ChronicStatinMig. A Multicentre, Triple Blind, Placebo Controlled, Parallel Group Study of Atorvastatin in Chronic Migraine
Phase: PHASE2
Conditions: Chronic Migraine
Sponsor: St. Olavs Hospital

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Protocol Identification Number:   CT EU 2022-502177-42-02 
Version number: 9 
 
  
Page Break  
National coordinating investigator:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ChronicStatinMig 
A multicentre, triple blind, placebo controlled, parallel group study of atorvastatin in chronic 
migraine  
ChronicStatinMig: Protocol Version 9 date: 250624 

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National coordinating investigator: 
Lise Rystad Øie, MD, neurologist, postdoc 
Norwegian Headache Research Centre – NorHEAD St. Olav’s Hospital and NTNU Norwegian 
University of Science and Technology  
Norway 
 
Supported by:  
The Research Council of Norway  
Postboks 564 
1327 Lysaker, Norway  
 
Sponsor  
Christian Samsonsen, MD, PhD, neurologist   
Head of Neurological Department 
St Olav’s hospital, Trondheim University Hospital  
Postboks 3250 Torgarden, Norway  
 
Monitor  
Lead monitor Elisabeth De Cerf    
Clinical Trial Unit,   
St Olav’s hospital, Trondheim University hospital   
postboks 3250 Torgarden, Norway  
 
Blinding and randomization  
Clinical Trial Unit,   
St Olav’s hospital, Trondheim University hospital  
postboks 3250 Torgarden, Norway 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS  
Signature page ...........................................................................................................................5 
Overview.....................................................................................................................................6  
List of Abbreviations and Definitions orTerms............................................................................7   
1. Study objectives......................................................................................................................8  
1.1 Primary objective .................................................................................................................8  
1.2 Secondary objective .............................................................................................................8 
2. Background and rationale.......................................................................................................8  
2.1 Background- Disease ............................................................................................................8  
2.2 Background- Therapeutic information..................................................................................8  
2.3 Pre-Clinical & Clinical Experience with Investigational Medicinal Product (IMP).................9  
2.4 Rationale for the study and purpose ..................................................................................10  
3 STUDY OBJECTIVES and related endpoints.............................................................................11  
3.1 Objectives of the study........................................................................................................11  
3.2 Endpoints.............................................................................................................................12  
4 Overall study design................................................................................................................12  
4.1. Study population ................................................................................................................12  
4.2 Inclusion criteria...................................................................................................................13  
4.3 Exclusion criteria .................................................................................................................15  
5 Study intervention .................................................................................................................15  
5.1 Investigational Medicinal product ......................................................................................15  
5.2 Drug identity…………………………………....................................................................................15  
5.3 Dosage and drug administration.........................................................................................16  
5.4 Randomisation....................................................................................................................16 
5.5 Subject numbering..............................................................................................................16  
5.6 Duration of therapy ............................................................................................................16 
5.7 Concomitant therapy..........................................................................................................16  
5.8 Subject adherence .............................................................................................................17 
5.9 Drug accountability.............................................................................................................17  
5.10 Drug labelling....................................................................................................................18  
6. Study procedures..................................................................................................................18  
7. Safety assessments...............................................................................................................21  
7.1 Definitions of adverse events.............................................................................................21 
7.2 Follow up of AEs.................................................................................................................23  
7.3 Safety monitoring...............................................................................................................24  
8 Intervention DISCONTINUATION...........................................................................................25 
8.1 Criteria for subject discontinuation ...................................................................................25  
8.2 Procedures for Discontinuation .........................................................................................26  
9. Statistical considerations .....................................................................................................26  
9.1 Hypotheses.........................................................................................................................26  
9.2 Determination of sample size ............................................................................................26  
9.3 Interim analyses .................................................................................................................27  
9.4 Procedure for statistical analyses ......................................................................................27 
9.5 Data Analyses.....................................................................................................................27  
10. Data collection and quality assurance ..............................................................................28  
10.1 Data collection forms......................................................................................................28  
10.2 Data Management .........................................................................................................29  
10.3 Quality Assurance...........................................................................................................29  
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY...................................................................30  
11.1 Institutional Review Board (IRB) Review........................................................................30  
11.2 Informed Consent Forms................................................................................................31  
11.3 Participant Confidentiality .............................................................................................31  

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11.4 GCP .................................................................................................................................31  
11.5 Study Discontinuation ....................................................................................................31 
11.6 Insurance and Liability....................................................................................................32  
11.7 Study report ...................................................................................................................32  
12 Safety data ........................................................................................................................32 
13 ETHICAL CONSIDERATIONS ...............................................................................................32 
13.1 Individual patient risks and benefits...............................................................................32 
14 PUBLICATION OF RESEARCH FINDINGS .............................................................................32 
 References ............................................................................................................................33 
   
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SIGNATURE PAGE  
Title:  ChronicStatinMig: 
A multicentre, triple blind, placebo controlled, parallel group study of atorvastatin in chronic 
migraine  
 
Protocol ID no: 9 
EU CTIS number: 2022-502177-42-02 
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  
Lise Rystad Øie 
MD, PhD 
National 
coordinating 
investigator 
St. Olavs Hospital 
 
 
Christian Samsonsen,  MD, PhD 
Sponsor 
 
 
Marte Bjørk 
MD, PhD 
Investigator 
Haukeland 
University Hospital 
 
 
Kjersti Grøtta Vetvik 
MD, PhD 
Investigator 
Akershus University 
Hospital 
 
 
Bendik Slagsvold 
Winsvoll 
MD, PhD 
Investigator Oslo 
University Hospital, 
Ullevål 
Linn Hofsøy 
Steffensen 
MD, PhD 
Investigator Oslo 
University Hospital, 
Northern Norway 
  
