MUscle Side-Effects of Atorvastatin in Coronary Patients (MUSE) -a Randomized Controlled Trial
Phase: PHASE4
Conditions: Statin Adverse Reaction
Sponsor: Vestre Viken Hospital Trust

 
  
MUscle Side-Effects of atorvastatin in coronary patients (MUSE)  
         -a randomized controlled trial 
  
 
 
Protocol Identification Number:   MUSE 
EudraCT Number:   2018-004261-14 
 
SPONSOR: 
Vestre Viken Trust 
Research Director,   
Bjørn Rishovd Rund 
Postboks 4956 Nydalen 
3004 Drammen 
Tel : +47 957 78 094 
E-mail: bjørn.r.rund@vestreviken.no 
 
 
 
 
 
 
 
 
PROTOCOL VERSION NO. 2.0  - 10-JANUARY-2019 
 

 
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CONTACT DETAILS  
Sponsor: 
Vestre Viken Trust 
Research Director,  Bjørn Rishovd Rund 
Address Postboks 800, 3004 Drammen 
Tel : +47 957 78 094 
E-mail: bjørn.r.rund@vestreviken.no 
Study Chair 
Vestre Viken Trust, Drammen hospital 
MD, PhD. John Munkhaugen 
Address Postboks 800, 3004 Drammen 
Tel: +47 975 24 194 
E-mail: johmun@vestreviken.no 
Principal investigator at Site 1: 
Vestre Viken Trust, Drammen hospital 
MD, PhD. John Munkhaugen 
Address Postboks 800, 3004 Drammen 
Tel: +47 975 24 194 
E-mail: johmun@vestreviken.no 
Principal investigator at Site 2 
Sykehuset i Vestfold 
MD, PhD Jan Erik Otterstad 
Address Postboks 2168 
3103 Tønsberg 
Tel: + 47 916 62 603 
E-mail: jan.erik.otterstad@siv.no 
Coordinating monitoring unit: 
Department of research, Vestre Viken Trust 
Address:  Postboks 800, 3004 Drammen 
Sponsor’s Medical Officer 
John Munkhaugen 
Steering Committee 
John Munkhaugen (Chair) (Drammen) 
Oscar Kristiansen (VV) 
Nils Tore Vethe (co-Chair and WP-leader pharmacology, 
OUS) 
Jan Erik Otterstad (Senior Study Chancellor, Tønsberg / SiV) 
Toril Dammen (WP leader psychosocial factors, UiO) 
Morten Wang Fagerland (study statistician, OUS)  

 
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Einar Husebye (VV) 
Executive Steering Committee 
John Munkhaugen (Chair) (Drammen) 
Nils Tore Vethe (co-Chair, OUS) 
Jan Erik Otterstad (Senior Study Chancellor, Tønsberg / SiV) 
Toril Dammen (UiO) 
Stein Bergan (OUS) 
Lars Gullestad (UIO/OUS) 
Oscar Kristiansen (VV) 
Elise Sverre (VV) 
Elena Kvan (VV) 
Morten Lindberg (SiV) 
Kari Peersen (SiV) 
Lars Gullestad (UIO/OUS) 
Erik Gjertsen (VV) 
Morten Wang Fagerland (OUS)  
Einar Husebye (VV) 
Joep Perk, Linneus University, Sweeden 
 

 
Protocol MUSE Version no.2.0- 15-JAN-2019 
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SIGNATURE PAGE 
 
Title: 
Muscle Side-Effects of atorvastatin in coronary patients (MUSE). 
Protocol ID no: 
MUSE  
EudraCT no: 
2018-004261-14 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
 
Name 
Title 
Role 
Signature 
Date 
John Munkhaugen 
MD PhD 
Principal 
Investigator and 
Study Chair 
     (e-sign) 
10.01.19 
Nils Tore Vethe 
PhD 
Study Co-Chair 
WP leader, 
pharmacology 
     (e-sign) 
10.01.19 
Jan Erik Otterstad 
MD PhD 
Senior Study 
Chancellor 
     (e-sign) 
10.01.19 
Einar Husebye 
MD PhD 
Member of 
Executive 
Steering Group 
     (e-sign) 
10.01.19 
Oscar Kristiansen 
MD 
PhD candidate 
(study physiscan) 
     (e-sign) 
10.01.19 
Morten Wang 
Fagerland 
PhD 
Study statistician 
     (e-sign) 
10.01.19 
Toril Dammen 
MD PhD 
WP leader, 
psychosocial 
factors 
     (e-sign) 
10.01.19 
 

 
Protocol MUSE Version no.2.0- 15-JAN-2019 
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SIGNATURE PAGE, PRINCIPAL INVESTIGATOR / COORDINATING 
INVESTIGATOR 
 
Title: 
Muscle Side-Effects of atorvastatin in coronary patients (MUSE). 
Protocol ID no: 
MUSE  
EudraCT no: 
2018-004261-14 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
John Munkhaugen 
MD, PhD. 
e-sign 
10.01.19 
Name 
Title 
     Signature 
Date 
 

 
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PROTOCOL SYNOPSIS 
 
Protocol title: Muscle Side-Effects of atorvastatin in coronary patients (MUSE) -a randomized clinical trial 
 
Sponsor 
Vestre Viken Trust, Drammen Hospital 
Phase and study type 
Prospective, randomized double-blinded placebo controlled cross-over 
phase 4 study. 
Investigational Medical 
Product (IMP) (including 
active comparator and 
placebo):        
The study aims to compare muscle symptoms during treatment with 
atorvastatin 40 mg x1 and matched placebo in coronary heart disease (CHD) 
patients with  subjective statin associated muscle symptoms (SAMS). 
Centers: 
Two hospitals (Drammen and Vestfold) in Norway 
Study Period: 
 
Estimated date of first patient enrolled: 1-MAR-2019 
Anticipated recruitment period: 6 months 
Estimated date of last patient completed: 31-DES-2019 
Treatment Duration: 
Estimated (non) treatment duration per patient:  7 weeks plus one week 
pharmacological wash-out.  
Follow-up: 
Subjects will be followed up for 16 weeks for the primary and secondary 
endpoints .  
Objectives  
The primary purpose of the study is to identify, and confirm 
pharmacologically, true SAMS (definition: at least a 25% higher muscle 
symptom intensity during the treatment period of atorvastatin than placebo) 
in CHD patients.  
The primary objective is to estimate the effect of atorvastatin on muscular 
symptom intensity in coronary patients with subjective SAMS.  
The key secondary objectives are:  
1. To determine the proportion of patients who report muscle 
symptoms on atorvastatin treatment compared with on placebo 
(dichotomous SAMS classification) 
2. To determine the relationship between muscle symptom intensity 
and blood concentrations of parent drug and the active metabolites 
of atorvastatin 
3. To determine the diagnostic properties of blood concentrations of 
parent drug and the active metabolites of atorvastatin for 
classification of true  SAMS (dichotomous SAMS)  
4. To determine the likelihood of statin discontinuation within and 
between the treatment periods 
5. To study statin adherence between the two study arms  
6. To compare blood concentrations of parent drug and the active 
metabolites of atorvastatin between patients with failing placebo-

 
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test for connecting SAMS to atorvastatin and the control group 
without muscle symptoms. 
7. To assess study safety 
 
Explorative objectives: 
1. To compare patients muscle symptom charcteristics  between the 
two study arms 
2. To study sociodemographic, clinical, and psychosocial characteristics 
(PROMS and clinical data) between the two study arms 
 
Endpoints: 
Primary endpoint:  
The primary end-point will be the individual mean difference in muscular 
symptom intensity between treatment periods with statin and placebo, 
reported by the patients over the last three weeks (i.e. week 4-7) measured 
with aggregated VAS scores. 
 
Secondary endpoints:  
1. The proportion of patients who report muscle symptoms on 
atorvastatin treatment and not on placebo (dichotomous SAMS 
classification) 
2. The correlation between individual mean difference in muscular 
symptom intensity between treatment periods with statin and 
placebo, reported by the patients over the last three weeks (i.e. week 
4-7) measured with aggregated VAS scores, and levels of atorvastatin 
and its metabolites in blood plasma and white blood cells. 
3. Sensitivity, specificity, and area under the curve of blood 
concentrations of parent drug and the active metabolites of 
atorvastatin for the classification of true SAMS  
4. Individual mean difference in likelihood of statin discontinuation 
between treatment periods with statin and placebo, reported by the 
patients over the last three weeks (i.e. week 4-7) measured with 
aggregated scores on a 1-10 Likert scale. 
5. Statin 
adherence 
 
measured 
with 
indirect 
(self-reported 
questionnaires and pill counts of returned packages) and direct 
(liquid chromatography-tandem mass spectrometry method) 
methods 
6. Levels of atorvastatin and its metabolites in blood plasma and white 
blood cells at study end 
 
 
 
7. Safety endpoints: 
- 
New-onset CHD symptoms (e.g. angina, dyspnea) 
- 
Intolerable muscle symptoms reported by the patient leading to 
discontinuation from the treatment arm  
- 
Creatine kinase (CK) > 10 times upper limit of the normal range 
or alaninaminotransferase  (ALT) > 3 times upper limit of the 
normal range in blood 
   Explorative endpoints: 
1. Features of SAMS characterized by McGill Pain Questionnaire (SF-
MPQ) and Brief Pain Inventory (BPI-SF) 
2. Sociodemographic, clinical, and psychosocial factors ascertained 
through self-reported questionnaires, clinical examinations, and 
blood samples 
 

 
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Assessment of primary study 
end points 
The primary study end-points will be measured with aggregated SAMS scores 
on VAS scales obtained through patient self-report questionnaires 
administred at study start, weekly during the 7 weeks  treatment periods, and 
at study end 
 
Assessment of study safety  
Study safety data will be collected: 
- 
Every 7th days: direct telephone contact with the patient  for 
assessment of intolerable muscle symptoms and symptoms of 
unstable CHD (i.e. new-onset angina pectoris and/or dyspnea) 
- 
Blood samples collected for analyses of ALT and CK at the end of each 
7 weeks treatment period or if intolerable muscle symptoms were 
reported by the patients   
- 
Continuous surveillance of serious adverse events (SAEs) obtained 
through direct weekly telephone contact with the patients and 
thorugh continuous monitoring of hospital admissions during the 
study period. 
Assessment of secondary 
end points 
Self-report questionnaires, a brief clinical examination, and blood samples 
collected at baseline, during the treatment periods, and at study-end. 
Study Design: 
This is a prospective, randomized placebo-controlled double-blinded, cross-
over study. CHD patients will be randomized to atorvastatin 40mg/day in the 
first period and matched placebo in the second period, or placebo in the first 
period and atorvastatin in the second period. Both periods consist of 7-weeks 
of treatment with a preceding 1-week pharmacokinetic wash-out. A control 
group of coronary patients on atorvastatin without a history of perceived 
SAMS and without other muscle symptoms will be included to study 
secondary objective number 6. The patients in the control group will undergo 
an open 7 weeks treatment period taking an atorvastatin dose  similar to that 
used in the cross-over arms  to patients with SAMS.  
Main Inclusion Criteria:    
• 
First or recurrent diagnosis (myocardial infarction) or treatments (PCI or 
CABG) for a CHD event 6-36 months prior to study start and prescribed 
atorvastatin.  
• 
Self-reported muscle complaints (i.e. pain, weakness, tenderness, 
stiffness or cramp to the body of any intensity) that they attribute to 
atorvastatin therapy at study inclusion  
• 
Self-reported muscle complaints that has led to atorvastatin 
discontinuation prior to study inclusion.  
 
Main Exclusion Criteria 
• 
First or recurrent diagnosis (myocardial infarction) or treatments (PCI or 
CABG) for a CHD event the a) past 12 months prior to study start in high 
risk patients (i.e. at least one of following comorbid conditions: systolic 
heart failure, >1 previous myocardial infarction, kidney failure, diabetes, 
and smokers) and b) the past 6  months prior to study start in low risk 
patients without any of the co-morbid conditions mentioned above and 
in patients who are not taking a statin at all.  
• 
Patients with symptomatic peripheral artery disease and patients with 
familial hypercholesterolemia 
• 
Patient has any contraindications for atorvastatin listed in the Summary 
of Product Characteristics (i.e. known hypersensitivity to the ingredients, 
acute liver failure/ ALT > 3 times upper limit of the normal range in blood 
at study start, pregnancy and breastfeeding  )  

 
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• 
History of previous rhabdomyolysis, myopathy or liver failure due to 
statin treatment with CK > 10 times upper limit of the normal range or 
ALT > 3 times upper limit of the normal range. 
• 
Any condition (e.g. psychiatric illness, dementia) or situation, that in the 
investigator’s opinion could put the subject at significant risk, confound 
the study results, interfere significantly with the subject participation in 
the study, or rendering informed consent unfeasible 
• 
Short life expectancy (<12 months) due to other medical conditions 
• 
Not being able to understand Norwegian. 
• 
Women of childbearing potential defined as all premenopausal female. 
• 
Participation in another randomized clinical trial 
 
Main entry criteria for the 
control group 
• 
Entry criteria for the control group are equal to those described above 
except for bullet point number 2 and 3 described under the inclusion 
criteria. A prerequisite for participation in the control group is no history 
of muscle symptoms. 
 
Sample Size: 
80 patients for the randomized cross-over study, plus an additional 40 
patients in a control group t that will be used to study secondary objective 
number 6 only 
Power Calculation 
Power calculations are based on our being able to detect a 1 cm difference in 
the VAS symptom score between the treatment periods on atorvastatin and 
placebo since the smallest change in VAS symptom score corresponding to ‘a 
little more’ or ‘a little less’ symptoms was 1.3 cm, with a lower limit of the CI 
at 1 cm in a previous study.(23) Gallagher et al. (23) report a standard 
deviation (SD) of 1.7  for a difference of 1.0 between  two VAS symptom 
scores. Because of the differences in both populations and specific VAS scale 
between that study in this one, we use SD=2.5 to account for a much larger 
variation in this study. With n=68, we shall will have 90% power to detect a 
difference of 1.0, using a one-sample T test. With n=68, we will also have 80% 
power to detect a difference of 40% SAMS under statins vs. 15% SAMS under 
placebo, using the McNemar test for paired probabilities. To account for 
some missing information data due to drop-outs or and protocol deviations, 
we plan to include (40x2) 80 patients.  
 
Efficacy Assessments: 
Not applicable 
Safety Assessments: 
Blood samples for analyses of ALT and creatinine kinase will be performed at 
the end-of each treatment period or if intolerable muscle symptoms are 
reported by the patinets. Participants will be interviewed by phone after a 
standardized protocol by a specially trained study nurse weekly for the 
assessment of the other safety endpoints. Due to the relatively low study 
sample, no safety analysis will be performed.  
Type, Dosage and 
Adherence of statin 
Treatment 
Information will be reported by the patients weekly in a diary and by counting 
pills in returned packages. Statin adherence will also be measured in blood by 
analyses of statin concentrations by a direct liquid chromatography-tandem 
mass spectrometry method. 
Statistical Analysis 
The primary outcome and all other continuous outcomes will be estimated 
with linear regression models with the stratification factors in the 
randomization (i.e. centre and previous statin discontinuation) as covariates. 

 
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Dichotomous outcomes will be analysed with conditional logistic regression 
models with treatment, centre, and previous statin discontinuation as 
covariates. Methods for analysis of ROC curves and measures of diagnostic 
accuracy will be used to identify cut-off values of metabolite concentrations 
that can discriminate between confirmed SAMS from other muscle 
symptoms. The correlations between individual mean difference in muscular 
symptom intensity between treatment periods with statin and placebo and 
levels of atorvastatin and its metabolites in blood plasma and white blood 
cells will be estimated with Spearman correlation coefficients and linear 
regression analyses. 
Oslo Centre for Biostatistics and Epidemiology (OCBE) is responsible for all 
statistics. A statistical analysis plan (SAP) describing all details in this respect 
will be produced prior to database lock. 
Safety analysis 
Deue to the low expect number of safety events, no safety analysis are 
planned, but descriptive data will be presented. 
Clinical Endpoint Committee  
 
 
No end-point commitee will be established for the present study due to the 
relative small study sample and since the primary and secondary outcomes 
are based on self-reported data and blood samples. 
 
