment. Clinically important (>3 times upper normal limit) elevations in serum transaminases occurred in 
0.8% patients on atorvastatin. These elevations were dose-related and were reversible in all patients.  
  
Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of 
patients on atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 
times the normal upper range occurred in 0.4% atorvastatin-treated patients (see section 4.4).  
  
The following adverse events have been reported with some statins:   
  
• 
Sexual dysfunction  
• 
Depression   
• 
Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)  
• 
Diabetes Mellitus: Frequency will depend on the presence or absence of risk  
factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of 
hypertension).  
  
Paediatric Population  
  
The clinical safety database includes safety data for 249 paediatric patients who received atorvastatin, among 
which 7 patients were < 6 years old, 14 patients were in the age range of 6 to 9, and 228 patients were in the 
age range of 10 to 17.   
  
Nervous system disorders  
 
Common:  Headache  
  
Gastrointestinal disorders  
 
Common:  Abdominal pain   
  
Investigations   
Common:   Alanine aminotransferase increased, blood creatine phosphokinase increased  
  
Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the 
same as in adults. There is currently limited experience with respect to long-term safety in the paediatric 
population.  
  
Reporting of side effects  
If you get side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in 
this leaflet.  
  
You can also report side effects directly via the Yellow Card Scheme at:  
www.mhra.gov.uk/yellowcard  

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By reporting side effects you can help provide more information on the safety of this medicine.  
  
 
4.9  OVERDOSE  
  
Specific treatment is not available for atorvastatin overdose. Should an overdose occur, the patient should be 
treated symptomatically and supportive measures instituted, as required. Liver function tests should be 
performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, 
haemodialysis is not expected to significantly enhance atorvastatin clearance.  
  
5       PHARMACOLOGICAL PROPERTIES  
  
5.1       PHARMACODYNAMIC PROPERTIES  
  
Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA reductase inhibitors  
ATC code: C10A A05  
  
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the ratelimiting enzyme responsible 
for the conversion of 3-hydroxy-3-methyl-glutarylcoenzyme A to mevalonate, a precursor of sterols, including 
cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins 
(VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is 
formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL 
receptor).  
  
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA 
reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL 
receptors on the cell surface for enhanced uptake and catabolism of LDL.  
  
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and 
sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL 
particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial 
hypercholesterolaemia, a population that has not usually responded to lipid-lowering agents.  
  
Atorvastatin has been shown to reduce concentrations of total-C (30%-46%), LDL-C (41%-61%), 
apolipoprotein B (34%-50%), and triglycerides (14%-33%) while producing variable increases in HDL-C and 
apolipoprotein A1 in a dose-response study. These results are consistent in patients with heterozygous familial 
hypercholesterolaemia, non-familial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including 
patients with noninsulin-dependent diabetes mellitus.  
  
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce the risk for cardiovascular 
events and cardiovascular mortality.  
 
Homozygous familial hypercholesterolaemia  
  
In a multicenter 8 week open-label compassionate-use study with an optional extension phase of variable 
length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia 
patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Atorvastatin 
was administered at doses up to 80 mg/day.  
  
Atherosclerosis  
In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of 
intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg 

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on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients 
with coronary heart disease. In this randomised, double- blind, multicenter, controlled clinical trial, IVUS was 
performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n=253), there was no 
progression of atherosclerosis.  
  
The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% 
(p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to 
pravastatin the effects of atorvastatin were statistically significant (p=0.02). The effect of intensive lipid 
lowering on cardiovascular endpoints (e. g. need for revascularisation, non fatal myocardial infarction, 
coronary death) was not investigated in this study.  
  
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 
3.89 mmol/l ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 
mmol/l ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 26) (p<0.0001). Atorvastatin also 
significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% 
(pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: -22.0%, p<0.0001). 
Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction 
in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).  
  
Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower 
dose strengths.  
  
The safety and tolerability profiles of the two treatment groups were comparable.  
  