 
 
 
 
 
 
 
 

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OVERVIEW  
Study number: CTIS number 2022-502177-42-02 
 
Title: A multicentre, triple blind, placebo controlled parallel group study of atorvastatin in 
chronic migraine 
Objectives: The primary objective is to evaluate whether the favorable preventative effect of 
Atorvastatin seen in three smaller studies, can be confirmed in a larger multicentre 
randomized, controlled study. Secondary objectives include number of responders and 
evaluation of side effects. 
Main trial endpoints: The primary endpoint is change in number of migraine days/4 weeks 
from the baseline period to the treatment period. 
Secondary trial endpoints: Secondary endpoints are number of responders (≥ 50% 
improvement from baseline), number of patients with adverse events, doses of triptans or 
analgesics per 4 weeks, and days with sick leave per 4 weeks. 
Trial design: A multicentre, randomized, triple blind (blinded to patients, study personnel, and 
statistician), parallel group study, comparing Atorvastatin 40 mg against placebo. There will 
be five Norwegian Centres. 
Trial population: 300 women and men with chronic migraine aged 18-65 years of age having 
chronic migraine days during the baseline period of 4 weeks. They should not using other 
migraine prophylactics, do not have kidney or liver/gallbladder disease, and use highly 
effective contraception if they are women of childbearing potential. 
Interventions: 1 tablet/day of placebo or Atovastatin 40 mg for 12 weeks (84 days). 
 
Ethical consideration: Atovastatin has been on the Norwegian market for many years, and 
the occurrence of severe side effects is well known and low. The potential positive preventive 
effect of Atorvastatin may be helpful for chronic migraine patients worldwide. The main 
drawback is that the participants need to fill in an electronic headache diary for 21 weeks. 
 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation or 
special term  
Explanation  
AE  
Adverse Event   
CRF  
Case Report Form (electronic/paper)  
CSA  
Clinical Study Agreement  
HMGCR 
3-hydroxy-3-methyl-glutaryl-coenzyme A reductase 
DAE  
Discontinuation due to Adverse Event  
DMP  
Data Management Plan  
DSMC  
Data Safety Monitoring Committee  
EC  
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)  
GCP  
Good Clinical Practice  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonization  
ICHD-3  
International Classification of Headache Disorders, version 3   
ISF  
Investigator Site file  
IMP  
Investigational Medicinal Product (includes active comparator and control 
group)  
MOH  
Medication overuse headache  
NCI  
National coordinating investigator  
RCT  
Randomised controlled trial  
SAE  
Serious Adverse Event    
SAP  
Statistical analysis plan  
SOP  
Standard Operating Procedure  
SUSAR  
Serious Unexpected Adverse Reaction  
 
 
 
 
 
 
 

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1. STUDY OBJECTIVES  
1.1 Primary objective  
The study aims to evaluate the prophylactic effect of atorvastatin 40 mg against chronic 
migraine headache in a large, multicentre study. To this end, the change from baseline to 
treatment period in number of days with migraine headache per 4 weeks is selected as a 
primary endpoint.  
 
1.2. Secondary objective  
Secondary endpoints include number of responders (≥ 50% improvement from baseline), 
number of patients with adverse events, doses of triptans or analgesics per 4 weeks, and days 
with sick leave per 4 weeks. In addition, a health economic analysis will be performed, taking 
into consideration the cost of atorvastatin, the cost of acute medication for chronic migraine 
and the cost of lost worktime. 
 
2. BACKGROUND AND RATIONALE  
2.1 Background- Disease  
Headaches are among the major public health issues globally. According to the Global Burden of 
Disease 2019 Study, headache disorders are ranked second on the list of the disorders causing 
most functional impairment on the population level, and the first cause in people under 50 
years of age (1). A large proportion is caused by migraine, affecting around 14% of the 
population globally (2). 
2.2 Background- Therapeutic information  
The treatment of migraine patients includes avoidance of headache triggers, optimization of 
attack treatment, and prophylactic treatments with various medications. However, for a large 
proportion of patients, standard migraine prophylactic medicines are not effective or well 
tolerated, and many patients fail to adhere to the prophylactic medication, or they overuse 
acute medications and develop medication overuse headache.  
Based on evidence, beta-blockers and angiotensin receptor blocker (candesartan), some 
antiepileptic’s (valproate, topiramate), and tricyclic antidepressants (amitriptyline) have been 
used for migraine prophylaxis (3-11). However, contraindications and side effects have to some 
degree limited their use. More recently, use of monoclonal antibodies acting on the calcitonin 
gene related peptide (CGRP) or its receptor is indicated for individual with frequent episodic 
migraine or with chronic migraine (12). However, in Norway the costs for CGRP inhibitors are 
only reimbursed by the state for chronic migraine, and the high price makes CGRP antibodies 
unavailable for many people who could benefit from migraine prophylaxis.   

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Prophylactic treatment is indicated in around 30% of patients with migraine, but in most 
countries the percentage actually using prophylactic treatment is in the range of 5-10% (13). 
Lack of diagnosis, limited efficacy of available drugs, side effects and high cost are the main 
causes for the under-utilization of prophylactics.  
During the last decade, the preventive effect of simvastatin (14), rosuvastatin (15) and 
atorvastatin (16-18) among migraine patients have been evaluated in some small randomized, 
controlled studies. Although all studies indicated an efficacy on migraine frequency, the 
majority of the studies have evaluated statins combined with other drugs (14, 15, 17, 18), or 
statins compared to another preventive drug (16). Thus, a randomized triple-blind controlled 
trial evaluating a statin against placebo in a larger groups of migraine patients is needed (14-
18). 
 