 
 
 

 
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TABLE OF CONTENTS  
CONTACT DETAILS .................................................................................................................................. 2 
SIGNATURE PAGE ................................................................................................................................... 4 
SIGNATURE PAGE, PRINCIPAL INVESTIGATOR / COORDINATING INVESTIGATOR ...................................... 5 
PROTOCOL SYNOPSIS ............................................................................................................................. 6 
TABLE OF CONTENTS ............................................................................................................................ 11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................... 14 
1 
INTRODUCTION ............................................................................................................................ 15 
1.1 Background ............................................................................................................................................. 15 
1.1 
Study rationale and implications for patients, healthcare providers and the society ....................... 16 
1.2 
Risk/Benefit ........................................................................................................................................ 16 
1.3 
Study Hypotheses ............................................................................................................................... 17 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS ............................................................................... 19 
3 
OVERALL STUDY DESIGN ............................................................................................................... 22 
3.1 
Recruitment Plan ................................................................................................................................ 22 
4 
STUDY POPULATION ..................................................................................................................... 22 
4.1 
Selection of Study Population ............................................................................................................ 22 
4.2 
Number of Patients ............................................................................................................................ 23 
4.3 
Inclusion Criteria for participation in the randomized study ............................................................. 23 
4.4 
Exclusion Criteria for participation in the randomized study ............................................................ 23 
4.5 
Inclusion and Exclusion Criteria for the control group....................................................................... 23 
5 
TREATMENT .................................................................................................................................. 24 
5.1 
Drug Identity, Supply and Storage ..................................................................................................... 24 
5.2 
Dosage and Drug Administration ....................................................................................................... 24 
5.3 
Concomitant Medication ................................................................................................................... 25 
5.4 
Subject Compliance ............................................................................................................................ 25 
5.5 
Drug Accountability ............................................................................................................................ 25 
5.6 
Subject Numbering ............................................................................................................................. 25 
6 
STUDY PROCEDURES ..................................................................................................................... 26 
6.1 
Flow Chart .......................................................................................................................................... 26 
6.1.1 
Informed Consent and Randomization ........................................................................................ 28 
6.1.2 
Data registered from the hospital medical records ..................................................................... 28 
6.1.3 
Patient self-report using commonly used and mainly validated questionnaires  ........................ 29 
6.1.4 
Laboratory evaluations and biobanking ....................................................................................... 29 
6.2 
Data Collected During Treatment and Follow-up .............................................................................. 30 

 
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6.2.1 
Clinical data .................................................................................................................................. 30 
6.2.2 
Safety data .................................................................................................................................... 30 
6.3 
Withdrawals and Procedures for Stopping Data Collection .............................................................. 31 
6.4 
Procedures for Discontinuation ......................................................................................................... 31 
6.4.1 
Patient Discontinuation ................................................................................................................ 31 
6.4.2 
Trial Discontinuation .................................................................................................................... 31 
6.5 
End of Study and post-trial care ......................................................................................................... 32 
7 
ASSESSMENTS ...............................................................……….  .32FEIL! BOKMERKE ER IKKE DEFINERT. 
7.1 
Primary and Secondary Endpoint Assessments ................................................................................. 32 
7.2 
Safety Assessments ............................................................................................................................ 32 
7.3 
Adherence Assessments .................................................................................................................... 33 
8 
SAFETY MONITORING AND REPORTING ......................................................................................... 33 
8.1 
Adverse Events ................................................................................................................................... 33 
8.2 
Serious Adverse Events (SAEs) ........................................................................................................... 33 
8.3 
Suspected Unexpected Adverse Events (SUSARs) ............................................................................. 34 
8.4 
Safety and Reporting .......................................................................................................................... 34 
8.4.1 
Annual Safety Report .................................................................................................................... 34 
8.4.2 
Clinical Study Report .................................................................................................................... 34 
9 
DATA MANAGEMENT AND MONITORING ...................................................................................... 35 
9.1 
Case Report Forms ............................................................................................................................. 35 
9.2 
Source Data ........................................................................................................................................ 36 
9.3 
Study Monitoring ............................................................................................................................... 36 
9.4 
Confidentiality .................................................................................................................................... 36 
9.5 
Database management ...................................................................................................................... 37 
9.6 
Determination of Sample Size and Power Calculation....................................................................... 37 
9.6.1 
Sample Size ................................................................................................................................... 37 
9.7 
Randomization ................................................................................................................................... 38 
9.7.1 
Allocation- sequence generation .................................................................................................. 38 
9.7.2 
Blinding and emergency unblinding ............................................................................................. 38 
9.8 
Planned analyses ................................................................................................................................ 38 
9.9 
Statistical Analysis .............................................................................................................................. 39 
9.9.1 
Safety analyses ............................................................................................................................. 39 
10 STUDY MANAGEMENT .................................................................................................................. 39 
10.1 Investigator Delegation Procedure .................................................................................................... 39 
10.2 Protocol Adherence ........................................................................................................................... 39 
10.3 Study Amendments ............................................................................................................................ 39 

 
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10.4 Audit and Inspections ......................................................................................................................... 39 
11 ETHICAL AND REGULATORY REQUIREMENTS ................................................................................. 40 
11.1 Ethics Committee Approval ................................................................................................................ 40 
11.2 Other Regulatory Approvals ............................................................................................................... 40 
11.3 Informed Consent Procedure ............................................................................................................. 40 
11.4 Subject Identification ......................................................................................................................... 40 
11.5 User involvement ............................................................................................................................... 41 
12 TRIAL SPONSORSHIP AND FINANCING ........................................................................................... 41 
13 TRIAL INSURANCE ......................................................................................................................... 41 
14 PUBLICATION POLICY .................................................................................................................... 41 
15 APPENDICES ................................................................................................................................. 42 
15.1 APPENDIX A – Screening letter........................................................................................................... 42 
15.2 APPENDIX B – Patient information and informed consent letter……………………………………………………43 
15.3   APPENDIX C - Self-reported questionnaire completed at baseline………………………….……………………..48 
15.4   APPENDIX D– Patient diary with self-reported questionnaire during the treatment periods………….66 
15.5 APPENDIX E – PHONE GUIDE TO PATIENTS FOR WEEKLY SAFETY ASSESSMENTS ............................. 65 
    15.6  APPENDIX F -  Drug label…………………………………………………………………………………………………………………67 
    15.7 APPENDIX  G - Biobank procedure.………………………………………………………………………………………………….68 
    15.8  APPENDIX  H- Pharmaceutical and chemical documentation atorvastatin………………………………………74  
    15.9 APPENDIX   I - Procedure for production of atorvastatin and placebo……………………………………………..80 
    15.10 APPENDIX  J- LAF patient insurance……………………………………………………………………………………………….80 
    15.11 APPENDIX K -Approval Regional Committee of Ethics………………………………………………..………………… 81 
    15.12 APPENDIX L -Approval from the National Medical Agency…………………….………………………………………83  
16 REFERENCES ................................................................................................................................. 85 
 
 
 
 
 
 
 
 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or special term 
Explanation 
CHD 
Coronary Heart Disease  
CV 
Cardiovascular 
eCRF 
Electronic Case Record Form 
IMP 
Investigational medicinal product 
LCMS-MS 
Liquid chromatography-tandem mass spectrometry 
LDL-C 
Low Density Lipoprotein Cholesterol  
RCT 
Randomized Controlled Trial   
PROMS 
Patient-reported outcome measures (on sociodemographic, 
clinical and psychosocial factors) 
SAMS 
Statin Associated Muscle Symptoms 
VAS 
Visual Analoge Scale 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5 
INTRODUCTION 
5.4 
Background  
Statins are the cornerstone drug treatment to reduce low-density lipoprotein cholesterol (LDL-C) with 
improvement of cardiac outcomes in coronary heart disease (CHD) patients. (1, 2) Statins are cost-effective 
(3) and recommended with the highest level of evidence in international guidelines. (1, 2) Statin treatment 
in CHD patients is, however, far from optimal in clinical practice. Both international (4) and our own data 
from the NORwegian-CORonary Prevention Study (5)  have revealed that 7-12% of the CHD patients did not 
use statin therapy at all, whereas 57-80% of those on statin therapy still have elevated LDL-C levels above 
the recommended target level of 1.8 mmol/L. Statin side-effects, mainly statin-associated muscle symptoms 
(SAMS), low statin adherence, and low statin doses have been reported as major independent determinants 
of unfavourably elevated LDL-C.(5) SAMS is one of the principal reasons for statin non-adherence and 
discontinuation leading to adverse cardiac outcomes.(6, 7), influence the patient’s quality of life, and may 
adversely affect health-related variables such as physical activity, muscle strength and ability to perform 
activities of daily living. (6, 7)  
Serious statin adverse-effects, including liver failure or myopathy with significantly elevated levels of creatine 
kinase in blood, are rare. (6, 7) Furthermore, side-effects are only reported in a minority (i.e. 1-5%) of CHD 
patients participating in randomized placebo-controlled statin trials.(8) SAMS, however, comprises a 
heterogeneous group of muscle symptoms including pain, aching, stiffness, tenderness or cramps, usually 
with normal or minimally elevated creatine kinase levels, amounts to 20-30% in observational studies (9). 
Strict entry criteria in the randomized trials, excluding patients with potentially polypharmacy, multiple 
comorbidities, elderly, females and low body weight, all factors that predispose to musculoskeletal 
symptoms, may in part explain variations in frequency of SAMS among these populations. (6, 7) A major 
limitation of observational studies is the lack of blinding. Patients on statins may expect side-effects, and 
therefore report a higher percentage of SAMS than untreated patients, the so-called ‘nocebo’ effect.  In a 
population-based randomized, double-blinded cross-over study of patients complaining of SAMS at study 
start, only 36% experienced that their muscle symptoms persisted during treatment with simvastatin 20 mg 
and disappeared during placebo treatment.(10) Accordingly, SAMS was confirmed to be related to the statin 
treatment (i.e. true SAMS) in only one-third of the patients. The prevalence of confirmed SAMS in a CHD 
population, treated with potent statins according to the guidelines, (1, 2) remains unknown. (6) 
 
Patients with psychosocial distress may be at increased risk of misattributing their symptoms to statins or 
being hypervigilant to true adverse effects of statins such as muscle pain.(11) In a randomized placebo-
controlled atorvastatin trial in patients without cardiovascular disease and depression, depression scores 
within normal range did not predict changes in muscle pain severity between the atorvastatin and placebo 
group after 6 months follow-up. (12)  Anxiety symptoms have been associated with non-adherence to statin 
therapy and with increased pain perception, in general.(13) Type D personality is associated with pain 
perception, pain inference, and musculoskeletal pain.(14)  The relationship between these psychosocial 
factors and SAMS remains to be investigated.   
 
It remains unclear how statins may produce muscle symptoms. Individual variations in statin 
pharmacokinetics, mitochondrial dysfunction, and vitamin D or coenzyme Q10 deficiency are suggested 
mechanisms for SAMS. (15) Reliable diagnostic biomarkers for the prediction or diagnosis of SAMS are not 
yet available. (6, 7) A few studies indicate that pharmacokinetic alterations in statin metabolites may 
contribute to SAMS. (16-18) The lactone metabolites of statins seem to be more potent in inducing myotoxic 
effects compared to the corresponding acid metabolites.  Plasma concentrations of atorvastatin lactones 
have been associated with clinical muscle symptoms.(17, 18) Accordingly, the lactones inhibit the 
mitochondrial complex III enzyme activity, thereby reducing the respiratory capacity in muscle cells.(19). We 
have recently developed and validated a fast, sensitive, and reliable LC-MS/MS method for precise 
quantification of atorvastatin and its major lactone and acid metabolites in blood.(20) We have also included 
the acyl glucuronide of atorvastatin as acyl glucuronide metabolites of drugs in general are associated with 

 
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toxicity.(21) Atorvastatin or metabolite levels have previously not been investigated as diagnostic markers of 
SAMS, under randomized, controlled conditions.    
The overall objective is to provide new clinical and pathophysiologic knowledge of SAMS in CHD patients that 
enables reliable detection of statin related SAMS and SAMS unrelated to statins. A novel LC-MS/MS method 
for quantification of atorvastatin and its major lactone and acid metabolites in blood (20) will be applied. 
Distinction of true SAMS in clinical practice may improve the management of CHD by personalized statin 
treatment and monitoring and subsequently improved lipid control compared to current practice.  
5.5 
Study rationale and implications for patients, healthcare providers and the 
society 
New knowledge of SAMS and the identification of diagnostic biomarkers are raised as major needs to 
improve lipid management in European and US guidelines (1, 2) and in Consensus documents. (6, 7) The 
study will address the major criticisms in previous evidence in studies of SAMS. The study is double-blinded 
and placebo-controlled and will thus confirm whether the patients muscle symptoms are truly related to 
the statin therapy or not. Additionally, the within-patient comparisons of muscle symptoms experienced 
while on placebo versus statin along with measurement of statin- and metabolite levels, will enable us to 
determine the relationship between these blood levels and muscle symptoms in patients with versus 
without true statin side-effects. 
This is the first randomized study to test the reproducibility of SAMS with assessment of objective 
pharmacological markers. The LC-MS/MS method developed for quantifications of atorvastatin and 
metabolites demonstrated to be accurate and precise over wide concentration ranges, and the lactone 
instability was controlled during the pre-analytical and analytical phases.(13) In addition, the study provides 
new knowledge about the clinical and psychosocial characteristics of patients with and without true SAMS. 
Our pilot data (Section 6.1.4) demonstrate that blood levels of atorvastatin metabolites are significantly 
higher in patients with subjective SAMS compared to those without SAMS. The present randomized placebo-
controlled study, enables us to determine the relationship between atorvastatin metabolite levels and 
muscle symptom intensity in patients with and without confirmed SAMS, and potentially pave the way for 
diagnostic testing of confirmed SAMS. In turn, this will identify patients in need of altered statin therapy or 
doses reduction due to intolerable side-effects and thus contribute to individualize statin treatment. 
Pharmacological data will facilitate to communicate to patients the role that statin drugs play for their muscle 
symptoms. Thus, alternative explanations for the patents complains may be elucidated. In turn, such a tool 
may prevent statin discontinuation, facilitate change of drug when indicated, and improve adherence. By 
adding a control group without muscle symptoms, we can also reveal whether atorvastatin and metabolites 
concentrations in study participants without confirmed SAMS are in line with blood concentrations in 
patients without muscle symptoms. The latter is of importance for the external validity of the study results.  
In 2014, Norwegian patients and health welfare spent 263.3 million NOK on statin therapy (14). Sufficient 
doses and adequate adherence are thus of major importance. The recent introduction of new, expensive 
drugs to target subclinical inflammation (e.g. canacinumab) (15) and to lower lipids (e.g. PSCK-9 inhibitors) 
(16), increases the relevance of this study. Costs of PSCK-9 inhibitors  are substantially higher than currently 
used statins. Therefore, optimizing treatment and adherence with cost-effective (3) statins is of outmost 
importance for the healthcare system. The study results are likely to translate to statin therapy in primary 
prevention. The potential impact on public health care is thus substantial 
5.6 
Risk/Benefit 
A potential risk in the present study is the risk of adverse cardiovascular events during the 8 week period 
without statin treatment and the risk of serious side-effects (e.g. acute liver failure, rhabdomyolysis, 
myopathy) during  treatment with atorvastatin. The investigating medical product (atorvastatin) has a strong 
scientific documentation (level 1A evidence) for CHD patients (1, 2) and a well-documented safety profile. 

 
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Dispite this, statin therapy is frequently discontinued for a longer period or permanently in the high-risk CHD 
sub-population with muscle symptoms that will be included in the present study. (22)  To our best knowledge, 
only two previous randomized studies that have investigated the risk associated with a  short time statin 
withdrawl. Heeschen and colleagues (23) reported a 3-fold increase in the risk of death and nonfatal MI when 
statins therapy was withdrawn after an admission for an acute coronary syndrome. The same group 
subsequently reassessed their analysis and found only a trend toward greater cardiac risk with abrupt statin 
discontinuation(24). In contrast, a large randomized study including more than 15 000 stable CHD patients, 
6 weeks statin discontinuation did not lead to increased risk of subsequent cardiovascular events and 
mortality.(25) Swedish nationwide real world data in post-myocardial infarction patients have documented 
that the risk of subsequent cardiovascular events are highest during the first 12 months following the index 
event.(26) They also demonstrated that patients with diabetes, previous myocardial infarction, no index 
myocardial infarction revascularisation, periferial artery disease, systolic heart failure and and kidney failure 
were at highest risk of subsequent events.  
Since our study population comprises patients who presently are not taking statins at all due to muscle 
symptoms or who report muscle symptoms that put them at significantly increased risk of statin 
discontinuation and thus subsequent cardiovascular events compared to a general CHD population, (6, 7) it 
is curical to gain new clinical and pathophysiologic knowledge about SAMS in these patients.  A short-term 
discontinuation of statin therapy of maximum 8 weeks (i.e. 1-week wash-out plus seven weeks during the 
placebo treatment period) required for the implementation of the study is regarded safe and sound in 
patients fulfilling the strict study entry criteria (See Section 4.3 and 4.4.). To minimize the risk of study 
participation, atorvastatin will be discontinued after the patients have been in a stable phase (without 
symptoms of angina/dyspnea) for at least 12 months following the index event in high risk patients (i.e. 
patients with at least one of following comorbid conditions: systolic heart failure, kidney failure, diabetes, , 
and smokers), whereas low risk patients without any of these co-morbid conditions and patients who are not 
taking a statin at all may be included 6 months after the coronary index event. To further reduce the risk of 
study participation, patients with familial hypercholesterolemia, symptomatic perpherial artery disease 
and/or patients with untreated signifificant stenoses on the main left coronary artery will be excluded from 
the study.  
Patients who have previously experienced rhabdomyolysis or myopathy will also be excluded from the study, 
based on information from their hospital medical records.   Patients with blood levels of ALT exceeding >3 
times upper limit of the normal range or creatinine kinase > 10 times upper limit of the normal range at study 
start or at the end of each 7-weeks treatment period will be withdrawn (Table 2). If new-onset CHD symptoms 
(i.e. angina pectoris and/or dyspnea) were revealed through the telephone interview or at the study visits, 
patients will be examined by the study cardiologists at the hospital outpatient clinics within two days. In 
addition, all Serious Adverse Events (SAEs) will be continuously monitored by the study cardiologists.  The 
sponsors medical officer will review all SAEs and evaluate whether the event is expected according to the 
reference safety information (RSI). The Summary of Product Characteristics will be used as RSI in this trial. All 
SUSARs will be reported to the Norwegian Medical Agency within 7/15 days by the medical officer. 
The greatest benefit will be to answer to what extent SAMS are caused by atorvastatin or not in CHD patients.  
Furthermore, if objective diagnostic markers of SAMS caused by statins are identified, treatment and 
monitoring for the most prescribed drug worldwide will be significantly improved.     
5.7 
Study Hypotheses 
Based on evidence from a previous randomized double-blinded study in a primary preventive population 
(10), the primary hypothesis is that 30-40% of the patients will report SAMS during treatment with 
atorvastatin compared to placebo (definition: at least a 25% higher muscle symptom intensity). 
The secondary hypothesis is that patients with confirmed SAMS will have higher levels of the parent drug 
(atorvastatin) and/or its metabolites than their counterparts without placebo-controlled SAMS, and that 
patients with confirmed SAMS can be identified with high sensitivity and specificity. We also hypothesize that 

 
Protocol MUSE Version no.2.0- 15-JAN-2019 
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the parent drug atorvastatin and its metabolite levels will neither relate to SAMS in the control group without 
muscle symptoms, nor in patients with failing placebo-test for connecting SAMS to atorvastatin.