The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. 
Therefore, the clinical significance of these imaging results with regard to the primary and secondary 
prevention of cardiovascular events is unknown.  
  
Acute coronary syndrome  
In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538; placebo 
n=1,548) with an acute coronary syndrome (non Qwave MI or unstable angina). Treatment was initiated during 
the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 
mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, 
nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring 
hospitalization, indicating a risk reduction by 16% (p=0.048). This was mainly due to a 26% reduction in 
rehospitalisation for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary 
endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).  
 
The safety profile of atorvastatin in the MIRACL study was consistent with what is described in section 4.8.  
  
Prevention of cardiovascular disease  
  
The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomised, double-
blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm 
(ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or 
treatment for angina, and with TC levels ≤6.5 mmol/L (251 mg/dL). All patients had at least 3 of the 
predefined cardiovascular risk factors: male gender, age ≥55 years, smoking, diabetes, history of CHD in a 
first-degree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior 
cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were 
estimated to have a high risk for a first cardiovascular event.  
  
Patients were treated with antihypertensive therapy (either amlodipine or atenololbased regimen) and either 
atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137).  
  
 
 

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The absolute and relative risk reduction effect of atorvastatin was as follows:  
  
Event  
Relative risk 
reduction (%)  
No. of events 
(atorvastatin vs 
placebo)  
Absolute 
risk 
reduction1(%)  
P value  
Fatal CHD plus 
non-fatal MI  
36%  
100 vs. 154  
1.1%  
0.0005  
Total 
cardiovascular 
events and 
revascularisation 
procedures  
20%  
389 vs. 483  
1.9%  
0.0008  
Total coronary 
events  
29%  
178 vs 247  
1.4%  
0.0006  
1 Based on difference in crude events rates occurring over a median follow-up of 3.3 years.  
CHD = coronary heart disease; MI = myocardial infarction.  
 
Total mortality and cardiovascular mortality were not significantly reduced (185 vs.  
212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% 
females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly 
due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher 
in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant 
treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal 
MI) was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32-0.69), 
p=0.00008), but not in those treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).  
  
The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomised, 
double-blind, multicentre, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in 
patients with type 2 diabetes,  
40-75 years of age, without prior history of cardiovascular disease, and with LDL-C  
≤4.14 mmol/L (160 mg/dL) and TG ≤6.78 mmol/L (600 mg/dL). All patients had at least 1 of the following 
risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.  
  
Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-
up of 3.9 years.  
  
 
 
 
 
 
 
 
 
 
 
 
 

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The absolute and relative risk reduction effect of atorvastatin was as follows:  
  
Event  
Relative risk 
reduction (%)  
No. of events 
(atorvastatin vs 
placebo)  
Absolute 
risk 
reduction1 (%)  
P value  
Major 
cardiovascular 
events (fatal and 
non-fatal AMI, 
silent MI, acute 
CHD death, 
unstable angina,  
CABG, PTCA,  
revascularisation, 
stroke)  
37%  
83 vs. 127  
3.2%  
0.0010  
MI (fatal and non-
fatal AMI, silent 
MI)  
42%  
38 vs. 64  
1.9%  
0.0070  
Strokes (fatal and 
non-fatal)  
48%  
21 vs 39  
1.3%  
0.0163  
 1 Based on difference in crude events rates occurring over a median follow-up of 3.9 years.  
AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart disease; 
MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty. 
 
There was no evidence of a difference in the treatment effect by patient’s gender, age, or baseline LDL-C 
level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 
deaths in the atorvastatin group, p=0.0592).  
  
Recurrent stroke  
In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of 
atorvastatin 80 mg daily or placebo on stroke was evaluated in 4,731 patients who had a stroke or transient 
ischaemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). 
Patients were 60% male, 21-92 years of age (average age 63 years) and had an average baseline LDL of 133 
mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with atorvastatin and 
129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.  
  