2.3 Pre-Clinical & Clinical Experience with Investigational Medicinal Products 
(IMPs)   
 
Statins are the first-line therapy for hypercholesterolemia and act by inhibition of β-hydroxy β-
methylglutaryl-CoA (HMG-CoA) reductase (19), and has been on the Norwegian market for 
more than 30 years (26). 
 
2.3.1 Atorvastatin: Atorvastatin has comparable effect compared to other statins (27, 28), is 
well tolerated (29) and lipophilic with good properties to penetrate the blood-brain barrier into 
the CNS (30). The most common adverse effects are usually mild (29), affecting less than 5% of 
the patients. Skin rash, musculoskeletal pain and gastrointestinal symptoms are most 
commonly (26) reported. The oral bioavailability of atorvastatin is 14%, and the peak plasma 
level is about 14 hours (27). Atorvastatin has an extensive first-pass metabolism in the gut wall 
and in the liver (27), and cytochrome P450 (CYP) 3A4 is responsible for the formation of two 
active metabolites. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-
life is about 7 hours, and between 7-14 hours for other metabolites (27).     
Previously, five randomized, controlled studies have evaluated the effect of statins in migraine 
patients, all including few participants (14-18). In a 24-week randomized, double-blind, placebo-
controlled trial, the efficacy of simvastatin 20 mg plus vitamin D3 was evaluated in 57 adults 
with episodic migraine during a 24-week period (14). In intervention weeks 13-24, the active 
group had a reduction of 9 migraine days compared to baseline period, whereas the placebo 
group had an increase of 3 migraine days (14). 
Furthermore, in a triple-blind controlled 4-week trial, 120 patients with migraine received 
rosuvastatin 10 mg once a day combined with propranolol 10 mg twice daily or propranolol 10 
mg twice daily and placebo (15). The number of migraine attacks decreased significantly for the 
group receiving rosuvastatin and propranolol in week two, three and four (15). 

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Moreover, in a triple-blind controlled 2-month trial, 68 patients having migraine with aura 
received atorvastatin 20 mg combined with sodium valproate or placebo plus sodium valproate 
(17). At the end of follow-up, participants with atorvastatin plus sodium valproate had less 
migraine days than the group receiving placebo plus sodium valproate (17). Furthermore, in a 
24-week triple-blind, placebo-controlled trial the combination of atorvastatin 40 mg plus 
nortriptyline was evaluated among 68 migraine patients (18). At the end of follow-up, more 
participants had less than 1 migraine attack per week in the active group compared to the 
placebo group (86% versus 47%). Finally, in a double-blind study atorvastatin 40 mg was 
evaluated against sodium valproate among 82 patients with episodic migraine (16). During the 
3-month follow-up, less adverse effects was reported among those who received atorvastatin 
compared to the sodium valproate group, whereas no difference was found in migraine 
frequency between the two groups (16).  
The exact mode of action of statins in migraine is not known (20). However, it may be of 
relevance that statins have a positive effects on endothelial cells and vascular inflammation (21-
23), platelets aggression (21), depressive symptoms (24) and also potent neuromodulatory 
effects (25). 
The influence of vitamin D deficiency on the efficacy of statins in migraine patients is very 
unclear. A cross-sectional population-based study performed in United States reported that 
statin use in those with normal vitamin D levels were associated with less migraine, whereas 
such relationship was less clear for those with vitamin D deficiency (35). The results in this 
cross-section study published in 2015 was the reason why Simvastatin was combined with 
Vitamin D in the placebo-controlled study performed by the same authors in 2015 (14). Similar 
mandatory vitamin D supplement has not been performed in the later studies evaluating 
rosuvastatin on migraine (15) or atorvastatin on migraine (16-18), although migraine patients 
with definite Vitamin D deficiency got vitamin D supplement in the study evaluating 
atorvastatin plus sodium valproate (17). Serum vitamin D3 was also checked at baseline in the 
study evaluating rosuvastatin and propranolol (15) and atorvastatin plus nortriptyline (18).  
Regarding adverse events of statins, summary data of 14 randomized placebo-controlled trials 
have found slightly increased risk of diabetes (absolute risk of 0.5%) and asymptomatic liver 
transaminase elevation (0.4%) among user of statins compared to the place group (36). On the 
other hand, one large-scale randomized placebo-controlled trial including more than 10 000 
patients reported a similar rate of adverse events among participants randomly assigned to 
atorvastatin or placebo with the exception of renal and urinary adverse events (37). Among the 
three RCTs testing Atorvastatin in migraine (16-18), the evaluation of side effects is hampered 
by the fact that Atorvastatin was used in combination with respectively sodium valproate or 
nortriptyline (17, 18). No previous studies have evaluated the efficacy of a statin in chronic 
migraine. 
 