 
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6 
STUDY OBJECTIVES AND RELATED ENDPOINTS 
 
 
Objectives 
Endpoints 
Assessments 
Primary 
To 
estimate 
the 
effect 
of 
atorvastatin 
on 
muscular 
symptom intensity in coronary 
patients with subjective SAMS.  
The individual mean difference in 
muscular symptom intensity over the 
last three weeks (i.e. week 4-7) between 
treatment periods with atorvastatin and 
placebo. 
Obtained through patient self-report measured with 
aggregated scores on a VAS scale administred at 
study start, weekly during the treatment periods 
and at study end .  
Secondary 
To determine the proportion of 
patients 
who 
report 
muscle 
symptoms 
on 
atorvastatin 
treatment compared with on 
placebo 
(dichotomous 
SAMS 
classification) 
 
The proportion of patients who report 
muscle 
symptoms 
on 
atorvastatin 
treatment 
and 
not 
on 
placebo 
(dichotomous SAMS classification) 
 
Obtained through patient self-report measured with 
aggregated scores on a VAS scale administred at 
study start, weekly during the treatment periods 
and at study end.  
 
To determine the relationship 
between 
muscular 
symptom 
intensity 
and 
blood 
concentrations of parent drug and 
the 
active 
metabolites 
of 
atorvastatin 
The correlation between individual 
mean difference in muscular symptom 
intensity over the last three weeks (i.e. 
week 4-7) between treatment periods 
with atorvastatin and placebo and levels 
of atorvastin and its metabolites in 
blood plasma and white blood cells 
Obtained through patient self-report measured with 
aggregated scores on a VAS scale administred at 
study start, weekly during the treatment periods 
and at study end. Drug and metabolites in blood 
measured with liquid chromatography-tandem 
mass spectrometry 

 
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Objectives 
Endpoints 
Assessments 
 
To determine the diagnostic 
properties 
of 
blood 
concentrations of parent drug and 
the 
active 
metabolites 
of 
atorvastatin for classification of 
true SAMS 
Sensitivity, specificity, and area under 
the curve of blood concentrations of 
parent drug and the active metabolites 
of atorvastin for the classification of true 
SAMS 
 
Obtained through patient self-report measured with 
aggregated scores on a VAS scale administred at 
study start, weekly during the treatment periods 
and at study end. Drug and metabolites in blood 
measured with liquid chromatography-tandem 
mass spectrometry 
 
To determine the likelihood of 
statin discontinuation within and 
between the treatment periods 
 
Individual mean difference in likelihood 
of statin discontinuation over the last 
three weeks (i.e. week 4-7) between 
treatment periods with statin and 
placebo.  
Obtained through patient self-report measured with 
aggregated scores on a 1-10 Likert scale administred 
at study start, weekly during the treatment periods 
and at study end 
 
 
To 
study 
statin 
adherence 
between the two study arms  
Statin adherence  measured with 
indirect methods and by parent drug and 
metabolite concentrations in blood 
Obtained through self-reported questionnaires , pill 
counts of returned packages, and from analyses of 
atortastatin level in blood determined by liquid 
chromatography-tandem 
mass 
spectrometry 
method  at the end of each treatment period 
 
To compare blood concentrations 
of parent drug and the active 
metabolites 
of 
atorvastatin 
between patients with failing 
placebo-test for connecting SAMS 
to atorvastatin and the control 
group without muscle symptoms. 
Levels 
of 
atorvastatin 
and 
its 
metabolites in blood plasma and white 
blood cells  
Drug and metabolites in blood measured with liquid 
chromatography-tandem mass spectrometry 
 
To descrive study safety 
-New-onset CHD symptoms (e.g. angina, 
dyspnea) 
- Intolerable muscle symptoms leading 
to discontinuation from the treatment 
arm  
- Creatine kinase (CK) > 10 times upper 
limit 
of 
the 
normal 
range 
or 
- 
Obtained every 7th days through direct 
telephone contact with the patient   
- 
Obtained every 7th days through direct 
telephone contact with the patient.  
 
- 
Obtained thorugh blood samples collected at 
the end of each 7 weeks treatment period or if 

 
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Objectives 
Endpoints 
Assessments 
alaninaminotransferase  (ALT) > 3 times 
upper limit of the normal range in blood 
- Continuous surveillance of serious 
adverse events (SAEs) and Suspected 
Unexpected Serious Adverse Reactions 
(SUSARS) 
intolerable muscle symptoms were reported by the 
patients   
- Obtained through direct telephone contact with 
the patient  and through monitoring of hospital 
admissions throughout the study period 
Explorative 
To compare patients with and 
without 
confirmed 
SAMS 
regarding 
muscle 
symptom 
charcteristics   
The proportion of patients who report 
muscle 
symptoms 
on 
atorvastatin 
treatment 
and 
not 
on 
placebo 
(dichotomous SAMS classification) 
Features of SAMS obtained through patient self-
report measured with McGill Pain Questionnaire 
(SF-MPQ) and Brief Pain Inventory (BPI-SF) 
administred at study start and at study end 
 
To 
study 
sociodemographic, 
clinical, 
and 
psychosocial 
characteristics 
(PROMS 
and 
clinical data) between the two 
study arms  
 
The proportion of patients who report 
muscle 
symptoms 
on 
atorvastatin 
treatment 
and 
not 
on 
placebo 
(dichotomous SAMS classification) 
 
Obtained through patient self-report measured with 
Hospitality Anxiety and Depression Scale, Patient 
Health 
Questionnaire-2, 
Penn 
State 
Worry 
Questionnaire, DS-14, Bergen Insomnia scale, 
Believes in Medicine questionnaire, and Short Form 
-12 and questionnaires covering education and 
lifestyle behavior administred at study start and at 
study end 

 
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7 
OVERALL STUDY DESIGN 
This is a randomized, double-blinded, multi-center, cross-over study in Norway that will include 80 CHD 
patients with subjective SAMS during atorvastatin therapy who report i) ongoing SAMS or ii) atorvastatin 
discontinuation because of SAMS. The patients will be randomized to either atorvastatin in the first period 
and placebo in the second period or placebo in the first period and atorvastatin in the second period, in an 
AB/BA cross-over design. The study flow chart is shown in Figure 1. In addition, 40 coronary patients without 
SAMS on atorvastatin will be included at random and undergo an open 7 weeks treatment period with 
atorvastatin in a similar dose as in those with SAMS.  
7.4 
Recruitment Plan 
Based on evidence from the NOR-COR 1 study, (5) we expect to identify about 850 patients with a CHD event 
by searching hospital medical records at the participating hospitals the past 2-36 months prior to study start. 
Among these, at least 200 patients will report subjective SAMS or statin discontinuation due to SAMS during 
a telephone screening interview. Based on the study entry criteria and significant non-participation rate, a 
conservative estimate is that 40% of these patients (n=80) along with the control group of n=40 may be 
enrolled over a 3 months period.  
Patient enrolment will start in March 2019. With mean follow-up time at end of inclusion of 3 months, the 
total study duration will be no more than 6 months. The results of primary endpoint are expected during fall 
2019 whereas results of the secondary endpoints are expected in 2020. 
 
Study Period 
 
Estimated date of first patient enrolled: 1--Mar-2019 
Anticipated recruitment period: 2 months (due to hospital medical record 
screening) 
Estimated date of last patient completed: 1-Sept-2019 
Treatment Duration: 
Until end of study period (16 weeks after randomization) 
 
Follow-up: 
Patients will be followed for 16 weeks after randomization.  
End of study 
Last patient last visit 
Post-trial follow-up 
Telephone contact with a study cardiologist 3 months after the last visit 
8 
STUDY POPULATION 
8.4 
Selection of Study Population 
The study will be conducted at two representative Norwegian hospitals (Drammen and Vestfold) with a total 
catchment area of 380,000 inhabitants, corresponding to 7.4% of the Norwegian population. Consecutive 
patients aged 18-80 years undergoing a first or recurrent coronary event or treatment (i.e. acute myocardial 
infarction (ICD-10; I21), coronary artery bypass graft operation, or elective or emergency percutaneous 
coronary intervention) will be identified from hospital patient discharge lists by searching chronologically 
after last admission for the index event during the past 6-36 months (2016-18). Screening for study 
participation will be performed by two study physicians through a standardized telephone interview. Patients 
reporting muscle complaints (defined as pain, weakness, tenderness, stiffness or cramps) perceived as 
related to atorvastatin through the telephone interview or discontinuation of atorvastatin due to muscle 

 
Protocol MUSE Version no.2.0- 15-JAN-2019 
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complaints will be invited to the hospital’s outpatient clinics for a comprehensive baseline screening and 
study eligibility evaluation. A prerequisite for participation in the randomized study is no coronary events in 
the past 6-12 months (dependent on risk profile, see Section 4,3 and 4.4) and no history of rhabdomyolysis/ 
or myopathy or significantly elevated levels of liver and muscle enzymes in blood at study start. A random 
selected control group without a history of muscle symptoms will aslo be reqruited based on the telephone 
interview. 
8.5 
Number of Patients 
Eighty CHD patients with ongoing  atorvastatin therapy or previous muscle symptoms that led to 
discontinuation of atorvastatin will be included in the randomized study.  Forty CHD patients  without a 
history of muscle symptoms will be included in the study as controls. 
8.6 
Inclusion Criteria for participation in the randomized study 
To be eligible for inclusion in the study, subjects must fulfill the following criteria at inclusion:  
• 
18 years or older 
• 
First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event 6-36 
months prior to study start and prescribed atorvastatin  (irrespective of dose) 
• 
Reporting muscle complaints (i.e. pain, weakness, tenderness, stiffness or cramp) that they attribute to 
atorvastatin therapy or atorvastatin discontinuation due to muscle complains  
• 
Signed informed consent and expected cooperation of the patient according to ICH/GCP and 
national/local regulations 
8.7 
Exclusion Criteria for participation in the randomized study 
Study subjects must not meet any of the following criteria: 
• 
First or recurrent diagnosis (myocardial infarction) or treatments (PCI or CABG) for a CHD event the a) 
past 12 months prior to study start in high risk patients (i.e. at least one of following comorbid conditions: 
systolic heart failure, >1 previous myocardial infarction, kidney failure, diabetes, and smokers) and b) the 
past 6  months prior to study start in low risk patients without any of the co-morbid conditions mentioned 
above and in patients who are not taking a statin at all 
• 
Patients  with symptomatic peripheral artery disease and patients with familial hypercholesterolemia 
• 
Patient has any contraindications for atorvastatin listed in the Summary of Product Characteristics (i.e. 
known hypersensitivity to the ingredients, acute liver failure/ ALT > 3 times upper limit of the normal 
range in blood at study start, pregnancy and breastfeeding  )  
• 
History of previous rhabdomyolysis, myopathy or liver failure due to statin treatment with CK > 10 times 
upper limit of the normal range or ALT > 3 times upper limit of the normal range. 
• 
Any condition (e.g. psychiatric illness, dementia) or situation, that in the investigator’s opinion could put 
the subject at significant risk, confound the study results, interfere significantly with the subject 
participation in the study, or rendering informed consent unfeasible 
• 
Short life expectancy (<12 months)  due to other medical conditions 
• 
Not being able to understand Norwegian. 
• 
Women of childbearing potential defined as all premenopausal female. 
• 
Participation in another randomized clinical trial 
8.8 
Inclusion and Exclusion Criteria for the control group 
The study entry criteria for the control group  are similar to those described above except for the inlcusion 
criterion  described in bullet point 3 under 4.3 (i.e. reporting muscle complaints). A prerequisite for 
participation in the control group is no history of muscle symptoms. 

 
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9 
TREATMENT 
If all eligibility criteria are met and written informed consent is provided, patients will be  randomized by the 
study physicians to double-blinded prescription of atorvastatin or a matched placebo tablet in a 1:1 ratio 
using the electronic randomisation system (Viedoc™) of the clinical trials unit (CTU) at OUH. Block 
randomization with block size 4 and 6 in random order, stratified according to centre (Drammen Hospital and 
Hospital of Vestfold) and previous statin discontinuation (yes/no), will be used.  
A standard dose of 40 mg will be used in all RCT and control patients. The study medication should be taken 
between 08:00 and 10:00 AM. Patients with ongoing statin treatment at baseline will undergo a 1-week 
pharmacological wash-out period before randomization (Figure 1). All RCT participants will then be treated 
for 7 weeks or until muscle symptoms are intolerable. After a second 1-week wash-out period patients will 
be switched from atorvastatin to placebo or vice versa for a subsequent 7-weeks period. In total, study 
participation comprises 3 clinical visits with blood sampling per patient. Control patients will have 2 visits, 
one before and after wash-out and one after 7 weeks treatment with atorvastatin 40 mg. Patients will be 
encouraged to continue the prescribed medication until the end of the study or until intolerable muscle 
symptoms persist for one week. Previous data from two observational studies using atorvastatin, indicate 
that 7-week treatment length is sufficient for muscle symptoms to appear and disappear in 100% and 80% 
of these patients, respectively. (19, 20)  
All study patients will receive an information letter (ID-card size) stating that they participate in a clinical  
study, containing information about the sponsor and contact information to the principal investigators (PI)  
and the study nurses. Contraindicated foods and drugs that interact strongly with atorvastatin are also  
listed  in the ID chard (See Section 5.2). Finally, is specifically mentioned that measurements of blood lipids  
(i.e. LDL- C, HDL-C and/or total cholesterol) are not allowed during the study period to prevent unblinding.   
Patients will be instructed to wear the ID-card in case of medical contact or primary care visits that may  
influence  adherence to treatment. 
9.4 
Drug Identity, Supply and Storage 
Atorvastatin 40 mg and placebo are the Investigation Medicinal Product (IMP)s. Atorvastatin and placebo 
pills will be fabricated and labelled at Kragerø Tablettproduksjon AS (Fabrication number 9101). Study drugs 
and codes will be stored in closed envelopes and sent directly to the study sites (not via the Pharmacy). The 
study medication will be stored in lockable cabitens at the Section for cardiology at the participating 
hospitals.  The study codes will be stored in a separate cabinets at the hospital departments and only the 
principal investigators (Otterstad and Munkhaugen) and two research cardiologist (one at each hospital  who 
are not participating in the trial will have access to the codes. The research cardiologists will be responsible 
for emergency unblinding (see also Section 8.5). This will minimize the risk of unblinding during the treatment 
periods. 
  
Study medication for each 7 –weeks treatment period will be provided to the study patients by dedicated 
research nurses at the baseline visit and at the visit before cross-over. Specific labelling of trial drugs will be 
performed by batch number registration. Participants will be asked to return all empty or unused pill packets 
at the next follow-up visit. The study nurses will be responsible for the medicines accounting. The drug label 
is shown in Appenix E.  
9.5 
Dosage and Drug Administration  
Atorvastatin and placebo tablets are  administered orally once daily for each 7 weeks treatment period. The 
recommened and most frequently used dose of atorvastatin for in CHD patients, tablets of 40 mg, is chosen.  

 
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9.6 
Concomitant Medication 
All concomitant medication will be registered at baseline and at study end.  The following contraindicated 
foods and drugs that  interact strongly with atorvastatin and thus influence the study results are listed in  
the ID chard: 
 
Grapefruitjuice 
Johanneswort (prikkperikum, hypericum perforatum) 
Barbiturates and derivates  
Ciklosporine  
Fucidinacid  
Glekaprevir  
Pibrentasvir  
Kobicistat 
Letermovir  
Rifampicin 
Ritonavir 
Sofosbuvir og ledipasvir  
Telaprevir  
Tipranavir  
Karbamazepin  
Fenytoin  
Claritromycin 
  
Fibrates (Lopid, Fenofibrat, Lipantil og Lipanthyl) are also contraindicated since they increase the risk of  
SAMS.   
  
9.7 
Subject Compliance 
Study participants will report adherence to study treatment weekly in a diary. In addition, remaining pills in 
returned packages will be counted (participants will be asked to return any empty or unused pill packets at 
the follow-up visits). Statin adherence will also be measured directly by spot measurements of parent drug 
and metabolite concentrations in blood, analyzed by a LC-MC/MS method. 
9.8 
Drug Accountability 
Drug accountability will be performed by local study nurses  
9.9 
 Subject Numbering 
Each subject is identified in the study by a unique subject number, which is assigned electronically after the 
subject has signed the Informed Consent Form. Once assigned the subject number cannot be re-used for any 
other subject.  