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% 
CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to 
placebo. All-cause mortality was 9.1% (216/2,365) for atorvastatin versus 8.9% (211/2,366) for placebo.  
  
In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischaemic stroke (218/2,365, 9.2% vs. 
274/2,366, 11.6%, p=0.01) and increased the incidence of haemorrhagic stroke (55/2,365, 2.3% vs. 33/2,366, 
1.4%, p=0.02) compared to placebo.  
  
• The risk of haemorrhagic stroke was increased in patients who entered the study with prior haemorrhagic 
stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57) and the risk of ischaemic 
stroke was similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).  
  

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• The risk of haemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct 
(20/708 for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischaemic 
stroke was also decreased in these patients (79/708 for atorvastatin versus 102/701 for placebo; HR 0.76; 95% 
CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who 
receive atorvastatin 80 mg/day.  
  
All-cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients with 
prior haemorrhagic stroke. All-cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for 
placebo in the subgroup of patients with prior lacunar infarct.  
  
Paediatric Population  
  
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old  
  
An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of 
atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial 
hypercholesterolemia and baseline LDL-C ≥ 4 mmol/L.  A total of 39 children and adolescents, 6 to 17 years 
of age, were enrolled.  Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B 
included 24 children, 10 to 17 years of age and at Tanner Stage ≥ 2.    
  
The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet 
formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target 
LDL-C of < 3.35 mmol/L at Week 4 and if atorvastatin was well tolerated.     
  
Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects.  For subjects 
whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after 
dose escalation.  The mean percent decreases in lipid parameters were similar for both cohorts, regardless of 
whether subjects remained at their initial dose or doubled their initial dose.  At Week 8, on average, the percent 
change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of 
exposures.  
  
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old  
  
In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal 
girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or 
severe hypercholesterolaemia were randomised to atorvastatin (n=140) or placebo (n=47) for 26 weeks and 
then all received atorvastatin for 26 weeks.. The dosage of atorvastatin (once daily) was  
10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was > 3.36 mmol/l.  Atorvastatin 
significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 
week double-blind phase.  The mean achieved LDL-C value was 3.38 mmol/l (range: 1.81-6.26 mmol/l) in the 
atorvastatin group compared to 5.91 mmol/l (range: 3.93-9.96 mmol/l) in the placebo group during the 26-
week double-blind phase.  
  
An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-
18 years demonstrated that atorvastatin (N=25) caused a significant reduction in LDL-C at week 26 (p<0.05) 
compared with colestipol (N=31).   
  
A compassionate use study in patients with severe hypercholesterolaemia (including homozygous 
hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to response 
(some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDL-cholesterol was lowered 
by 36%.  
  
The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has 
not been established.   
  

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The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in 
children aged 0 to less than 6 years in the treatment of heterozygous hypercholesterolaemia and in children 
aged 0 to less than 18 years in the treatment of homozygous familial hypercholesterolaemia, combined (mixed) 
hypercholesterolaemia, primary hypercholesterolaemia and in the prevention of cardiovascular events (see 
section 4.2 for information on paediatric use).  
  
5.2        PHARMACOKINETIC PROPERTIES  
  
Absorption  
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 
1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, 
atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute 
bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase 
inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance 
in gastrointestinal mucosa and/or hepatic first-pass metabolism  
  
Distribution  
Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is  
≥98% bound to plasma proteins.  
  
Metabolism  
Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various 
beta-oxidation products. Apart from other pathways these products are further metabolised via 
glucuronidation. In vitro, inhibition of HMGCoA reductase by ortho- and parahydroxylated metabolites is 
equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA 
reductase is attributed to active metabolites.  
  
Excretion  
Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, 
atorvastatin does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-
life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA 
reductase is approximately 20 to 30 hours due to the contribution of active metabolites.  
  