 
 

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2.4 Rationale for the study and purpose   
ChronicStatinMig is a part of the Norwegian Headache Research Centre – NHRC that got a large 
grant from the Research Council of Norway in 2021.  
There is no doubt that migraine is a large public health problem, which is both disabling and 
costly, and that safe and efficient preventative treatment is needed for a large proportion of 
patients.  
Although five randomized controlled studies have evaluated statins as migraine prophylactic 
treatment (14-18), they have all included few participants. In addition, the vast majority of 
them have combined statins with other drugs, and not evaluated statins alone with group 
receiving placebo tablets only. Thus, a large-scale randomized triple-blind controlled trial 
evaluating a statin versus placebo are needed (14-18). Many patients with chronic migraine 
have limited response to available preventive treatment, and a potential positive effect of statin 
treatment in chronic migraine will benefit a large group of patients. 
The overarching goal of the present study is to evaluate whether atorvastatin is an effective, 
safe and cost-saving prophylactic treatment of frequent, chronic migraine. 
 
2.4.2 Rationale for the choice of dose 
The recommended starting dose of atorvastatin according to the product information (31) is 10 
mg/day with a maximum dose of 80 mg per day. The previous migraine studies evaluating 
atorvastatin used either 20 mg (17) or 40 mg (16, 18), and two of the three studies combined 
atorvastatin with other preventive drugs (17, 18). Atorvastatin 40 mg was well tolerated in the 
study given atorvastatin 40 mg alone in the active group (16). Based on the previous studies, we 
will evaluate efficacy and side effects in one active group with 40 mg atorvastatin compared to 
placebo in chronic migraine patients.  
 
3. STUDY OBJECTIVES AND RELATED ENDPOINTS  
3.1 Aims of the study  
These are to evaluate whether atorvastatin is an effective, safe and cost-saving prophylactic 
treatment of chronic migraine. More specifically, we wish to answer the following questions: 
Primary objective: 
1) Is there a favourable effect of atorvastatin 40 mg in chronic migraine patients in this large 
multicentre study? 
Secondary objectives: 
2) Is the favourable side effect profile of atorvastatin 40 mg, seen in the previous studies, 
replicated in this larger study? 
4) What is the cost of atorvastatin treatment, considering cost of the medicine, of acute 
medicines for attacks, and lost worktime? 

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3.2 Endpoints  
3.2.1 Primary endpoint  
1. Difference between groups receiving atorvastatin 40 mg daily and placebo in change from 
baseline in number of migraine days per 4 weeks. 
Migraine days are defined as days with moderate or severe headache accompanied by nausea, 
and/or phono- and photophobia, and lasting ≥ 4 hours or is treated with the patient’s usual 
migraine medication (usually a triptan). This is in accordance with the Guidelines for controlled 
trials with migraine prophylactics (31).   
 
3.2.2 Secondary endpoints  
2. Difference between groups receiving atorvastatin 40 mg daily and placebo in change from 
baseline in number of: 
o Days with headache (defined by headache intensity > 0 and/ or intake of the patient’s acute 
headache medication) 
o Days with sick leave 
o Headache intensity (0-3 scale) on days with headache 
o Number of responders (≥ 50% decrease in migraine days compared with baseline) 
3. Number of reported side effects in the placebo and atorvastatin 40 mg  
4. Health economic analysis: Comparison of cost in the placebo and atorvastatin treatment, 
taking into consideration price of the medicine, price of acute medication, and lost worktime. 
 
4. OVERALL STUDY DESIGN  
The study is a phase II study exploration of a new therapeutic approach, randomized, triple 
blind (patients, study personnel, statistician), placebo-controlled, multicentre study.  
 
4.1. Study population  
4.1.1 Recruitment of study population  
The webside of NorHead, the Norwegian Headache research centre, include a long list of 
available studies. Every day many migraine patients read about these studies and contact the 
NorHead centre using a contact form by the webside of NorHead under the “participation in 
Research” tab, or by using an email address (hodepine@ntnu.no). In the structured form, they 
could tic of the relevant study and that they allow to be contacted. A nurse employed at 
NorHead will then make an informal contact by email or telephone in an unstructured way to 
discuss if they really are interested in study participation, and in which of the many available 
studies they fit. Usually they  forward the trial’s informed consent form so that the migrainuers 

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can read about the studies in more details. The correspondence with these persons will not be 
part of the present study. Individuals with interest will be offerend a clinical interview by 
performed by a neurologist at St. Olav’s Hospital, Haukeland University Hospital, Oslo University 
Hospital Ullevål, University Hospital Nothern Norway (UNN) or Akershus University Hospital 
depending on the patient place of residence. Information about the study and the trial’s 
informed consent would be given by an independed qualified study nurse or study doctor and 
not by the treating physician, and no study related procedures would be performed before the 
patient have signed the informed consent form.  
Some potential participants can be identified by ordinary patients evaluated by the outpatient 
clinics of the neurological departments of the study hospitals St. Olav’s Hospital, Haukeland 
University Hospital, Oslo University Hospital Ullevål, University Hospital Nothern Norway (UNN) 
and Akershus University Hospital . In such case, information about the study and the trial’s 
informed consent would be given by an independed qualified study nurse or study doctor and 
not by the treating physician. No study related procedures would be performed before the 
patient have signed the informed consent form.  The present study will not needs access to 
information from patient medical records to identify potential participants.   
The proportion of eligible chronic migraine patients at each centre is not easy to predict, as 
other similar RCT studies with e.g. candesartan is still ongoing. Thus, an inclusion period of at 4 
years can be expected. As a consequence, the last included patients being to the last visit 
defined as the end of the active part of the study is estimated to be before 31/12/2028. 
 
4.1.2 Number of patients  
300 patients (See 9.2) will be included in this trial. There will be competitive inclusion, in the 
sense that if a department fulfils its quota before end of the study, it can include more. 
Inclusion at all departments is terminated when 300 patients have been included altogether.  
 