26 
 
 
10 
STUDY PROCEDURES 
10.4 
Flow Chart  
 
 
 
 
 
 
 
 
 
 
 
 
1 week pharmacokinetic wash-out  
 
 
 
 
 
 
 
Study-end 
 ‘ 
 
 
 
 
 
 
   Statin (N=40) 
Placebo (N=40)  
Primary end-point: Mean difference in muscle symptoms measured with VAS  
Secondary end-points:  
- Relationship between confirmed SAMS and atorvastatin and metabolites levels in blood   
-Presence of muscle symptoms during statin treatment and not on placebo treatment   
- Likelihood of statin discontinuation  
-Clinical and psychosocial factors 
    Eligible for randomization (N=80) 
Self-report 
questionnaire, 
clinical examination 
and blood samples 
Coronary heart disease patients with subjective atorvastatin-associated muscle 
symptoms or atorvastatin discontinuation due to muscle symptoms based on telephone 
interview (N~200)  
Self-report symptoms 
and blood samples 
Refuse study participation  
   Statin (N=40) 
Placebo (N=40)  
Self-report symptoms 
and blood samples 
Self-report symptoms 
and blood samples 
Evaluation of inclusion and exclusion 
criteria and baseline screening (N~180) 
Did not meet the study entry criteria 
or refuse participation 
7 weeks treatment  
 
 
 
 
 
    1 week pharmacokinetic  
    wash-out and cross-over   
 
 
 
 
7 weeks treatment  

27 
 
 
 
Table 1.  Schedule of activities  
Table 2 Study data collection  
 
  
The randomized controlled study group (N=80) 
 
Control group 
(N=40) 
 
Baseline 
screening  
(n~180) 
Baseline 
evaluation/ 
randomizati
on 
(n=80) 
Visit 
after 
first 7 weeks 
treatment 
period 
Visit after second 
7 
weeks 
treatment period 
(Study end) 
With 
drawal 
visits 
 
 
Day-60 to -
2 
Day 1 
Week 8 
Week 16 
 
 
Inclusion 
and 
exclusion 
evaluation1)   
 
X 
 
X 
 
 
 
 
X 
Informed 
consent 
and 
randomization2)  
 
 
X 
 
 
 
 
X 
Extradition of 
the IMPs 
 
 
 
 
 
 
 
Collection 
of 
relevant 
hospital record 
data3)   
 
X 
 
 
 
 
X 
Self-reported 
questionnaires 
(PROMs)4) 
 
X 
 
X 
 
 
  X 
 
 
X 
Collection 
of 
blood samples5) 
 
 
X 
 
X 
 
X  
 
X 
 
X 
Safety 
assessment 
obtained 
from 
blood samples6) 
 
 
 
X 
 
X 
 
 
Safety 
assessment 
obtained 
weekly 
from 
patient 
self-
report6) 
 
 
 
 
X 
 
 
X 
 
 
1.   Inclusion/exclusion evaluation to the randomized study and to the control group will be performed 
during the telephone interview (See Appendix A) and at the baseline visit by the study physicians.  
2.   Randomization and collection of informed consent will be performed at baseline visit by the study 
physician. 
3.   Relevant hospital record data will be registered at baseline in an eCRF by specially trained study nurses. 
The following variables will be recorded: Age, gender, ethnicity, medical history (in particular a history 
of liver failure, rheumatic and thyroid disease), index cardiac event (NSTEMI, STEMI, stable or unstable 
angina), angiographic findings, coronary treatment (PCI with or without stent implantation, 

28 
 
 
thrombolysis), prescribed medical treatment at discharge including statin type and doses, and adverse 
statin reactions including ALT or CK elevations. 
4.    A self-report questionnaire comprises lifestyle behaviour (smoking history, physical activity), Beliefs 
about medicines questionnaire (BMQ), muscle symptoms (i.e. pain/aching, stiffness, tenderness or 
cramps) measured on 1-10 Visual Analogue Scales and on 1-10 Numeric rating scales, muscle symptom 
characteristics (short-form McGill Pain Questionnaire and Brief Pain Inventory)), anxiety and depression 
(the Hospital Anxiety and Depression Scale), Penn State Worry Questionnaire, Type D personality (DS-
14 questionnaire), insomnia (Bergen Insomnia scale), health-related quality of life (Short Form-12). In 
addition, muscle symptoms (i.e. pain/aching, stiffness, tenderness or cramps) and likelihood of statin 
discontinuation will be measured on 1-10 Visual Analogue Scales reported in a diary by the patients 
weekly during the treatment periods.  
5.  Blood sample collection at baseline and at the end of each 7-weeks treatment period will be performed 
by the local study nurse or a bioengineer. The following tests will be included: HbA1c, hemoglobin, hs-
CRP, eGFR, cystatin C, creatinine, CK, myoglobin, AST, ALT, total protein, albumin, non-fasting lipid 
profile (total cholesterol, HDL cholesterol, LDL-cholesterol) and concentrations of atorvastatin and 
metabolites (e.g. atorvastatin acid, atorvastatin lactone, atorvastatin 4-hydroxy [OH] lactone and acid, 
and atorvastatin 2-hydroxy [OH] lactone and acid)  
6. 
Safety data during the treatment will be collected from blood samples at baseline and at the end of 
each treatment period and from weekly telephone interviews. Patients with blood levels of ALAT 
exceeding >3 times upper limit of the normal range or creatinine kinase > 10 times upper limit of the 
normal range will be withdrawn from the study. All Serious Adverse Events (SAEs) will be continuously 
monitored by the study Medical Advisor.  Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be limited to symptoms and signs not listed in the Summary of Product Characteristics. 
 
10.4.1 Informed Consent and Randomization 
Informed written consent must have been given voluntarily by each subject before any study specific 
procedures are initiated.  
A subject who has signed the informed consent form and has been assigned a subject identification number 
generated by Viedoc™ is considered registered (but not yet randomized). A subject who has been assigned 
to one of the two groups and has been assigned a randomization number is considered randomized.  
All subjects will receive a study specific ID card stating that they participate in a clinical trial, containing 
information about the sponsor and contact information to the local PI/study nurse as well as the treatment 
allocation. 
10.4.2 Data registered from the hospital medical records 
The following relevant hospital record data will be registered in an eCRF by specially trained study nurses.  
• 
Age, gender, ethnicity  
• 
Medical history (in particular a history of liver failure, rheumatic and thyroid disease), index cardiac event 
(NSTEMI, STEMI, stable or unstable angina), angiographic findings, coronary treatment (PCI with or without 
stent implantation, thrombolysis, CABG),  
• 
Prescribed medical treatment at discharge including statin type and doses, and adverse statin reactions 
including ALT or CK elevations. 

29 
 
 
10.4.3 Patient self-report using commonly used and mainly validated questionnaires (See 
Appendix C) 
• 
Lifestyle behaviour: Smoking history, physical activity and alcohol consumption .  
• 
Statin treatment, 
o Current statin treatment including type and doses  
o Previous statin discontinuation or dose reduction due to muscle symptoms 
• 
Muscle symptoms  
o Pain, aching, stiffness, tenderness or cramps will be measured on Visual Analogue Scales and 
on 1-10 Numeric rating scales 
o Characteristics will be measured with the short-form McGill Pain Questionnaire and Brief 
Pain Inventory 
• 
Psychosocial factors: 
o Anxiety and depression: The Hospital Anxiety and Depression Scale (HADS)(27), contains 14 
items covering symptoms of anxiety (HADS-A) and depression (HADS-D). Cut-off scores >8 
on each subscale define clinical significant symptoms of distress (27). Patient Health 
Questionnaire-2 (PHQ-2) a 2-item screening questionnaire for depression.  
 
o Type D personality: DS-14 questionnaire(28), contains 14 items, with 7 items each on 
subscales of negative affectivity and social inhibition. To be categorized with type D 
personality a score ≥10 points on both subscales is required.  
o Bergen Insomnia scale(29):  Contains 6 items about sleep onset, maintenance of sleep and 
early morning wakening.  In addition the average sleep duration will be measured  
o Penn state worry questionnaire(30) 
o Beliefs about medicines questionnaire (BMQ)(31)  
o Short Form-12 (SF-12)(32): Provides information on mental and physical health status and 
may be used for measurement of the patients quality of life. 
The local study nurse will overview all self-reported questionnaires obtained at baseline to ensure that the 
risk of missing data is reduced. Multiple imputation tecniques will be used to replace missing data.  
10.4.4 Laboratory evaluations and biobanking  
Blood sample collection at baseline and at the end of each 7-weeks treatment period will be performed by 
the local study nurse or a bioengineer. All blood samples will be sent to the laboratory at Drammen hospital 
for  analyses of standard blood samples (i.e. haematology, clinical chemistry and lipids), pharmacological 
analyses and biobanking. Details on the collections, shipment of samples and reporting of results will be 
prepared in a laboratory manual.  
 
Hematology 
The following tests are included in the haematology:  HbA1c and haemoglobin,  
 
Clinical chemistry 
The following tests are included in the chemistry: hsCRP creatinine, CK, myoglobin, AST,ALT, LD, total protein, 
albumin.   
 

30 
 
 
Non fasting lipid profile 
The following tests are included in the non-fasting lipid profile: total cholesterol, HDL-C, LDL-C 
 
Pharmacological biomarker analyses 
Concentrations of atorvastatin in blood will be quantified by a direct liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) methods  and  pharmacokinetic (concentrations), pharmacogenetic (known CYP 
enzymes SLCO1B1 and CYP3A associated with uptake and metabolism of atorvastatin)  and direct drug-
related metabolites(atorvastatin acid, atorvastatin lactone, atorvastatin 4-hydroxy [OH] lactone and acid, and 
atorvastatin 2-hydroxy [OH] lactone and acid ) associated with SAMS. 
 
Pharmacokinetic pilot data 
We have pilot data indicating that the atorvastatin lactone/acid ratio was is three-fold higher in peripheral 
blood mononuclear cells compared with plasma. Atorvastatin and metabolites levels in white blood cells will 
therefore also be a relevant candidate marker for SAMS. Furthermore, pilot data from our clinical study 
indicate higher dose-normalized levels of the potential myotoxic 4-OH-atorvastatin lactone in patients 
reporting muscle symptoms (n = 4) compared with those not reporting muscle symptoms (n = 6). At 1 and 3 
hours after dosing the patients with muscle symptoms had on average 3.0-fold higher lactone concentration 
(0.39 ±+/- 0.30 vs. 0.13 ±+/- 0.09 nmol/L) and 1.7-fold higher level concentration (0.38 ±+/- 0.27 vs. 0.23 ±+/- 
0.10 nmol/L), respectively. 
10.5 
Data Collected During Treatment and Follow-up 
10.5.1 Clinical data 
Muscle symptoms and blood samples for statin analyses will be assessed during the follow-up period from 
randomization until study-end.  
• 
Muscle symptoms will be assessed weekly in a diary by the patients on a VAS Likert scale and a 1-10 
Numeric Ratin Scale (NRS). Simultaneously, the likelihood for these symptoms to result in statin 
discontinuation will be assessed on a corresponding scale. 
• 
Blood samples for concentration measurements of atorvastatin and their lactones (incl. reactive 
acylglucuronide) in plasma and in white blood cells (i.e. lymphocytes) will be collected in the end of each 
wash-out period (to confirm statin naivity before entering the treatment period) and in the end of each 
7 weeks treatment period. Patients who experience intolerable muscle symptoms will have blood 
samples collected in the morning as soon as possible to prevent discontinuation before blood sampling.  
At the last day on each treatment period, blood samples will be collected immediately before the 
morning dose and 1 and 3 hours after observed tablet intake. This sampling scheme will allow both the 
trough and peak exposure of the drug to be investigated as diagnostic markers of SAMS.  Covariates that 
potentially may explain diversity in the pharmacokinetics of atorvastatin and its metabolites will be 
assessed: Age, gender, weight, renal and liver function, concomitant medication and pharmacogenetic 
variants in SLCO1B1 and CYP3A. (6, 7)   
10.5.2 Safety data  
The Steering Committee has chosen the following events considered important for safety reasons:  
- 
Intolerable muscle symptoms reported by the patients will result in discontinuation from the actual 
treatment arm and blood sample collections within 48 hours. The patient can then cross-over to the the 
other treatment arm after the 1 week wash-out period.  
-    Patients reporting new-onset symptoms of angina pectoris and/or dyspnea during the telephone interview 
or at the clinical visits will be withdrawn from the study  

31 
 
 
- 
Patients with blood levels of ALT exceeding >3 times upper limit of the normal range or creatinine kinase 
> 10 times upper limit of the normal range will be withdrawn from the study.  
-    All Serious Adverse Events (SAEs) will be continuously monitored by the study Medical Advisor  
-     Unexpected Serious Adverse Reactions (SUSARs) will be limited to symptoms and signs not listed in the      
Summary of Product Characteristics (i.e.”Preparatomtalen”). 
 
In addition, patients in need of treatment with any of the drugs listed in Section 5 interacting strongly with  
atorvastatin will be withdrawn from the study. 
10.6 
Withdrawals and Procedures for Stopping Data Collection 
Once randomized into the study, all patients will be assessed until study closure unless informed consent is 
withdrawn for study participation. Patients can withdraw their consent to participate at any time during 
follow-up without prejudice to further treatment. Data collection will stop at the time of withdrawal.  
All randomized patients will be included in the study population. Patients who withdraw or are withdrawn 
from the study after randomization will not be replaced. 
10.7 
Procedures for Discontinuation 
10.7.1 Patient Discontinuation 
Patients may be discontinued from study treatment and assessments at any time. Specific reasons for 
discontinuing a patient for this study are: 
• 
Voluntary discontinuation by the patient who is at any time free to discontinue his/her    
participation in the study, without prejudice to further treatment. 
• 
Safety reason as judged by the Principal Investigator including: 
o Blood levels of ALT exceed >3 times upper limit of the normal range or creatinine kinase > 
10 times upper limit of the normal range during the treatment periods 
o Symptoms of symptomatic CHD (i.e. new-onset angina pectoris and/or dyspnea)  
o Occurrence of SAEs/SUSARS 
• 
Major protocol deviation  
• 
Patient’s non-compliance to  study treatment and/or procedures 
 
10.7.2 Trial Discontinuation 
The whole trial may be discontinued at the discretion of the PI or the sponsor in the event of any of the 
following: 
• 
Occurrence of AEs unknown to date in respect of their nature, severity and duration 
• 
Medical or ethical reasons affecting the continued performance of the trial 
• 
Difficulties in the recruitment of patients 
The sponsor and principal investigator(s) will inform all investigators, the relevant Competent Authorities 
and Ethics Committees of the termination of the trial along with the reasons for such action. If the study is 
terminated early on grounds of safety, the Competent Authorities and Ethics Committees will be informed 
within 15 days. 

32 
 
 
10.8 
End of Study and post-trial care 
The study period ends the day after the last treatment day has been completed and the study blinding is 
uncovered. All study patients will then be thoroughly informed about the study results by the study 
cardiologists at the hospital outpatient clinics. This will be considered as the end of trial for participants, and 
recommendations for further lipid management will be given in written form to the patients and their 
primary care physicians. In patients with confirmed SAMS, we will recommend treatment with rosuvastatin 
and subsequently proprotein convertase subtilisin kexin 9 [PCSK 9] inhibitors if indicated.(24) Three months 
after completion of the randomized trial, all patients will receive a phone call from the study PI to evaluate 
their experiences with study participation, their current statin medication and whether muscle symptoms 
still are present or not. In addition, hospitalizations for SAEs during this period will be registered.  
7. Assessments 
7.1 Assessment of the Primary and Secondary Endpoint 
Assessment of the primary and secondary end-points will be obtained by patient self-report measured with 
aggregated scores on a VAS Likert scale and a 1-10 numeric rating scale administered at study start, weekly 
during the treatment periods and at study end.  
Other secondary end-point will be: 
• 
The proportion of patients who report muscle symptoms on atorvastatin treatment and not on 
placebo (dichotomous SAMS classification) 
• 
Individual mean difference in likelihood of statin discontinuation between treatment periods with 
statin and placebo, reported by the patients over the last three weeks (i.e. week 4-7) measured with 
aggregated scores on a 1-10 Likert scale. 
• 
Statin adherence  measured with indirect (self-reported questionnaires and pill counts of returned 
packages) and direct (liquid chromatography-tandem mass spectrometry method) methods 
• 
Levels of atorvastatin and its metabolites in blood plasma and white blood cells 
7.1.1. Explorative endpoints: 
• 
Features of SAMS characterized by McGill Pain Questionnaire (SF-MPQ) and Brief Pain Inventory 
(BPI-SF) 
• 
Sociodemographic, clinical, and psychosocial factors ascertained through self-reported 
questionnaires, clinical examinations, and blood samples 
 
7.2. Safety Assessments  
 Safety endpoints will be under the responsibility of the primary investigators at the participating centers and 
will be collected: 

33 
 
 
- 
Every 7th days: direct telephone contact with the patient  for assessment of intolerable muscle symptoms 
and symptoms of unstable CHD (i.e. new-onset angina pectoris and/or dyspnea) after a standardized protocol 
by a specially trained study nurse.  
- 
Blood samples collected for analyses of ALAT and CK at the end of each 7 weeks treatment period or if 
intolerable muscle symptoms were reported by the patients   
- 
Continuous surveillance of serious adverse events (SAEs) obtained through direct weekly telephone 
contact with the patients and thorugh continuous monitoring of hospital admissions during the study period.  
Due to the relatively low study sample, no safety analysis will be performed in this study, but descriptive data 
will be presented. 
7.3 Adherence Assessments    
Information about adherence to the study medication will be reported by the patients weekly in a diary and 
by counting pills in returned packages. Statin adherence will also be measured in blood by analyses of statin 
concentrations by a direct liquid chromatography-tandem mass spectrometry method. 
8. SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an adverse event (AE) or serious adverse event (SAE). Each patient will be instructed to contact 
the investigator immediately should they manifest any signs or symptoms they perceive as serious. 
The methods for collection of safety data are described below. 
8.1. Adverse Events 
Suspected Unexpected Serious Adverse Reactions (SUSARS) will be reported to NoMA by using CIOMS forms. 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs.  
If an abnormal laboratory value/vital sign is associated with clinical signs and symptoms, the sign/symptom 
should be reported as an AE and the associated laboratory result/vital sign should be considered additional 
information that must be collected on the relevant CRF.  
8.2. Serious Adverse Events (SAEs) 
A Serious Adverse Event is defined as any untoward medical occurrence that:  
• 
Results in death 
• 
Is immediately life-threatening 

34 
 
 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity 
• 
Is an important medical event that may jeopardize the subject or may require medical intervention to 
prevent one of the outcomes listed above. 
 
Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical 
events may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the listed outcomes in the definitions above. In such 
situations, or in doubtful cases, the case should be considered as serious. Hospitalization for administrative 
reason (for observation or social reasons) is allowed at the investigator’s discretion and will not qualify as 
serious unless there is an associated adverse event warranting hospitalization. 
A pre-planned hospitalization admission (ie, elective or scheduled surgery arranged prior to the start of 
treatment) for pre-existing condition is not considered to be a serious adverse event. 
8.3. Suspected Unexpected Serioud Adverse Reactions (SUSARs) 
The Sponsor’s Medical Officer will review all SAEs and evaluate whether the event is expected according to 
the Reference Safety Information (RSI).  The SPC (section 4.8 «Bivirkninger») of the IMPs is used as Reference 
Safety Information (RSI) in this trial and will be used to define whether serious adverse event is a serious 
adverse reaction. 
 
SUSARs will be reported to the Competent Authority according to national regulation.  
The sponsor will ensure that all relevant information about suspected serious unexpected adverse reactions 
that are fatal or life-threatening is recorded and reported as soon as possible to the Competent Authorities 
in any case no later than seven (7) days after knowledge by the sponsor of such a case, and that relevant 
follow-up information is subsequently communicated within an additional eight (8) days. 
All other suspected serious unexpected adverse reactions will be reported to the Competent Authority 
concerned concerned as soon as possible but within a maximum of fifteen (15) days of first knowledge by 
the sponsor. 
SUSARs will be reported using the CIOMS form.  
8.4. Safety and Reporting 
Safety assessments will be continuously monitored throughout the study. Please see Section 6.3and 7.2 were 
this is described in detail.   
8.4.1. Annual Safety Report 
The study is planned to be completed within 1 year and therefore an annual safety report will not be needed. 
If the study is to continue for more than a year, the sponsor will provide the Competent Authority with an 
annual safety report. The format will comply with national requirements. 
8.4.2. Clinical Study Report 
The adverse events and serious adverse events occurring during the study will be discussed in the safety 
evaluation part of the Clinical Study Report. 

35 
 
 
8.5 Procedures in Case of Emergency  
Emergency unblinding should only be undertaken when knowledge of the treatment allocation is essential 
for treating the patient safely and efficaciously. Accordingly, unblinding can be indicated when either statin 
treatment may have caused the emergency situation (i.e. acute liver failure, myopathy or rabdomyolysis)  or 
when no statin treatment (i.e. placebo treatment) may have caused the emergency situation (i.e. new-onset 
acute coronary syndrome). In case of hospitalization for  acute liver failure, myopathy or rabdomyolysis, all 
drugs used by the patient (including the study intervention) will be temporary stopped according to routine 
clinical practice. In case  of hospitalization for acute coronary syndrome, high-dose atorvastatin (i.e. 80 mg 
x1) treatment will be routinely prescribed to all patients regardless of participation in the present study or 
not. Since immediate knowledge of the treatment allocation  (i.e. emergency unblinding) will not influence 
how these  patients are treated in the acute phase, we do not consider a  24-hour guard preparedness for 
emergency unblinding necessary. Potentially, the need for treatment initination with any of the drugs listed 
in 5.3 (that interact with atorvastatin) may also require unblining. However, none of these drugs will be 
initiated within 24 hours following acute hospitalizations.  
In case of need for emergency unblinding the envelopes with the code will be opened within 12 hours after 
the SAE event has occurred after discussions with the medical officer and/or the study PI. Emeregency 
unblinding will be performed by research cardiologists who are not a part of the study to prevent unblinding 
of the study physicians.  
9. DATA MANAGEMENT AND MONITORING   
Study monitoring will be performed by two research cardiolgists, one from each center, who are not 
participating in the study.  
A risk assessment of the study will be performed by the study medical officer (JM) prior to study start under 
supervision of a representant at the Clinical Trial Unit at OUH.  
9.1. Case Report Forms 
Electronic Case Report Forms (eCRFs) 
The Clinical Data Management System (CDMS) used for the eCRF in this study is Viedoc™. The setup of the 
study specific eCRF in the CDMS will be performed by the Clinical Trial Unit at Oslo University Hospital. The 
eCRF system will be FDA Code of Federal Regulations 21 Part 11 compliant. 
The designated investigator staff will enter the data required by the protocol into the eCase report forms 
(eCRF). The Investigator is responsible for assuring that data entered into the eCRF is complete, accurate, 
and that entry is performed in a timely manner. The signature of the investigator will attest the accuracy of 
the data on each eCRF. If any assessments are omitted, the reason for such omissions will be noted on the 
eCRFs. Corrections, with the reason for the corrections will also be recorded.  
After database lock, the investigator will receive a digital copy of the subject data for archiving at the 
investigational site. 
Paper Case Report Forms (pCRF) 
Paper forms are only relevant for patient reported data (questionnaires), which will be produced by the 
Clinical Trial Unit, Oslo University Hospital.  

36 
 
 
The data will be entered into Viedoc™ by the study staff.   
9.2. Source Data  
Source data are all information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents (original records or certified copies). 
The medical records for each patient should contain information which is important for the patient’s safety 
and continued care, and to fulfill the requirement that critical study data should be verifiable.  
To achieve this, the medical records of each patient should clearly describe at least that the patient is 
participating in the study, e.g. by including the enrollment number and the study code or other study 
identification; 
• 
Date when Informed Consent was obtained from the patient and statement that patient received a copy 
of the signed and dated Informed Consent; 
• 
Results of all assessments confirming a patient’s eligibility for the study; 
• 
Treatments withdrawn/withheld due to participation in the study; 
• 
Results of assessments performed during the study; 
• 
Treatments given, changes in treatments during the study and the time points for the changes;  
• 
Visits to the clinic / telephone contacts during the study, including those for study purposes only; 
• 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments;  
• 
Date of, and reason for, discontinuation from study treatment 
• 
Date of, and reason for, withdrawal from study; 
• 
Additional information according to local regulations and practice. 
Specify and provide details if any source data will be recorded directly into the Case Report Form (meaning 
that for the defined parameters, CRF is source data and not the hospital records).  
A source data list will be agreed upon for each site specifying the source at a module or a variable level.  
9.3. Study Monitoring  
Study monitoring will be based on the risk assessment and will be described in a monitor plan that will be 
prepared prior to study start. Study monitoring will be performed by two research cardiologists at Drammen 
hospital and the hospital of Vestfold that are otherwice not involved in the study.  
9.4. Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. Patient 
files shall be kept for the maximum period of time permitted by each hospital. The study documentation 

37 
 
 
(CRFs, Site File etc) shall be retained and stored during the study and for 25 years after study closure). All 
information concerning the study will be stored in a safe place inaccessible to unauthorized personnel. 
9.5. Database management 
Data management will be performed by the Clinical Trial Unit, Oslo University Hospital. The Data 
management procedures will be performed in accordance with the department’s SOPs and ICH guidelines. 
The data management process will be described in the study specific data handling plan and the study specific 
data handling report after database closure.  
Data entered into the eCRF will be validated as defined in the data validation plan. Validation includes, but is 
not limited to, validity checks (e.g. range checks), consistency checks and customized checks (logical checks 
between variables to ensure that study data are accurately reported) for eCRF data and external data (e.g. 
laboratory data). A majority of edit checks will be triggered during data entry and will therefore facilitate 
efficient ‘point of entry’ data cleaning. 
Data management personnel will perform both manual eCRF review and review of additional electronic edit 
checks to ensure that the data are complete, consistent and reasonable. The electronic edit checks will run 
continually throughout the course of the study and the issues will be reviewed manually online to determine 
what action needs to be taken. 
Manual queries may be added to the system by clinical data management or study monitor. Clinical data 
managers and study monitors are able to remotely and proactively monitor the patient eCRFs to improve 
data quality. 
All updates to queried data will be made by authorized study center personnel only and all modifications to 
the database will be recorded in an audit trail. Once the queries have been resolved, eCRFs will be signed by 
electronic signature Any changes to signed eCRFs will be approved and resigned by the Investigator. 
Once the full set of eCRFs have been completed and locked, the Sponsor will authorize database lock and all 
electronic data will be sent to the designated statistician for analysis. Subsequent changes to the database 
will then be made only by written agreement. 
The data will be stored in a dedicated and secured area at Vestre Viken, Drammen Hospital. Data will be 
stored in a de-identified manner, where each study participant is recognisable by his/her unique trial subject 
number. The data will be stored until 31.12.2038.  
Adverse events and medical history will be coded from the verbatim description (Investigator term) using the 
Medical Dictionary for Regulatory Activities, MedDRA.  
Once the database has been completed and locked, the Sponsor will authorise database lock and all 
electronic data will be sent to the designated statistician for analysis. Subsequent changes to the database 
will then be made only by written agreement. 
9.6. Determination of Sample Size and Power Calculation 
9.6.1. Sample Size 
Power calculations are based on our being able to detect a 1 cm difference in the VAS symptom score 
between the treatment periods on atorvastatin and placebo since the smallest change in VAS symptom score 
corresponding to ‘a little more’ or ‘a little less’ symptoms was 1.3 cm, with a lower limit of the CI at 1 cm in 

38 
 
 
a previous study.(23) Gallagher et al. (23) report a standard deviation (SD) of 1.7  for a difference of 1.0 
between  two VAS symptom scores. Because of the differences in both populations and specific VAS scale 
between that study in this one, we use SD=2.5 to account for a much larger variation in this study. With n=68, 
we shall will have 90% power to detect a difference of 1.0, using a one-sample T test. With n=68, we will also 
have 80% power to detect a difference of 40% SAMS under statins vs. 15% SAMS under placebo, using the 
McNemar test for paired probabilities. To account for some missing information data due to drop-outs or 
and protocol deviations, we plan to include 80 patients. 
9.7. Randomization 
9.7.1. Allocation- sequence generation 
Eligible patients will be  randomized by the study physicians to double-blinded prescription of atorvastatin 
or a matched placebo tablet in a 1:1 ratio using the electronic randomisation system of the clinical trials unit 
(CTU) at OUH. Block randomization with block size 4 and 6 in random order, stratified according to centre 
(Drammen Hospital and Hospital of Vestfold) and previous statin discontinuation (yes/no), will be used.  
Details of block size and allocation sequence generation will be provided in a separate document that is 
unavailable to those who enrol patients or assign treatment.   
9.7.2. Blinding and emergency unblinding 
The participant and trial team will all be blind to the participant’s sequence allocation. Placebo will be 
manufactured specially to match the atorvastatin by the manufacturer. Capsules and packaging will be 
identical in appearance for both active treatment and placebo.The primary investigator will be responsible 
for assuring that there are procedures and expertise available to cope with emergencies during the study. 
Emergency unblinding will be performed in the following situations:  
- in case of a SUSAR    
-in case of Serious Adverse Events that could be related to atorvastatin discontinuation including 
hospitalization for subsequent myocardial infarction,  stable/unstable  angina or ventricular arrytmias 
requiring coronary revascularization and death. 
Doubtful cases will be discussed with the medical officer and senior cardiologists in the steering committee 
(Gullestad, Otterstad) before unblinding.  
 Emergency unblinding will be performed within 24 hours by two research  cardiologists at Drammen Hospital  
and at the Hospital of Vestold who otherwice are not participating in the study.   
9.8. Planned analyses 
The main statistical analysis is planned when all patients have been followed for 16 weeks, all data have been 
entered, verified and validated, and the database has been locked. 
Oslo Centre for Biostatistics and Epidemiology (OCBE) will be responsible for the statistical quality of the trial. 
Prior to the main statistical analysis, the data base will be locked for further entering or altering of data. A 
statistical analysis plan (SAP) describing all the statistical methods will be produced prior to database lock. 
The treatment allocation will be revealed after the database lock and used in the statistical analysis. 

39 
 
 
Deviation from the original statistical plan will be described and justified in the Clinical Study Report. 
Amendments to plan can be done until day of DB lock. 
9.9. Statistical Analysis 
The primary outcome and all other continuous outcomes will be estimated with linear regression models 
with the stratification factors in the randomization (i.e. centre and previous statin discontinuation) as 
covariates. Dichotomous outcomes will be analysed with conditional logistic regression models with 
treatment, centre, and previous statin discontinuation as covariates. Methods for analysis of ROC curves and 
measures of diagnostic accuracy will be used to identify cut-off values of metabolite concentrations that can 
discriminate between confirmed SAMS from other muscle symptoms. The correlations between individual 
mean difference in muscular symptom intensity between treatment periods with statin and placebo and 
levels of atorvastatin and its metabolites in blood plasma and white blood cells will be estimated with 
Spearman correlation coefficients and linear regression analyses. 
9.9.1. Safety analyses 
Due to the low number of patients, no safety analyses are planned for this study, but descriptive data will 
be presented. 
10. STUDY MANAGEMENT 
10.1. Investigator Delegation Procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all the involved 
co-workers and their role in the project. He will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information of relevance to the performance of this study is forwarded 
to the staff involved. 
10.2. Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations.  
All significant protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
10.3. Study Amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study 
protocol (Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics 
Committee according to EU and national regulations. 
10.4. Audit and Inspections 
Authorized representatives of a Competent Authority and Ethics Committee may visit the study centers to 
perform inspections, including source data verification. Likewise the representatives from sponsor may visit 
the center to perform an audit. The purpose of an audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were conducted, 
and data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 

40 
 
 
(ICH GCP), and any applicable regulatory requirements. The principal investigator will ensure that the 
inspectors and auditors will be provided with access to source data/documents. 
11. ETHICAL AND REGULATORY REQUIREMENTS  
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. 
Registration of patient data will be carried out in accordance with national personal data laws. 
11.1. Ethics Committee Approval 
The study protocol, including the patient information and informed consent form to be used, must be 
approved by the regional ethics committee before enrolment of any patients into the study. 
The investigator is responsible for informing the ethics committee of any serious and unexpected adverse 
events and/or major amendments to the protocol as per national requirements. 
11.2. Other Regulatory Approvals 
The protocol will be submitted and approved by the applicable competent authorities before 
commencement of the study. 
The protocol will also be registered in www.clinicaltrials.gov and the European Clinical Trials Database 
(EudraCT) as before inclusion of the first patient. 
11.3. Informed Consent Procedure 
The investigator is responsible for giving the patients full and adequate verbal and written information about 
the nature, purpose, possible risk and benefit of the study. They will be informed as to the strict 
confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by 
authorized individuals other than their treating physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever she/he wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent must be obtained for all patients included in the study before they are 
registered in the study. This will be done in accordance with the national and local regulatory requirements. 
The investigator is responsible for obtaining signed informed consent. 
A copy of the patient information and consent will be given to the patients. The signed and dated patient 
consent forms will be filed in the Investigator Site File binder.  
11.4. Subject Identification 
The investigator is responsible for keeping a list of all patients (who have received study treatment or 
undergone any study specific procedure) including patient’s date of birth and personal number, full names 
and last known addresses.  
The patients will be identified in the CRFs by patient number, initials and date of birth (define as applicable). 

41 
 
 
11.5. User involvement 
The NOR-COR study user-group comprising user-group representatives from the Norwegian Health 
Association (n=1), “Landsforeningen for Hjerte og Lungesyke” in Buskerud and Vestfold (n=2), general 
practitioners (GPs) (n=5), cardiac nurses (n=3), and clinical cardiologists (n=2) from the hospitals of Drammen 
and Vestfold have provided feedback in the study design, the self-reported study questions, patient 
information letters, and the data collection tools. The group will also play an important role in disseminating 
the study results. 
12. TRIAL SPONSORSHIP AND FINANCING 
Vestre Viken Trust is financing the trial, which is funded by grants from Vestre Viken Trust and Department 
of Pharmacology, OUH. Further applications for funding and researchers have been submitted. Other than 
mediating financial support, the financial sponsors are not involved in the conduction of this study.   
13. TRIAL INSURANCE 
The Principal investigator will provide insurance coverage for this study through membership of the Drug 
Liability Association before study start (see http://www.laf.no for more details).  
14. PUBLICATION POLICY 
Upon study completion and finalization of the study report the results of this study will either be submitted 
for publication and/or posted in a publicly assessable database of clinical study results.  
The results of this study will also be submitted to the Competent Authority and the Ethics Committee 
according to EU and national regulations. 
All personnel who have contributed significantly with the planning and performance of the study (Vancouver 
convention 1988) may be included in the list of authors. 
 