Special populations  
− 
Elderly: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly 
subjects than in young adults while the lipid effects were comparable to those seen in younger patient 
populations.  
− 
Paediatric: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage ≥ 2 (N=24) 
paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline 
LDL-C ≥ 4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated 
atorvastatin tablets once daily, respectively. Body weight was the only significant covariate in 
atorvastatin population PK model.  Apparent oral clearance of atorvastatin in paediatric subjects 
appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C 
and TC were observed over the range of atorvastatin and o-hydroxyatorvastatin exposures.  
− 
Gender: Concentrations of atorvastatin and its active metabolites in women differ from those in men 
(women: approximately 20% higher for Cmax and approximately 10% lower for AUC). These 
differences were of no clinical significance, resulting in no clinically significant differences in lipid 
effects among men and women.  
− 
Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of 
atorvastatin and its active metabolites.  
− 
Hepatic insufficiency: Plasma concentrations of atorvastatin and its active metabolites are markedly 
increased (approximately 16-fold in Cmax and approximately 11-fold in AUC) in patients with chronic 
alcoholic liver disease (Childs-Pugh B).  
− 
SLOC1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including 
atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a 
risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis (see 
section 4.4). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with 

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a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant 
(c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients. 
Possible consequences for the efficacy are unknown.  
  
 
 
5.3        PRECLINICAL SAFETY DATA  
 
Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo 
assay. Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the 
AUC0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males 
and hepatocellular carcinomas in females.   
There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the 
development of embryos or fetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility and was not 
teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and rabbits. The 
development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to 
high doses of atorvastatin. In rats, there is evidence of placental transfer. In rats, plasma concentrations of 
atorvastatin are similar to those in milk. It is not known whether atorvastatin or its metabolites are excreted in 
human milk.  
  
6       PHARMACEUTICAL PARTICULARS  
6.1       LIST OF EXCIPIENTS  
              Tablet core  
Microcrystalline cellulose  
Sodium carbonate anhydrous Maltose  
Croscarmellose sodium  
Magnesium stearate  
  
Film-coating  
Hypromellose (E464)  
Hydroxypropylcellulose  
Triethyl citrate (E1505)  
Polysorbate 80  
Titanium dioxide (E171).  
  
 6.2      INCOMPATIBILITIES  
Not applicable  
   
6.3       SHELF LIFE  
2 years  
  
6.4  
SPECIAL PRECAUTIONS FOR STORAGE  
Store below 30°C   
  
6.5        NATURE AND CONTENTS OF CONTAINER  
Aluminium-aluminium blisters.  
Atorvastatin 20 mg Film-coated Tablets are available in pack sizes of 7, 10, 14, 15, 20, 28, 30, 50, 50x1, 56, 
60, 84, 90, 98, 100 or 200 tablets.  
High density polyethylene bottle with a polypropylene cap provided with a compartment for desiccant.  
  

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Atorvastatin 20 mg Film-coated Tablets is available in pack sizes of 50, 100 tablets and as multipack 
containing 100 tablets (2 bottles of 50 tablets)  
  
Not all pack sizes may be marketed.  
  
 6.6      SPECIAL PRECAUTIONS FOR DISPOSAL  
No special requirements.  
 
Any unused product or waste should be disposed of in accordance with local requirements.  
  
 7      MARKETING AUTHORISATION HOLDER  
TEVA UK Limited  
Brampton Road,  
Hampden Park,  
Eastbourne,  
East Sussex BN22 9AG  
UNITED KINGDOM  
  
 8     MARKETING AUTHORISATION NUMBER(S)  
             PL 00289/1290  
  
 9     DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION  
            03/08/2010  
  
 10   DATE OF REVISION OF THE TEXT  
            02/09/2015  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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StatinWISE Patient Recruitment Pathway, FINAL Version 1.0, 23 May 2017 
Appendix 9: StatinWISE Patient Recruitment Pathway  
IRAS: 197990 
 
Diagram illustrating communication pathway following patient initiated contact  
 
 
 
 
 
 
 

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