4.1.3 Participating investigators and departments  
MD, PhD, neurologist Lise Rystad Øie 
St. Olavs Hospital   
7006 TRONDHEIM  
MD, PhD, neurologist Marte-Helene Bjørk  
Haukeland Hospital   
5021 BERGEN 
MD, PhD, Kjersti Grøtta Vetvik  
Akershus University Hospital  
1478 LØRENSKOG  
MD, PhD, Bendik Slagsvold Winsvoll  
Ullevål- Oslo University Hospital  
0424 OSLO  
MD, PhD, Linn Hofsøy Steffensen 
Universitetssykehuset Nord-Norge 
9038 Tromsø 
  
 

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4.2 Inclusion criteria  
1. Age 18 to 64 years 
2. Signed informed consent 
3. Chronic migraine according to ICHD-3 criteria (32) 
4. At inclusion, patients should retrospectively have at least 15 headache days per month wheof 
at least 8 migraine days during the last 3 months. This frequency must be confirmed in the 
headache diary before randomisation to treatment (See below). 
5. Debut of migraine at least one year prior to inclusion based on information in the patient 
record or by careful examination of previous headache history  
6. Start of migraine before age 50 years. 
7. No use of other migraine prophylactics during the study 
8. For women of child-bearing potential (WOCBP, see below) there must be no pregnancy or 
planned pregnancy during the study period, and use of highly effective contraception (See 
below).  
After the baseline period, just before randomisation to the study drug, inclusion criteria will be 
evaluated once more, and the headache diary will be evaluated. If there are, according to the 
headache diary, fewer migraine days than 8 per month, the baseline period can be extended to 
8 weeks.   
 
4.2.1 Women of child-bearing age potential (WOCBP) 
This is defined as fertile women, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause.  WOCBP must agree to perform urinary 
pregnancy tests and can only be included in the study if they have a negative test result. During 
the treatment period, home pregnancy test should take every month (week 4 and week 8) and 
until 3 days after the end of the treatment period. A pregnancy test will also be performed after 
the final visit. 
  
4.2.2 Highly effective contraception 
Such methods include combined (oestrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); 
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable); intrauterine device (IUD); intrauterine hormone-releasing system 
(IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence, in women for whom 
that is the preferred and usual lifestyle. This group of patients should not be using other drugs 
that might interact and reduce the efficacy of the used anticonceptive medicine. 
 

15 
 
4.2.3 Blood and urinary samples. 
After signed consent forms are obtained, but before randomization, blood samples evaluating 
liver and kidney function (creatinine, ASAT, ALAT), muscle function (creatine kinase), non-
fasting glucose, CRP and LDL cholesterol will be performed for all patients. Creatinine, ASAT and 
ALAT must be within normal limits before randomization. In the case of known previous liver 
failure or deviant ALAT, additional tests will be taken to assess ASAT, gamma GT and total 
bilirubin. CK must be below 5 times upper reference value before randomization. Deviation in 
the CRP-value will be assessed individually by the study physician before randomization. 
Participants with increased LDL-cholesterol at baseline will be randomized, but will be asked to 
control their lipid status with their own doctor after the end of the study. 
Because non-fasting glucose will be tested, serum glucose should be <11,0 mmol/l. To eliminate 
pregnancy, a negative urinary test is required. The blood samples would be destroyed 
immediately after the analyses, and the test is useful as reference values for the follow-up tests.  
Approximately in week 4 and week 8 of the treatment period, a new blood 
sample will be drawn of all participant, evaluating ALAT, creatine kinase (CK), 
non-fasting glucose and CRP. After the final visit, a new blood sample will be 
drawn of all paricipants, evaluating creatinine, ALAT, creatine kinase (CK), non-
fasting glucose and CRP. All these analyses is performed to detect rare, but potential 
harmful side effect of Atorvastatin. The blood samples would be destroyed 
immediately after the analyses. 
During the treatment period, home pregnancy test should take every month (week 4 and week 
8) and until 3 days after the end of the treatment period. 
If the participants have severly increased creatine kinase (>5 times upper reference value) and 
report new onset occurrence of muscle pain, proximal paresis or muscle atrophy an additional 
blood sample will be collected to assess the presence of HMGCR-antibodies. Testing for 
HMGCR-antibodies will be initiated by the principle investigator at the relevant centre and the 
sample will be sent to the University Hospital of Oslo for analysis. The blood samples will be 
destroyed immediately after the analysis. 
 
4.3 Exclusion criteria  
Patients will be excluded from the study if they meet any of the following criteria: 
1) Medication overuse headache requiring detoxification from acute medication (triptans, 
opioids). Exception could be made for those fulfilling A and B:  
A. Have tried a withdrawal period of at least 2 months without impact on headache frequency  
B: Use of opiods (of any type) ≤ 8 days /months. 
2) Pregnancy, planning to get pregnant, inability to use contraceptives (See inclusion 
criteria, point 8), and lactating 
3) Clinical information on or signs of cholestasis or decreased hepatic or renal function.  