 
 
 

42 
 
 
15. APPENDICES 
15.1. APPENDIX A – Screening letter sent by postal prior to telephone interview 
 
Opplever du muskelplager når du tar dine 
kolesterolmedisiner? 
           MUscle Side-Effects of atorvastatin in coronary patients (MUSE) 
 
Kjære hjertepasient! 
Vi planlegger en studie der vi skal kartlegge sammenhengen mellom muskelplager og behandling 
med den kolesterolsenkende medisinen atorvastatin (salgsnavn Lipitor eller Atorvastatin) hos 
pasienter med påvist sykdom i hjertets kransårer (hjerteinfarkt, angina). Vi vet lite om hvorfor 
mange pasienter opplever bivirkninger fra musklene under behandling med slike medisiner. Studien 
inngår i det forebyggende hjerteprosjektet NOR-COR som gjennomføres ved sykehusene i Drammen 
og Vestfold. 
Da du tilhører denne pasientgruppen, mottar du dette enkle og uforpliktende spørreskjemaet som 
en kartlegging rundt hvorvidt du kan være en kandidat for å delta i studien.  
Dersom du enten bruker eller tidligere har brukt atorvastatin/Lipitor og opplever eller har opplevd 
muskelbivirkninger er du hjertelig velkommen til å kontakte oss for en uforpliktende samtale om 
mulig deltagelse i denne studien.  Hvis vi ikke hører fra deg vil vi ta kontakt deg per telefon om noen 
dager. Vi vil da stille deg følgende spørsmål:   
1. Bruker du kolesterolsenkende medisin av typen atorvastatin eller lipitor? 
2. Dersom ja, opplever du vesentlige muskelplager som du relaterer til behandlingen med 
atorvastatin? 
3. Har du tidligere brukt atorvastatin eller lipitor og sluttet med medisinen grunnet 
muskelplager? 
 
Med vennlig hilsen 
 
Oscar Kristiansen 
 
 
 
 
       Kari Peersen 
Lege og forsker, Medisinsk avdeling,  
 
       Spesialfysioterapeut og forsker 
Drammen sykehus 
 
 
 
 
       Hjerteavdelingen Sykehuset i Vestfold 
Telefon: 47682535   
 
 
 
       Telefon: 99267726 
e-post: osckri@vestreviken.no    
 
 
       E-post: kari.peersen@siv.no 

43 
 
 
15.2.  APPENDIX B – Informed consent letter 
                                                                                                   
FORESPØRSEL OM DELTAGELSE I FORSKNINGSPROSJEKT                                            
MUscle Side-Effects of atorvastatin in coronary patients (MUSE) 
 
Kjære hjertepasient 
 
Dette er en forespørsel til deg om å delta i forskningsprosjektet, MUSE, som har til hensikt å 
undersøke sammenhengen mellom kolesterolmedisinen atorvastatin og muskelsymptomer hos 
pasienter med påvist koronar hjertesykdom. Vi vet fortsatt for lite om hvorfor mange pasienter 
rapporterer bivirkninger fra muskler under behandling med statiner. Studien inngår i det 
forebyggende hjerteprosjektet NOR-COR ved sykehusene i Drammen og Vestfold og ledes fra 
Medisinsk avdeling, Drammen sykehus. Studien skal inkludere til sammen 120 pasienter. 
 
HVA INNEBÆRER DELTAGELSE I DENNE DELSTUDIEN?                                            
Pasienter som har gjennomgått hjerteinfarkt, fått utført PCI behandling (utblokking) eller utført by-
pass operasjon (byttet kransårer) i tidsrommet 2016-18 vil bli kontaktet og forespurt om deltagelse 
via et telefonintervju. Dersom du opplever muskelplager (bl.a. smerter, stivhet, svakhet, ømhet, 
kramper) som du tror skyldes din kolesterolmedisin eller du har sluttet med kolesterolmedisiner på 
grunn av slike plager vil du bli invitert til vår poliklinikk på sykehuset for å vurdere om du er kandidat 
for å kunne delta. Dersom du vurderes å være kandidat for å delta, vil du få behandling med 
kolesterolmedisinen atorvastatin i 7 uker og behandling med en identisk tablett uten kolesterolmedisin 
(placebo) i 7 uker. Det blir bestemt ved tilfeldig uttrekk (randomisert) hvorvidt du får tablett med 
kolesterolmedisin den første 7 ukers perioden eller den siste. Verken du eller studielegen vil vite 
rekkefølgen på behandlingen før etter at studien er gjennomført. Hensikten med dette er å undersøke 
best mulig i hvor stor grad dine muskelplager er forbundet med kolesterolmedisin. Den siste uken før 
og etter hver behandlingsperiode skal du ikke ta studiemedisin i det hele tatt. Dette for å sikre at all 
studiemedisin er gått ut av blodet før neste behandlingsperiode starter.  Du skal registrere dine 
muskelplager i en dagbok en gang per uke i de 16 ukene som studien pågår. I tillegg skal du komme 
på laboratoriet på sykehuset for å ta to blodprøver med 2 timers mellomrom til analyse av 
kolesterolprofil, muskelproteiner og nivåer av kolesterolmedisin før og etter hver 7 ukers behandling. 
Du skal også komme til sykehuset dersom dine muskelplager er såpass ubehagelige at du ikke ønsker 
å fortsette med medisinen.  
 
Vi vil også invitere et utvalg pasienter med koronarsykdom som bruker atorvastatin og som  aldri har 
opplevd muskelplager til å delta i denne studien. Dersom du tilhører denne gruppen vil du bli bedt 
om å kutte ut din kolesterolmedisin i 1 uke og deretter ta kolesterolmedisin daglig i 7 uker før du 
kommer til laboratoriet på sykehuset for å ta en blodprøve til analyse av nivåer av kolesterolmedisin 
i blodet.   
Hvis du takker nei til deltagelse vil det ikke ha noe konsekvens for annen behandling eller oppfølging 
som er planlagt på sykehuset.  
 
HENSIKTEN MED STUDIEN 
Formålet med studien er å undersøke sammenhengen kolesterolmedisinen atorvastatin og 
muskelsymptomer hos pasienter med etablert koronar hjertesykdom. Det er ofte krevende både for 

44 
 
 
pasienten og legen å vite om pasientens muskelplager skyldes kolesterolmedisinen eller ikke.  Denne 
studien vil gi ny og svært etterspurt kunnskap om sammenhengen mellom kolesterolmedisiner og 
muskelplager og kan kanskje gi oss en blodtest som kan si hvorvidt muskelplager skyldes medisinen 
eller ikke. Dette kan i så fall bidra til mer skreddersydd og bedre kolesterolbehandling til den enkelte 
pasient enn det som er tilfelle i dag.  
 
MULIGE FORDELER, ULEMPER OG ALVORLIGE BIVIRKNINGER 
Siden kolesterolmedisin gis rutinemessig til koronarpasienter i dag, er den ukjente potensielle risikoen 
i denne studien forbundet med å erstatte kolesterolmedisin med en tablett uten kolesterolmedisin. 
Imidlertid har vi data fra over 15000 hjerteinfarktpasienter som ikke viser noen økt risiko for nye 
hjerte-kar hendelser hos pasienter som kutter ut kolesterolmedisin noen uker når det gjøres i 
forbindelse med en studie under nøye oppfølging av hjertelege slik som i denne studien.  Risikoen 
ved å få behandling med kolesterolmedisin er legemiddelets kjente bivirkninger (muskelplager, 
kvalme og diare). Dersom du opplever at du får muskelplager eller andre bivirkninger som er så 
plagsomme at du ikke ønsker å fortsette, kan du når som helst be om å få avslutte behandlingen og 
komme for å ta blodprøve til analyse av kolesterolmedisin.  
 
Ved å delta i denne studien vil de ansvarlige hjerteleger gi den en grundig personlig gjennomgang av 
din kolesterolprofil og informasjon om i hvilken grad dine muskelplager skyldes kolesterolmedisinen 
eller ikke. Du og din fastlege vil også få en detaljert anbefaling for videre kolesterolbehandling. I de 
tilfeller hvor det viser seg at dine muskelplager ikke skyldes medisinen, vil vi gi råd til din fastlege 
om mulige alternative behandlinger.  
 
Ved å delta i studien bidrar du også med ny kunnskap som potensielt kan bidra til mer skreddersydd 
og korrekt kolesterolbehandling til et stort antall pasienter med og uten hjertesykdom som opplever 
muskelplager når de tar kolesterolmedisin. 
  
HVA SKJER MED INFORMASJONEN OM DEG?  
Informasjonen som registreres om deg skal kun brukes slik som beskrevet i hensikten med studien. 
Alle opplysningene og prøvene vil bli behandlet uten navn og fødselsnummer eller andre direkte 
gjenkjennende opplysninger. En kode knytter deg til dine opplysninger og prøver gjennom en 
navneliste. Listen som kan koble ditt navn til koden vil bli oppbevart på sykehuset og bare personell 
med ansvar for studien har tilgang til denne. Deltakelse innebærer at opplysninger om din 
helsetilstand og behandling registreres og benyttes i forskningsøyemed. Det blir registrert 
opplysninger om behandlingen og din hjertesykdom ved start av studien og gjennom 
behandlingsperiodene på til sammen 14 uker. Opplysningene blir samlet fra flere kilder:  
- Relevante opplysninger om din hjertesykdom blir registrert fra din pasientjournal og din 
kjernejournal på sykehuset  
- Opplysninger du gir i det vedlagte spørreskjemaet som du besvarer før og etter studien 
- Dagboken som du fyller ut ukentlig gjennom studien 
- Undersøkelser og blodprøver av deg ved oppstart, underveis og ved avslutning av studien  
 
Det vil ikke være mulig å identifisere deg i resultatene av studien når disse publiseres.  
 
 
 
Utlevering av materiale og opplysninger til andre 

45 
 
 
Hvis du sier ja til å delta i studien, gir du også ditt samtykke til avidentifiserte opplysninger utleveres 
til våre samarbeidspartnere. Våre viktigste samarbeidspartnere er Universitet i Oslo og Oslo 
Universitetssykehus.  
 
Innsynsrett og oppbevaring av materiale 
Hvis du takker ja til å delta i studien, har du rett til å få innsyn i hvilke opplysninger som er registrert 
om deg. Du har videre rett til å få korrigert eventuelle feil i de opplysningene vi har registrert. Dersom 
du trekker deg fra studien, kan du kreve å få slettet innsamlede prøver og opplysninger, med mindre 
opplysningene allerede er inngått i analyser eller brukt i vitenskapelige publikasjoner. Opplysningene 
vil da ikke brukes videre i studien. 
 
BLODPRØVER TIL BIOBANK 
I denne samtykkeforespørselen ber vi deg også ta stilling til om vi kan ta blodprøver av deg for lagring i 
en forskningsbiobank (NOR-COR Biobank) lokalisert på Drammen sykehus. Senere analyser av disse 
blodprøvene med andre metoder enn de som eksiterer i dag, vil kunne gi oss nye markører til å studere 
legemiddelnivåer, virkningsmekanismer og bivirkninger ved kolesterolmedisiner samt andre hjerte/kar-
medisiner.  
 
Avdelingssjef ved Medisinsk avdeling, Drammen sykehus er ansvarshavende for NOR-COR Biobank. 
Biobanken opphører 25 år etter studieslutt, det vil si i 2047. Studiespesifikke prøver blir destruert og slettet 
etter interne retningslinjer når alle planlagte analyser er gjort. Det biologiske materialet kan bare bli 
anvendt til medisinske formål jf, Bioteknologiloven (§5) og kan kun brukes videre etter godkjenning fra 
Regional komité for medisinsk og helsefaglig forskningsetikk (REK).  
 
Hvis du sier ja til å delta i studien, gir du også ditt samtykke til at blodprøver og avidentifiserte 
opplysninger også kan oppbevares, analyseres og behandles ved Avdeling for klinisk Farmakologi ved 
Oslo Universitetssykehus.  
 
GENETISKE UNDERSØKELSER 
Studien ber også, som et tredje samtykke, om tillatelse til å gjennomføre genetiske undersøkelser 
(gensekvenser og sammensetning i arvestoffet DNA, spesifikke genuttrykk målt som RNA, samt 
spesifikke proteiner, peptider og metabolitter) av blodprøvene som er samlet inn. Studiens analyser er 
begrenset til genetiske markører som enten har eller som kan ha betydning for legemiddelomsetning eller 
bivirkninger ved behandling med kolesterolmedisiner og andre hjertemedisiner. Analyser av kjente 
genetiske markører som har betydning for legemiddelomsetning og bivirkninger med kolesterolmedisiner 
vil bli gjennomført underveis i studien og svar på disse undersøkelsene vil bli gitt til studiedeltagerne 
siden det potensialt kan få betydning for videre behandling med kolesterolmedisiner og andre 
hjertemedisiner. Det vil også  
kunne bli utført analyser flere år frem i tid og svar på disse undersøkelsene kan derfor ikke gis til 
studiedeltagerne, med mindre fremtidig forskning avdekker at slike funn bør følges opp. Genetiske 
undersøkelser som skal gjennomføres frem i tid vil ikke bli gjennomført før man har innhentet nye 
godkjenninger fra REK. 
• Dersom det i forbindelse med studien eller i fremtiden påvises funn av genvarianter som har 
betydning for pasientenes prognose eller aktuell behandling med kolesterolmedisin eller andre 
hjertemedisiner, vil deltagere få tilbakemelding av studiens hjerteleger og ved behov bli tilbudt 
genetisk veiledning ved Avdeling for Medisinsk genetikk på Rikshospitalet.  
• Mulig reidentifisering: Selv om navn og personnummer fjernes, er genomsekvensen så unik at den i 
teorien ikke kan sies å være anonym.  
 

46 
 
 
GODKJENNING  
Regional komité for medisinsk og helsefaglig forskningsetikk har vurdert prosjektet, og har gitt 
forhåndsgodkjenning [saksnr. hos REK (2018/2302]. Studien er også godkjent av Statens 
legemiddelverk (SLV) (nr. 18/17102-7). 
Etter ny personopplysningslov har behandlingsansvarlig [Vestre Viken HF- Drammen sykehus] og 
prosjektleder [John Munkhaugen] et selvstendig ansvar for å sikre at behandlingen av dine 
opplysninger har et lovlig grunnlag. Dette prosjektet har rettslig grunnlag i EUs personvernforordning 
artikkel 6a. Du har rett til å klage på behandlingen av dine opplysninger til Datatilsynet.  
FORSIKRING  
Ordinær pasientskadeerstatning er gjeldende. Du er også forsikret i henhold til Lov om produktansvar 
i Legemiddelforsikringen. 
FRIVILLIG DELTAKELSE OG MULIGHET FOR Å TREKKE SITT SAMTYKKE  
Det er helt frivillig å delta i studien. Du kan når som helst og uten å oppgi noen grunn trekke ditt 
samtykke til deltagelse i studien. Dette vil ikke få konsekvenser for din videre behandling. Du 
undertegner samtykkeerklæringen dersom du ønsker å delta. Dersom du senere ønsker å trekke deg 
eller har spørsmål om studien kan du kontakte prosjektleder PhD John Munkhaugen på tlf. 975 
24 194, PhD stipendiat Oscar Kristiansen på tlf. 476 82 535 eller spesialfysioterapeut/forsker Kari 
Peersen på Telefon: 99267726 .  
 
Du kan ta kontakt med institusjonens personvernombud dersom du har spørsmål om behandlingen av 
dine personopplysninger i prosjektet. Drammen sykehus: Henriette Henriksen, tlf +47 41764786, 
epost: Henriette.Henriksen@vestreviken.no. Sykehuset i Vestfold: Ida Mollerud, tlf.  +47 33 34 33 
86, epost: PVO@siv.no 
 
 
 
ØKONOMI  
Studien er finansiert gjennom forskningsmidler fra Nasjonalforeningen for folkehelsen og de 
deltagende sykehusene; Sykehuset i Drammen, Vestre Viken og Sykehuset i Vestfold. Disse har ingen 
økonomiske interesser i forskningsresultatene. 
 
SAMTYKKE TIL DELTAGELSE 
Du kan velge kun å gi samtykke til deltakelse alene. Du kan også velge å gi tillatelse til deltakelse og 
biobank men ikke genetiske analyser, eller du kan samtykke til alle fire spørsmål. Den som har spurt deg 
om deltakelse kan besvare eventuelle spørsmål du måtte ha.  
 
Jeg er villig til å delta i HOVEDstudien  
 
 
 
 
 
Sted og dato   
 
 
 
 
 
----------------------------                ------------------------- 
                                           
 
  Deltakers signatur 
 
Deltakers navn med 
                                                                                                 
 
 BLOKKBOKSTAVER  
 
                                                                                                   
 
    
 

47 
 
 
 
 
 
Jeg er villig til å gi materialet til biobank (blodprøve)  
 
Sted og dato 
 
 
----------------------------                ------------------------- 
                                           
 
  Deltakers signatur 
 
Deltakers navn med 
                                                                                                 
 
 BLOKKBOKSTAVER  
 
 
Jeg er villig til at det kan utføres genetiske analyser 
 
Sted og dato 
 
 
 
 ----------------------------                ------------------------- 
                                           
 
  Deltakers signatur 
 
Deltakers navn med 
                                                                                                 
 
 BLOKKBOKSTAVER  
 
 
 
Jeg bekrefter å ha gitt informasjon om prosjektet 
 
 
Sted og dato Sted og dato 
 
----------------------------                ------------------------- 
                                           
 
  Signatur 
 
 
       Rolle i prosjektet  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

48 
 
 
15.3 Baseline and 16 weeks questionnaire 
Spørreskjema MUSE studien 
Kjære NOR-COR MUSE studiedeltager. Tusen takk for at du vil svare på et nytt spørreskjema. Vi håper 
du vil svare på alle spørsmålene nedenfor så nøye som mulig. De fleste vil bruke ca 15-20 minutter på å 
svare. 
 
Bor du alene eller sammen med andre?  
Sett ett kryss. 
 
Bor alene…………….…………………………………………………………… 
Bor sammen med ektefelle eller samboer……………….………………….... 
Bor alene etter separasjon/skilsmisse……………….……………………....... 
Bor for tiden på sykehjem, aldershjem eller liknende……….…………..…...   
 
Hvilken utdanning er den høyeste du har fullført?  
Sett ett kryss  
 
Grunnskole 7-10 år, framhaldsskole, folkehøgskole………………………….  
 