16 
 
4) High degree of comorbidity and/or frailty associated with reduced life expectancy or 
high likelihood of hospitalization, at the discretion of the investigator 
5) Hypersensitivity to statins or previous use of statins 
6) History of angioneurotic oedema 
7) Use of per oral migraine prophylactic drugs less than 4 weeks prior to start of study. Use of 
Aimovig, Ajovy 225mg or Emgality less than 8 weeks prior to start of study. Use of botulinum 
toxin, Ajovy 675mg or Vyepti less than 16 weeks prior to start of study. 
8) Current use of antiviral treatment agaist hepatitis C  
9) Significant psychiatric illness 
10) Alcohol or illicit drug dependence. 
11) Inability to understand study procedures and to comply with them for the entire length 
of the study 
12) Treatment for hypothyroidism 
13) Lactose intolerance 
 
5. STUDY INTERVENTION  
5.1 Investigational Medicinal product  
For this study atorvastatin is defined as Investigational Medicinal Product(s) (IMP).   
5.2 Drug identity  
Atorvastatin has marketing authorization in Norway. Film-coated tablets containing 
Atorvastatin Xiromed 20 mg will be bought on the marked (Medical Valley Xiromed Sweden). 
Identical film-coated placebo tablets will be produced by Kragerø tablettproduksjon AS. They 
will buy marketed Atorvastatin Xiromed 20 mg film-coated tablets which have to be covered 
not showing the correct mg of the tablet. 40 mg tablets vill be made by covered two 20 mg 
tablets. Identical film-coated placebo tablets will be made. Identical film-coated placebo tablets 
will be made. Lactose is used as a supplement in Atorvastatin, and will also to be included in the 
placebo tablets. These tablets will be sent in plastic boxes with appropriate labels to 
participating centres where they will be stored in the departments’ regular medicine 
storerooms.  
 
5.3 Dosage and drug administration  
The study medicine box will be handed out to participants by authorized site personnel.  There 
will be one box for each participant, each box containing 84 encapsulated tablets. The 
participant will take one capsule orally each day, preferably at the same time of the day.  
 
5.4 Randomization and blinding of medicine 

17 
 
A randomisation list containing 300 patient numbers is made before the start of the study. This 
list will be sent to the medicine producer, who will label each medicine box with a number from 
1 to 300 and make the content of the capsules as indicated on the list. The producer sends 
medicine boxes to each centre. As patients are randomised, they are given the lowest available 
box number at that centre. The inclusion number of the participants is written in the electronic  
CRF and registered in the electronic headache diary, and is also noted in the hospital records. 
The patients will take one capsule orally every day (See 5.3). Each box will be labelled with box 
number, inclusion number, name of drugs in the trial, name of project leader and sponsor, and 
contact telephone number. For all patients, there will be a sealed envelope containing 
information about the content of capsules in the box, in case of emergency (see 7.2.3).  
 
5.5 Subject numbering  
Each subject is identified in the study by a unique subject number that is assigned when subject 
signs the Informed Consent Form. Once assigned the subject number cannot be reused for any 
other subject. The same primary identifier will be used throughout the study.  
 
 
5.6 Duration of therapy  
Patients will take the medicines every day for 12 weeks (84 days).   
 
5.7 Concomitant therapy   
The following medication is not allowed while the patient is included in the study of the study: 
 Any migraine prophylactic drug (See exclusion criteria) 
All concomitant medication (including vitamins, herbal preparation and other “over-the-
counter” drugs) used by the patient will be recorded in the patient’s file and clinical record form 
(CRF). 
 
5.8 Subject adherence  
5.8.1 Definitions 
The definition of protocol deviation and violation are based on the following statement (33), 
and should in this study cover all incidences of participant non-adherence to study procedures 
after enrolment, as defined in the protocol and standard operating procedures (SOP). Study 
personnel non-compliance with protocol, SOP and other study requirements is defined in 
section 10.3.2. 
 
Protocol deviation 
A protocol deviation occurs when, without significant consequences to the quality or 
completeness of the data, the activities of a study participant diverge from the study 

18 
 
requirements, e.g., missing a visit window because the subject is traveling. A protocol deviation 
should not have a significant effect on the subject’s rights, safety, or welfare. 
 
Protocol violation 
Serious participant non-adherence: A divergence from the protocol that materially reduces the 
quality or completeness of the data or have a significant consequence on the subject’s rights, 
safety, or welfare. 
 
Headache diary and medication adherence assessment 
Adherence to the study regimen (per-protocol patients) is defined as registration of at least 90% 
of days (i.e. 76 days) in the Headache Diary during the treatment period (weeks 5 – 16).  
Participants with less days registered will be counted as protocol violators and included in the 
intention-to-treat (ITT) analysis. 
 
5.9 Drug accountability 
The drug will be sent from producer to each department and stored in the department’s 
medicine room. A drug accountability form will be kept at each department. Dispensing entries 
on the Drug Accountability Record Form includes: 
• Protocol number and title, study medication (name/strength) and manufacturer, study site 
and local investigator, storage location and conditions. 
• Information on reception of medicines (medication ID, batch and expiry date, number, and 
date of reception) 
• Information on dispensing medicine (Patient number and initials, number of tablets, date of 
dispensing) 
• Information on returned medicine (number of tablets, date of returning) 
• Date of destruction of medicines 
 
 
 
 
 
 
 
 
 

19 
 
6. STUDY PROCEDURES  
6.1 Trial flow chart 
 
TABLE 1: STUDY PLAN 
Inclusion period 
Baseline 
period1 
Treatment period 
Follow-up period 
End 
Week 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 
14 15 16 17 
18 
19 
20 
21 
Visit doctor 
X 
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
   Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   Inclusion/exclusion 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   Previous treatment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   Physical examination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   BP/pulse 
X 
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Exclusion/inclusion criteria 
X    
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test (WOCBP) 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X3 
(X)4 
Blood samples 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Randomization  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Diary 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Drug dispensing 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug retrieval 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Telephone from study nurse 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
  
  
AE/SAE recording 
  
  
X 
  
  
X 
  
X    
  
  
X 
  
  
  
  
  
  
  
  
X 
Withdrawal visit2 
Can happen any time during the study2 
1If needed, the baseline period can be extended to 8 weeks, see 4.2 2 The participants can withdraw their consent to participate 
during the study without providing a reason for this. If natural, they will be asked if they want to take part in a final visit or 
meeting with a representative from the study group.  3The final pregnancy test should be taken 3 days after the last intake of 
study medicine.  4 If the final pregnancy test in week 17 was not performed, WOCBP should perform this before the final visit in 
week 21. AE: Adverse event; WOCBP: Women of child-bearing potential. 
 

20 
 
6.1 Trial flow chart  
 
6.1.1 Informed consent  
Informed consent must have been given voluntarily by each subject before any study specific 
procedures are initiated. The information about the study and the Informed contsent Form (ICF) 
should be given by an independed qualified study personal not involved in the regular 
treatment of the patient. The participant can read the Informed consent form and consider to 
participate, and can re-consider by seeing the ICF during the study period. 
 
6.1.2 Clinical status at week 0  
After the informed consent form is signed, medical history (including disease 
history and corresponding treatment details), physical examination (cor/pulm), 
vital signs (blood pressure and pulse) will be obtained and recorded in the CRF. 
Also, all planned other treatments must be registered. It will be checked if 
women are of child-bearing potential WOCB (See 4.2.1), and if so, whether they 
use highly effective contraception (see 4.2.2).  
Blood samples will be performed for all patient (see 4.2.3). 
 
6.1.3 Concomitant medication  
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” 
drugs) used by the subject within 28 days of treatment start will be recorded in the CRF.  
 
6.1.4 Electronic headache diary  
All included patients have to fill in an electronic headache diary during the baseline period, the 
12 weeks treatment period, and the four-week follow-up period (in total 21 weeks). The 
patients have to log on with a personal code in a study version of BrainTwin. The participants 
get a reminder every day from Brain Twin asking if they have headache or not. AE could not be 
reported in the current version, but may be included in an updated version before the present 
study will be started. may be If they have headache, they have to report the intensity (mild, 
moderate or severe) and the use of analgesics as demonstrated in Figure 1: 

21 
 
 
 
6.1.5 Baseline period 
If needed, the baseline period can be extended to 8 weeks if the patients did not fulfil the 
criteria of chronic migraine, or some blood tests for unclear reason are outside normal limits.  
 
6.1.6 Randomization visit (week 5)  
The visit can be postponed to week 9 if more registrations in the baseline period 
is needed (See 4.2). The headache diary is reviewed, AEs are registered, and a 
pregnancy test performed in WOCBP (as defined in 4.2.1). Vital signs are 
measured. The headache diaries are reviewed. If cholestasis or renal/hepatic 
disease was suspected at inclusion, negative blood analyses must be 
documented (See 4.2.3). 
If the patient is still eligible (inclusion and exclusion criteria, negative pregnancy 
test in WOCBP), the patient can receive the boxes containing the tablets 
(atorvastatin 40 mg or placebo). For randomization of drugs, see 5.4. 
 
6.1.7 Telephone contact by the study nurse and blood sample at follow-up 
The patient is asked about AEs and whether he or she is keeping the headache 
diary and whether there are problems with keeping it, and whether there are any 

22 
 
health issues (AEs). Fertile women are asked about the results of home 
pregnancy tests. In the telephone call in week 3 and week 7 of the treatment 
period, the study nurse will remind the patient to bring the blood test form 
related to week 4 and week 8 of the treatment period for a new blood sample. 
 
6.1.8 Evaluation of blood samples at baseline and follow-up 
The baseline blood samples for creatinine, ASAT and ALAT must be within the normal limit, e.g. 
ASAT should be <50. CK must be below 5 times upper reference value. Deviation in the CRP-
value will be assessed individually by the study physician before randomization. Participants 
with increased LDL-cholesterol at baseline will be randomized, but will be asked to control their 
lipid status with their own doctor after the end of the study. Non-fasting blood samples will be 
drawn, and plasma glucose should be <11 mmol/l.  In the additional blood test in week 4 and 
week 8 of the treatment period, 3 times higher values of ALAT can be accepted, because 
asymptomatic elevated transaminases (3 times higher values) occur in 0.4%  among user of 
statins compared to the placebo group (35).  
 
6.1.9 Patient withdrawal  
The participants can withdraw their consent to participate during the study 
without providing a reason for this. The patient can contact the study personal or 
by using a study-specific email for withdrawal. If natural, they will be asked if 
they want to take part in a final visit or meeting with a representative from the 
study group. If so, AEs and the reason for withdrawal can be noted.   
 
6.1.10 After end of treatment (follow-up period) 
After end of medication intake (week 16) patients will use an electronic  
headache diary for another 4 weeks in order to register potential rebound 
effects. All ongoing (S)AEs will be followed-up at least until at least 30 days after 
last IMP administration, resolve or return to baseline value. 
  
6.1.11 End of study visit treatment (follow-up period) 
The electronic headache diary is reviewed, and SAE/AEs are registered.  
 
7. SAFETY ASSESSMENTS  
7.1 Definitions of adverse events   
7.1.1 Adverse Event (AE)  
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.   