Realskole, middelskole, yrkesskole, 1-2 årig videregående skole…………  
 
Artium, øk. gymnas, allmennfaglig retning i videregående skole…………..  
 
Høgskole/universitet, mindre enn 4 år………………………………………….  
 
Høgskole/universitet, mer enn 4 år……………………………………………..  
 
MEDISINBRUK 
Bruker du kolesterolsenkende medisiner av typen statin (Simvastatin, Zocor, Atorvastatin, 
Lipitor, Lescol, Pravachol, Pravastatin,  Lovastatin, Rosuvastatin, Crestor) ? 
 
Ja…… 
 
 Nei……..   
 
Hvis ja, vennligst oppgi navn og styrke på alle dine kolesterolmedisiner: 
Navn:  …………………..            Dose: ……………. mg 
 
Navn:  …………………..            Dose: ……………. mg 
 
Opplever du bivirkninger når du tar dine kolesterolmedisiner i dag? 
Nei……  
        Ja ………                     
 
I så fall kan du beskrive hvilke bivirkninger? …….………………………………………… 
 
    
 
 
                                  …….………………………………………… 

49 
 
 
Er bivirkningene så plagsomme at du har sluttet å ta kolesterolmedisinen i perioder 
eller vurdert å slutte med de? 
 
Nei………..            Ja ………                     
 
 
Har du tidligere opplevd bivirkninger ved inntak av kolesterolmedisiner? 
 
Nei……..  
        Ja……….                      
 
 
I så fall hva het medisinen(e) som gav deg bivirkninger? …………………………….. 
 
                 ……………………………… 
 
 
Kan du beskrive hvilke bivirkninger du opplevde?          ………………………………… 
 
    
 
 
                                                      ………………………………… 
 
                                              ………………………………… 
 
Har du tidligere sluttet med kolesterolmedisiner pga. bivirkninger? 
 
Nei…….            Ja……..                
 
 
 I så fall hva het medisin (ene)?    …….……………… og hvilken dose tok du?............mg 
 
            …….……………… og hvilken dose tok du?............mg 
 
 
 
 
 
 
 
 
 
 
 
                       …….……………… og hvilken dose tok du?............mg 
 
 
Har du tidligere redusert dose eller byttet dine kolesterolmedisiner pga. bivirkninger? 
 
Nei……        Ja……   I så fall hvilken medisin/dose? …….…………………………………… 
 
Hvor ofte tok du dine kolesterolsenkende medisiner som forskrevet sist uke? 
Sett ett kryss 
 
Hver dag        6 av 7 dager       5 av 7 dager         4 av 7 dager           < 4 av 7 dager         Jeg tar dem ikke  
 
 
Hvor sannsynlig er det at du vil komme til å slutte med dine kolesterolmedisiner på 
grunn av bivirkninger de neste ukene? 
 
 
Usannsynlig          0       1       2          3         4        5        6         7          8        9        10           Svært sannsynlig  

50 
 
 
 
Her følger noen spørsmål om ditt syn på medisinene som du har fått foreskrevet inkludert 
dine kolesterolmedisiner. Vennligst indiker om du er enig eller uenig ved å sette en strek 
under utsagnet som passer best med ditt syn. Ingen svar er rett eller galt. Vennligst sett en 
strek per rute. 
1) Min helse for tiden er avhengig av mine kolesterolmedisiner  
Svært enig                     Enig 
Usikker 
   Uenig 
    Svært uenig 
 
2) Det å matte ta kolesterolmedisiner bekymrer meg  
Svært enig                     Enig 
Usikker 
   Uenig 
    Svært uenig 
 
3) Mitt liv ville vært umulig uten mine kolesterolmedisiner  
 Svært enig                    Enig 
Usikker 
    Uenig 
     Svært uenig 
 
4) Uten mine kolesterolmedisner vil jeg bli svært syk  
 Svært enig                          Enig 
 
Usikker 
 
Uenig  
Svært uenig 
 
5) Av og til bekymrer jeg meg for langtids effektene av mine kolesterolmnedisiner 
 Svært enig                          Enig 
 
Usikker 
 
Uenig  
Svært uenig 
 
6) Mine kolesterolmedisner er et mysterium for meg  
 
 
 
 
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig  
  
 
7) Helsen min i fremtiden er avhengig av mine kolesterolmedisiner  
  
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig 
 
8) Mine kolesterolmedisiner forstyrrer livet mitt  
  
 
 
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig 
  
 

51 
 
 
 
10) Mine kolesterolmedisiner beskytter meg mot å bli værre av hjertesykdommen min.  
  
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig 
  
 
11) Leger foreskriver for mange medisiner   
  
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig 
   
  
12) Pasienter som tar medisiner burde av og til stoppe å ta sin behandling for en 
periode  
  
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig 
 
13) De fleste medisiner er avhengighetsskapende.  
  
 
 
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig  
  
15) Medisiner gjør mer skade enn nytte  
  
 
 
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig  
 
  
  
 
  
  
14) Naturlegemidler er tryggere enn medisiner 
  
 
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig    
 
 
  
16) Alle medisiner er giftige   
  
  
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig    
 
 
 
17) Leger har for stor tro på medisiner  
  
 
 
 
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig     
  
  
18) Hvis legene hadde hatt mer tid til pasientene ville de foreskrevet færre medisiner   
  
Svært enig                          Enig  
Usikker 
 
Uenig  
Svært uenig     
  
 

52 
 
 
LIVSSTIL  
 
Hvor ofte driver du med fysisk aktivitet? (Ta et gjennomsnitt)                   
  Sett ett kryss   
Aldri…………………………………………………………………………………... 
Sjeldnere enn 1 gang i uken………………………………………………………… 
En gang i uken…………………………………………………….…………………. 
2-3 ganger i uken…………………………………………………………………….. 
Omtrent hver dag…………………………………………………………………… 
 
Dersom du driver fysisk aktivitet så ofte som en eller flere ganger i uken: 
Hvor hardt tar du i? (Ta et gjennomsnitt) 
 
Tar det rolig uten å bli andpusten eller svett……….………….…………………. 
Tar det så hardt at jeg blir andpusten og svett ………………………………….. 
Tar meg nesten helt ut……………..……………………………………………….. 
 
Hvor lenge holder du på hver gang? (Ta et gjennomsnitt) 
 
Mindre enn 15 minutter …………………………………………………………… 
16-30 minutter………………………………………………….…………………… 
30 minutter – 1 time………………………………………………………………… 
Mer enn 1 time…….………………………………………………………………… 
 
 
Hvor mye veier du uten klær? ………………..……………… kg 
 
 
Hvor høy er du?..................................................................... cm 
 
 
Røyker du? (sett ett kryss under alternativet som passer)  
 
Nei, jeg har aldri røykt  
 
      Ja, jeg røyker av og til   
 
 
Nei, jeg har sluttet å røyke 
 
       Ja, jeg røyker daglig 
 
Alkoholbruk 
  
I løpet av de siste 12 måneder, hvor ofte vil du si at du har drukket alkohol? 
Sett strek under alternativet som passer 

53 
 
 
 
Aldri      Månedlig eller sjeldnere       2-3 x pr mnd       2-3 x pr uke          4 x pr uke eller mer  
 
 
MUSKEL SYMPTOMER OG PLAGER 
 
Har du vært plaget med symptomer (smerter, ømhet, svakhet, stivhet, kramper) fra 
muskler den siste måneden?  
 
Generelle symptomer i hele kroppen? (sett ring rundt det tallet som beskriver dine plager best) 
 
Ingen symptomer      0       1       2          3         4        5        6         7          8        9      10       Verst tenkelig  
 
Symptomer fra hofte og lår? (sett ring rundt det tallet som beskriver dine plager best) 
 
Ingen symptomer      0       1       2          3         4        5        6         7          8        9      10       Verst tenkelig  
 
 
Symptomer fra leggene? (sett ring rundt det tallet som beskriver dine plager best) 
 
Ingen symptomer      0       1       2          3         4        5        6         7          8        9      10       Verst tenkelig  
 
 
Symptomer fra skuldre og nakke? (sett ring rundt det tallet som beskriver dine plager best) 
 
Ingen symptomer      0       1       2          3         4        5        6         7          8        9      10     Verst tenkelig  
 
Symptomer fra rygg? (sett ring rundt det tallet som beskriver dine plager best) 
 
Ingen symptomer      0       1       2          3         4        5        6         7          8        9      10      Verst tenkelig  
 
 
 
 
 
 
 
Smerteskjema:  
 
1. Gjennom livet har de fleste av oss hatt smerter (som lett hodepine, forstuelser eller 
tannpine). 
 
Har du i dag smerter av et eller annet slag enn slike dagligdagse smerter?   
 
JA         NEI 
 

54 
 
 
 
2. Vil du skravere alle de områdene av kroppen hvor du har smerter. Marker med et 
kryss der du har mest vondt. 
 
 
 
 
 
3. Vennligst sett ring rundt det tallet som best beskriver de sterkeste smertene du har 
hatt i løpet av de siste 24 timer: 
 
Ingen smerter      0       1       2          3         4        5        6       7       8        9      10   Verst tenkelig smerter 
 
 
4. Vennligst sett ring rundt det tallet som best beskriver de svakeste smertene du har 
hatt i løpet av de siste 24 timer: 

55 
 
 
 
Ingen smerter      0       1       2          3         4        5        6       7       8        9      10   Verst tenkelig smerter 
 
5. Vennligst sett ring rundt det tallet som best angir hvor sterke smerter du har i 
gjennomsnitt de siste 24 timer: 
 
Ingen smerter      0       1       2          3         4        5        6       7       8        9      10   Verst tenkelig smerter 
 
 
6. Vennligst sett ring rundt det tallet som best angir hvor sterke smerter du har 
akkurat nå: 
 
Ingen smerter      0       1       2          3         4        5        6       7       8        9      10   Verst tenkelig smerter 
 
7. Hvilken behandling eller medisiner får du for å lindre smertene dine? 
 
……………….. 
 
………………. 
 
……………… 
 
8. I hvor stor grad har behandling eller medisiner lindret smertene dine de siste 24 
timene? 
 
Vennligst sett en ring rundt det prosenttallet som best viser hvor stor smertelindring du har 
fått: 
 
Ingen lindring  0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Fullstendig lindring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

56 
 
 
Vennligst beskriv smertene dine i løpet av siste uke 
Sett ett kryss i en rute på hver linje  
 
 
Vurder dine muskelsymptomer i løpet av siste uke  
Den følgende linja står for smerte av økende intensitet fra ”ingen symptomer” til ”verst tenkelige symptomer”. 
Sett en strek (|) tvers over linja som beskriver smerten din i løpet av siste uke.  
 
Ingen   
 
 
 
 
 
 
 
 
 
      Verst tenkelig             
symptomer 
 
 
 
 
 
 
     
 
 
        symptomer
 
               
 
 
 

57 
 
 
Nåværende grad av muskelsymptomer  
Sett ring rundt ett tall 
1. Ingen symptomer 
2. Milde    
3. Ubehagelig    
4. Meget ubehagelig  
5. Forferdelig  
6. Uutholdelig 
 
OPPFØLGING HOS FASTLEGE 
 
Har du tidligere diskutert bruk av kolesterolmedisiner og bivirkninger med din 
fastlege siste året? 
 
      Ja, 3 ganger eller mer            Ja, 1-2 ganger             Nei, ingen ganger    
 
 
Dersom du har diskutert bivirkninger med fastlege, hvor fornøyd er du med svarene 
du fikk og tiltakene som ble iverksatt på en skala fra 0 til 10? 
Svært misfornøyd        0        1        2        3        4        5        6        7        8        9       10    Svært fornøyd 
 
Tidligere sykdommer og medisiner 
Har du noen av disse sykdommene eller plagene? 
Reumatisk sykdom (som leddgikt, Bekhterevs sykdom)…..   ja              nei 
 
Slitasjegikt (artrose) …………………………………………... ja              nei 
 
Fibromyalgi……………………………………………………. 
ja              nei 
 
Andre muskel/skjelett plager………………………………… 
ja              nei           
 
Lavt stoffskifte (hypothyreose)……………………………… 
ja              nei 
 
Høyt stoffskifte (hyperthyreose)……………………………. 
ja              nei 
 
Bruker du medisiner av typen kortikosteroider (kortison, prednisolon)? 
ja              nei  

58 
 
 
LIVSKVALITET, PSYKSISK HELSEPLAGER OG SØVN 
 
1. Stort sett, vil du si at din helse er  
 
 
 
 
 
                          
Sett ett kryss 
Utmerket                 Meget god 
        God 
       Nokså god           Dårlig 
 
De neste spørsmålene handler om aktiviteter som du kanskje utfører i løpet av en vanlig uke. Er din 
helse slik at den begrenser deg i utførelsen av disse aktivitetene nå? Hvis ja, hvor mye?  
 
2. Moderate aktiviteter som å flytte ett bord, støvsuge, gå en tur eller drive med hagearbeid 
Ja, begrenser meg mye              Ja, begrenser meg litt              Nei, begrenser meg ikke i det hele tatt 
 
3. Gå opp trappen flere etasjer 
Ja, begrenser meg mye              Ja, begrenser meg litt              Nei, begrenser meg ikke i det hele tatt 
 
I løpet av den siste uken, har du hatt noen av de følgende problemer i ditt arbeid eller i andre av dine 
daglige gjøremål på grunn av din fysiske helse? 
4. Du har utrettet mindre enn du hadde ønsket                               Ja               Nei 
 
5. Du har vært hindret i å utføre visse typer arbeid eller gjøremål  Ja                 Nei 
 
I løpet av de siste 4 ukene, har du hatt noen av de følgende problemer i ditt arbeid eller i andre av 
dine daglige gjøremål på grunn av følelsesmessige problemer (som for eksempel å være deprimert 
eller engstelig)? 
6. Du har utrettet mindre enn du hadde ønsket                                         Ja         Nei 
 
7. Du har utført arbeidet eller andre gjøremål mindre grundig enn vanlig Ja         Nei 
 
8. I løpet av de siste 4 ukene, hvor mye har smerter påvirket ditt vanlige arbeid (gjelder både arbeid 
utenfor hjemmet og husarbeid)? 
Ikke i det hele tatt                 Litt                   En del                  Mye                     Svært mye 
 

59 
 
 
De neste spørsmålene handler om hvordan du har følt deg og hvordan du har hatt det de siste 4 
ukene. For hvert spørsmål, vennligst velg det svaralternativet som best beskriver hvordan du har 
hatt det. Hvor ofte i løpet av siste 4 ukene har du: 
9. Følt deg rolig og harmonisk? 
 
Hele tiden          Nesten hele tiden            Mye av tiden            En del av tiden            Litt av tiden           Ikke i det hele tatt 
 
10. Hatt mye overskudd? 
Hele tiden          Nesten hele tiden            Mye av tiden            En del av tiden            Litt av tiden          Ikke i det hele tatt 
 
 
11. Følt deg nedenfor og trist? 
Hele tiden          Nesten hele tiden            Mye av tiden            En del av tiden            Litt av tiden          Ikke i det hele tatt 
 
 
12. I løpet av de siste 4 ukene, hvor mye av tiden har din fysiske helse eller følelsesmessige 
problemer påvirket din sosiale omgang (som det å besøke venner, slektninger osv.)? 
Hele tiden             Nesten hele tiden             En del av tiden                       Litt av tiden               Ikke i det hele tatt 
 
Her kommer noen spørsmål om hvorledes du føler deg. For hvert spørsmål setter du kryss 
for ett av de fire svarene som best beskriver dine følelser den siste uken. Ikke tenk for 
lenge på svaret – de spontane svarene er best. 
 
1. Jeg er nervøs eller anspent 
8. 
Jeg 
føler 
meg 
som 
om 
alt 
går 
langsommere 
 For det meste 
 Ofte 
 Noen ganger 
 Ikke i det hele tatt 
 
 Nesten hele tiden 
 Svært ofte 
 Fra tid til annen 
 Ikke i det hele tatt 
 
2. Jeg gleder meg fortsatt over ting jeg pleide 
å glede meg over 
9. Jeg føler meg urolig liksom jeg har 
sommerfugler i magen 
 Avgjort like mye 
 Ikke fullt så mye 
 Bare lite grann 
 Ikke i det hele tatt 
 Ikke i det hele tatt 
 Fra tid til annen 
 Ganske ofte 
 Svært ofte 
 
 

60 
 
 
 
 
 
 
 
 
3. Jeg har en urofølelse som om noe 
forferdelig kommer til å skje 
10. Jeg har sluttet å bry meg om hvordan  jeg 
ser ut 
 Helt sikkert og svært ille 
 Ja, men ikke så veldig ille 
 Litt ille, men det bekymrer meg ikke 
så mye 
 Ikke i det hele tatt 
 Ja, helt klart 
 Jeg bryr meg ikke så mye som jeg 
burde 
 Det kan nok hende jeg ikke bryr meg 
nok 
 Jeg bryr meg utseendet like mye som 
jeg alltid har gjort 
 
4. Jeg kan le og se det morsomme i 
situasjoner 
 
11. Jeg føler meg rastløs som om jeg stadig 
må være i aktivitet 
 Like mye som jeg alltid har gjort 
 Ikke like mye nå som før 
 Avgjort ikke så mye nå som før 
 Ikke i det hele tatt 
 Uten tvil svært mye 
 Ganske mye 
 Ikke så veldig mye 
 Ikke i det hele tatt 
 
5. Jeg har hodet fullt av bekymringer 
 
12. Jeg ser med glede frem til hendelser og 
ting 
 Veldig ofte 
 Ganske ofte 
 Av og til 
 En gang i blant 
 Like mye som jeg alltid har gjort 
 Heller mindre enn jeg pleier 
 Avgjort mindre enn jeg pleier 
 Nesten ikke i det hele tatt 
 
 
6. Jeg er i godt humør 
 
13 Jeg kan plutselig få en følelse av panikk 
 Aldri 
 Noen ganger 
 Ganske ofte 
 For det meste 
 Uten tvil svært ofte 
 Svært ofte 
 Ikke så veldig ofte 
 Ikke i det hele tatt 
 
7.Jeg kan sitte i fred og ro og kjenne meg 
avslappet 
 
14. Jeg kan glede meg over en god bok eller 
et radio eller et TV program 
 Ja, helt klart 
 Vanligvis 
 Ikke så ofte 
 Ikke i det hele tatt 
 Ofte 
 Fra tid til annen 
 Ikke så ofte  
  Svært sjelden 

61 
 
 
I løpet av de siste 2 ukene, hvor ofte har du vært plaget med ett eller flere av disse 
problemene?   
sett ring rundt ett tall  
 
A. Liten interesse for eller glede over å gjøre ting?  
0. Ikke i det hele tatt            1. Noen dager        2.Mer enn 7 dager         3. Nesten hver dag   
 
B. Følt deg nedfor, deprimert eller fylt av håpløshet  
0. Ikke i det hele tatt             1. Noen dager          2 Mer enn 7 dager      3. Nesten hver dag   
 
 
SØVNPLAGER 
Instruksjon. På spørreskjemaet under er det 6 spørsmål knyttet til søvn og tretthet. 
Vær vennlig og sett ring rundt det alternativet (antall dager pr uke) som passer best for 
deg. 0 er ingen dager i løpet av en uke, 7 er alle dager i løpet av en uke. 
 
                                                                                            Antall dager pr. uke 
 
1. I løpet av den siste måneden, hvor 
mange dager pr. uke har du brukt mer 
enn 30 minutter for å sovne inn etter at 
lysene ble slukket?  
 
 
 
 
 0    1    2    3    4    5    6    7   
 
2. I løpet av den siste måneden, hvor 
mange dager pr. uke har du vært 
våken mer enn 30 minutter innimellom 
søvnen? 
 
 
 
 
 
             0    1    2    3    4    5    6    7 
 
3. I løpet av den siste måneden, hvor 
mange dager pr. uke har du våknet 
mer enn 30 minutter tidligere enn du 
har ønsket uten å få sove igjen?  
 
 
  0    1    2    3    4    5    6    7 
 
4. I løpet av den siste måneden hvor 
mange dager pr. uke har du følt deg 
for lite uthvilt etter å ha sovet? 
 
 
 
   0    1    2    3    4    5    6    7 
 
5. I løpet av den siste måneden, hvor 
mange dager pr. uke har du vært så 
søvnig/trett at det har gått ut over 
skole/jobb eller privatlivet? 
 
                         0    1    2    3    4    5    6    7     
 
6. I løpet av den siste måneden, hvor 
mange dager pr. uke har du vært 
misfornøyd med søvnen din? 
 
      
 
    0    1    2    3    4    5    6    7 
 
 

62 
 
 
Hvor mange timer sover du vanligvis per døgn i gjennomsnitt? …. timer og …... min. 
Har du brukt sovemedisiner siste uke? (sett kryss)  
Ja ___Nei____ 
 
Dersom du har svart JA: 
Navn __________________Styrke (mg)_________      Antall dager siste uke:_____ 
 
 
 

63 
 
 
For hvert av utsagnene nedenfor krysser du av for det svaralternativet som beskriver deg 
best, eller som er mest typisk for deg. 
Ikke be-               Noe be-              Veldig be-                                
skrivende           skrivende             skrivende 
                                                                                                 1 
  2 
  3 
 4 
 5 
1. Jeg blir ikke bekymret selv om jeg ikke har tid å  
gjøre alt. 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Jeg blir overveldet av mine bekymringer. 
 
 
 
 
 
 
 
 
3. Jeg pleier ikke å bekymre meg.  
 
 
   
 
 
 
 
 
4. Jeg blir bekymret i mange situasjoner.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Jeg vet jeg ikke burde bekymre meg, men jeg klarer 
 ikke la være.  
 
 
 
 
 
 
 
 
 
 
 
6. Jeg bekymrer meg mye når jeg blir stresset.  
 
 
 
 
 
 
 
7. Jeg bekymrer meg alltid for noe. 
 
 
 
 
 
 
 
 
 
8. Jeg synes det er lett å se bort 
 
 
 
 
 
 
 
 
 
fra bekymringer. 
 
 
 
 
 
 
 
 
 
 
 
 
9. Straks jeg er ferdig med en oppgave begynner jeg å 
 bekymre meg for alt annet jeg må gjøre.  
 
 
 
 
 
 
 
10. Jeg bekymrer meg aldri for noe som helst. 
 
 
 
 
 
 
 

64 
 
 
 
11. Når det ikke er noe jeg kan gjøre med et problem,  
slutter jeg å bekymre meg.  
 
 
 
 
 
 
 
 
 
 
12. Jeg har vært en som bekymrer seg hele mitt liv. 
 
 
 
 
 
 
 
13. Jeg har merket meg at jeg har bekymringer.  
 
 
 
 
 
 
 
14. Har jeg først begynt å bekymre meg, kan jeg ikke slutte. 
 
 
 
 
 
 
15. Jeg bekymrer meg hele tiden.  
 
 
 
 
 
 
 
 
 
16. Jeg bekymrer meg for oppgaver inntil de alle er 
 gjennomførte. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tusen takk for at du tok deg tid til å svare på disse spørsmålene 
 
 
 
 
 
 
 
 
 

65 
 
 
15.4 APPENDIX D – Patient diary with self-reported questionnaire to be completed 
during the treatment periodes 
 
Please refer to the attached document. 
15.5. APPENDIX E – PHONE GUIDE TO PATIENTS FOR WEEKLY SAFETY ASSESSMENTS  
Følgende spørsmål skal stilles til alle pasienter når disse kontaktes av lokal studiesykepleier ukentlig etter 
randomisering 
1. Har du tatt alle dine studiemedisiner som foreskrevet? 
2. Er dine muskelplager så sterke at du ikke ønsker å fortsette i studien? 
3. Har du merket hjertesymtpomer  slik som brystsmerter eller tung pust? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

66 
 
 
15.6. APPENDIX F – Drug label IMP 
Products will arrive with this label applied to the front of each packet 
 
 

67 
 
 
15.7. APPENDIX G – Biobank procedure 
 
 
 
 
 
RR HF 
Instruction to the 
users: This template is 
a guide 
      
instr 
      
 

68 
 
 
Generell informasjon 
• Hos pasienter med selvrapporterte muskelsymptomer (n = 80). 
Blodprøver tas ved tre visitter (5 prøvetakinger): 
o Visitt 1, baseline (T0): Prøver til medisinsk biokjemi + biobank 
o Visitt 2, uke 8 (T0 og T2): Prøver til medisinsk biokjemi + biobank 
o Visitt 3, uke 16 (T0 og T2): Prøver til medisinsk biokjemi + biobank 
 
o Dersom pasienter ønsker å slutte ila. studien skal det tilstrebes å gjennomføre en 
fremskyndet visitt med standardisert prøvetaking (= uke 8/16, T0 og T2) 
 
• Hos pasienter uten selvrapporterte muskelsymptomer (kontrollgruppe, n = 40). 
Blodprøver tas ved to visitter (3 prøvetakinger): 
o Visitt 1, baseline (T0): Prøver til medisinsk biokjemi + biobank 
o Visitt 2, uke 8 (T0 og T2): Prøver til medisinsk biokjemi + biobank 
 
• Visitt 1, 2 og 3: Pasientene skal møte medikamentfastende (dvs. uten å ha tatt 
morgendosene av medisiner) slik at T0-prøve kan tas i tidsrommet kl 8-10. 
• Visitt 2 og 3: T2-prøve tas 2 timer (±10 min) etter dose 
 
• Prøver til medisinsk biokjemi tas ved T0 
• Prøver til biobank tas ved T0 og T2 
 
• Praktisk ifb. prøvehåndtering 
o Man kan bruke den type prøvetakingsglass som er standard på de respektive 
steder. 
o Alikvotering i cryo-rør med tilpasset volum (fortrinnsvis 0.5 mL eller 2 mL 
polypropylen) 
o Bruk separate esker for hver type materiale (eks. EDTA-blod, EDTA-plasma, 
heparin-plasma, celler) 
o Alt alikvotert materiale til biobank fryses i ultrafryser  (- 80 °C) 
Uke 0 
Baseline 
(test + kontroll) 
Visitt 1 
Uke 8 
(test + kontroll) 
Visitt 2 
Uke 16 
(test) 
Visitt 3 
T0: Medisinsk biokjemi 
T0: Medisinsk biokjemi 
T0: Medisinsk biokjemi 
T0: Biobank* 
T0: Biobank 
T0: Biobank 
 
T2: Biobank 
T2: Biobank 

69 
 
 
Dose tas i tidsrommet kl 8-10. T0 = like før dose. T2 = 2 timer (±10 min) etter dose. 
Medisinsk biokjemi: HbA1C, hemoglobin, hs-CRP, kreatinin, eGFR, CK, ALAT, ASAT, total protein, 
albumin, myoglobin, INR, fastende lipid profil (triglyserider, total kolesterol, HDL-kolesterol, LDL-
kolesterol). 
Myoglobin 
analyseres 
på 
OUS. 
Biobank: Legemiddelanalyser, biomarkører. *Inkludert DNA-prøve. 
NB: Prosedyren som følger nedenfor gjelder kun prøver til biobank (ikke T0-prøver til medisinsk-biokjemiske 
analyser 
som 
spesifisert 
i 
tabellen 
ovenfor. 
Medisinsk-biokjemiske analyser: Utføres fortløpende i Drammen. I Vestfold fryses prøvemateriale ned og 
sendes 
senere 
til 
Drammen 
for 
batch-analyse. 
 
Merking og sporing av prøver som skal lagres i biobank 
• Sykehus kode 
o D = Drammen, V = Vestfold  
• Pasientnr (XXX) = randomiseringsnr 
• Visittnr X 
o (X=1 ved baseline, X=2 ved visitt 2 osv.) 
• Type materiale 
▪ 
EDTA-fullblod (EDTA-B), lilla farge 
▪ 
EDTA-plasma (EDTA-P), lilla farge 
▪ 
EDTA-plasma RNA-stabilisert (P-RNA) 
▪ 
Serum, rød farge 
▪ 
PAX RNA, grå farge 
▪ 
Celler pellet (PBMC) 
▪ 
Celler suspensjon (PBMC-PBS) 
▪ 
Celler RNA-stabilisert (PBMC-RNA) 
 
▪ Merking med farge brukes dersom det er mer praktisk enn å bruke tekst 
  
• Merking av esker (fortrinnsvis 10x10 esker) 
o MUSE 
o Sykehus kode: D eller V 
o Kun ved visitt 3, 5 og 1K: 
▪ Ta med pasientnr (skriv individuelle pasientnr utenpå esken) 
o Visitt: 1, 2, 3, 4, 5 eller 1K 
o Materiale: EDTA-B, EDTA-P, serum eller celler 
 
o Eksempel på merking av eske: 
MUSE 
EDTA-P 
D  
Visitt 3 
3-5-9-11-2-20-14 

70 
 
 
Merking av alikvoterte rør: 
Eksempel A: Pasientnr. 12, baseline, Drammen sykehus, EDTA-plasma 
o Alternativ 1 
Studie; sykehus - pasient – visitt – tidspunkt mht. dose; materiale 
▪ 
MUSE 
▪ 
D-12-1-T0 
▪ 
EDTA-P (evt. lilla farge, tilsvarende rød og blå) 
 
o Alternativ 2 
▪ 
MUSE 
▪ 
Sykehus: D 
▪ 
Pasient: 12 
▪ 
Visitt: 1 
▪ 
Tidspunkt: T0 
▪ 
EDTA-P (evt. lilla farge, tilsvarende rød og blå) 
 
Eksempel B: Pasientnr. 12, visitt 5, T1, Drammen sykehus, celler 
 
o Alternativ 1 
Studie ; sykehus – pasient - visitt – tidspunkt mht. dose; materiale 
▪ 
MUSE 
▪ 
D12-5-T1 
▪ 
Celler (evt. blå farge) 
 
o 
Alternativ 2 
▪ 
MUSE 
▪ 
Sykehus: D 
▪ 
Pasient: 12 
▪ 
Visitt: 5 
▪ 
Tidspunkt: T1 
▪ 
Celler (evt. blå farge) 
 
• Prøvetakingsliste (eget Excel-ark: MUSE-biobank_Prøvetakingsliste_Sykehusnavn.xls) 
 
Prøvehåndtering og alikvotering 
Tabellene angir hvilke prøveglass som skal tas, samt hvordan prøvene skal prosesseres. Alt alikvotert 
materiale lagres i ultrafryser (-70/80 °C). Ikke bruk rør som er større enn 2 mL til alikvotering (rørene 
fylles maks ca. 80% ved alikvotering). 
• Fullblod homogeniseres (vendes) før eventuell alikvotering. 
• Celler isoleres og alikvoteres etter egen prosedyre (på Rikshospitalet) 
• Prøve til plasma (samt avpipettert plasma) holdes kjølig hele tiden og det tilstrebes å fryse 
innen 1 time etter prøvetaking 
• Serum fryses så snart som mulig, det tilstrebes innen 2 timer etter prøvetaking 

71 
 
 
• PAX-rør skal stå vertikalt ved romtemperatur i 2 timer, deretter fryses de direkte 
 
Visitt 1: Uke 0, baseline, testgruppe og kontrollgruppe 
Tid 
Prøveglas
s 
Type 
Farge 
Temp. 
Sentrifugering 
Fordeling 
T0 
Biobank 
1 x 5mL 
EDTA 
u/gel 
Lilla 
RT 
Ingen 
Fullblod: 
x 
2 
aliq  
(DNA/genetikk) 
1 x 3mL 
PAX RNA 
Grå 
RT 
Ingen 
(2 timer henstand v/RT) 
Ingen,  
fryses direkte (RNA) 
 
 
 
 
 
 
1 x 5mL 
EDTA 
u/gel 
Lilla 
På is 
Kjøl (2500 rct, 15 - 20 min ) 
Plasma: x 2 aliq 
(+1 aliq ca 200 uL 
plasma + 600 uL RNA 
later reagens, blandes) 
1 x 5mL 
Uten 
tilsetning, 
u/gel 
Rød 
RT 
Henstand ca. 30 min, vanlig 
(2000 rct 10-15 min) 
Serum: x 2 aliq 
• 
T0:  I tillegg kommer standard prøveglass  til medisinsk-biokjemiske analyser som rekvireres og 
analyseres som vanlige prøver. 
• 
Myoglobin analyseres i biobanket materiale (dvs. trenger ikke eget prøveglass til myoglobin). 
• 
Biobanket fullblod fra baseline kan benyttes til CYP-analyser som utføres i Drammen. 
 
Visitt 2 og 3: Uke 8 og 16, testgruppe (kontrollgruppe kun visitt 2, uke 8) 
Tid 
Prøveglas
s 
Type 
Farge 
Temp. 
Sentrifugering 
Fordeling 
T0 + T2 
Biobank 
1 x 5mL 
EDTA 
u/gel 
Lilla 
Kjøl 
Ingen. 
Leveres 
til 
RH 
(transporteres i kjølebag) 
RH: Celler: x 4 aliq  
(+1 aliq RNA-stabilisert) 
1 x 5mL 
EDTA 
u/gel 
Lilla 
På is 
Kjøl (2500 rct, 15 - 20 min ) 
Plasma: x 2 aliq 
(+1 aliq ca 200 uL 
plasma + 600 uL RNA 
later reagens, blandes) 
1 x 5mL 
Uten 
tilsetning, 
u/gel 
Rød 
RT 
Henstand ca. 30 min, vanlig 
(2000 rct 10-15 min) 
Serum: x 2 aliq 

72 
 
 
Ekstra 
ved T0 
Biobank 
1 x 2-3 mL 
EDTA 
u/gel 
Lilla 
RT 
Ingen 
Fullblod: 
x 
2 
aliq  
(epigenetikk) 
1 x 3mL 
PAX RNA 
Grå 
RT 
Ingen 
(2 timer henstand v/RT) 
Ingen,  
fryses direkte (RNA) 
• 
T0:  I tillegg kommer standard prøveglass  til medisinsk-biokjemiske analyser som rekvireres og 
analyseres som vanlige prøver. 
• 
Myoglobin analyseres i biobanket materiale (dvs. trenger ikke eget prøveglass til myoglobin). 
 
Dersom pasienter ønsker å slutte ila. studien skal det tilstrebes å gjennomføre en fremskyndet visitt med 
standardisert prøvetaking tilsvarende visitt 2/3 (T0 og T2) før de slutter med studiemedisin. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

73 
 
 
15.8 APPENDIX H- Pharmaceutical and chemical documentation atorvastatin 
 
 
 

74 
 
 
 
 
 
 
 
 

75 
 
 
 
 
 

76 
 
 
 
 
 
 
 

77 
 
 
 
 
 
 
 

78 
 
 
 

79 
 
 
15.9 APPENDIX I- Procedure for production of atorvastatin and placebo 
 
 
 
 
 
 
 

80 
 
 
15.10 APPENDIX J- LAF -patient insurance 
 
 
 
 
 
 
 

81 
 
 
15.11 APPENDIX K- Approval Regional Committee of Ethics 
 

82 
 
 
 
 

83 
 
 
15.12 APPENDIX L- Approval the National Medical Agency 
 

84 
 
 
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