23 
 
An adverse event (AE) can therefore be any unfavourable 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.  
Symptoms or signs that are clearly related to migraine will not be recorded. This includes typical 
migraine headache with concomitant nausea, vomiting, phono- or photophobia, and of visual or 
sensory migraine aura if present before randomisation to study medicine.   
 
7.1.2 Adverse event severity evaluation  
Mild:  The adverse event is transient and easily tolerated.   
Moderate:  The adverse event causes the subject discomfort and interrupts the subject's usual 
activities.   
Severe:  The adverse event causes considerable interference with the subject's usual activities, 
and may be incapacitating or life-threatening.  
 
7.1.3 Serious Adverse Event (SAE)  
Any untoward medical occurrence that at any dose:   
 
Results in death  
 
Is immediately life-threatening  
 
Requires in-patient hospitalization or prolongation of existing hospitalization   
 
Results in persistent or significant disability or incapacity  
 
Is a congenital abnormality or birth defect  
 
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 
hospitalisation, 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 (i.e., elective or scheduled surgery arranged prior to 
the start of treatment) for pre-existing condition is not considered to be a serious adverse 
event.  
 
7.1.4 Expected Adverse Events  

24 
 
These are those listed for the Summary of Product Characteristics (SmPC) of atorvastatin.  
 
7.1.5 Unexpected Adverse Event   
An experience not previously reported in the SmPC for atorvastatin.   
 
7.1.6 Suspected Unexpected Serious Adverse Reaction (SUSAR)   
SAE (see section 7.1.3) that is unexpected as defined in section 7.1.5 and possibly related to the 
investigational medicinal product(s) (See 7.1.8).  
  
7.1.7 Causality of AEs   
All available evidence for the cause of the AE should be considered, such as, the pharmacology 
of the IMP, the nature of the event, timing with respect to IMP administration, and other 
causes. Possible other causes could include:  
 
 The subjects medical history.   
 
 Lack of efficacy or worsening of the treated condition.   
 
 Other treatment, concomitant or previous.   
 
 Withdrawal of study treatment.   
 
 Treatment error.   
 
 Protocol-related procedure.   
 
 Other factors.   
 
7.1.8 AE relationship to IMP   
The causal relationship between the IMP and the AE should be indicated, such as:   
Unrelated: No evidence of a relationship with IMP use.   
Unlikely: There is a temporal relationship only with IMP use; there is little or no 
pharmacological plausibility to suggest a relationship; there is at least one other more likely 
cause for the AE.   
Possible: There is a temporal relationship with IMP use; it is pharmacologically plausible that 
the IMP is the cause of the AE; there may be one or more other possible causes for the AE.   
Probable: There is a strong temporal relationship with IMP use; it is pharmacologically likely 
that the IMP is the cause of the AE; other causes of the AE are unlikely.   
Definite: All available evidence indicates that the IMP is the cause of the AE.   
For data analysis and SAE reporting purposes, AEs classified as ‘unrelated’ and ‘unlikely’ will be 
regarded as ‘not related’; AEs classified as ‘possible’, ‘probable’ and ‘definite’ will be regarded 
as ‘related’.  

25 
 
 
7.2 Follow up of AEs and SAEs 
7.2.1 Follow-up of unresolved AEs   
All ongoing (S)AEs will be followed-up at least until at least 30 days after last IMP 
administration, resolve or return to baseline value.  
 
7.2.2. Time Period for Reporting AE and SAE   
All study investigators at each hospital shall report SAEs to the sponsor without any delay and 
not later than within 24 hours of obtaining knowledge of the events. Where relevant, the 
investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether 
the SAE has an impact on the benefit-risk balance of the clinical trial.  
For each patient the standard time period for collecting and recording AE and SAEs will begin 
after the first dose has been taken and continue for at least 12 weeks (84 days) throughout the 
study. During the study all AEs and SAEs will be proactively followed up for each patient as 
described in the section above; events will be followed up to resolution, unless the event is 
considered by the investigator to be unlikely to resolve due to the underlying disease. Every 
effort will be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. If the patient should become pregnant, in spite of the 
precautions taken, the outcome of the pregnancy will be recorded.   
 
7.2.3 Reporting of SUSARs  
SUSARs will be reported to the EudraVigilance system operated by The European Medicines 
Agency (EMA).  The timeline is the following: 
1) In the case of fatal or life-treating SUSARs, as soon as possible and in any event not later than 
7 days after the sponsor become aware of the reaction. 
2) In the case of non-fatal or non-life-threating SUSARs, not later than 15 days after the sponsor 
become aware of the reaction 
3) In the case of a SUSAR which was initially considered to be non-fata or non-life threating but 
which turns out to be fata or life-treatining, as soon as possible and in any event not later than 
7 days after the sponsor become aware of the reaction being fatal- or life-treating. 
The current practice in Norway is that report of SUSARs in the EudraVigilance system is 
performed by Haukeland University Hospital with an encrypted datafile using a CIOMS report 
form in an unblinded manner.  
 
7.2.4 Procedures in Case of Emergency   
In cases of emergency, the patients will be referred to the nearest relevant hospital 
department.  
 

26 
 
 
7.3 Safety monitoring  
7.3.1 Study monitoring  
Monitoring the study will be coordinated by the research department, St Olav’s Hospital. The 
investigator will be visited on a regular basis by the Clinical Study Monitor, who will check the 
following:  
 Informed consent process  
 Reporting of adverse events and all other safety data  
 Adherence to protocol  
 Maintenance of required regulatory documents  
 Study Supply accountability  
 Facilities and equipment (example: laboratory, pharmacy, ECG machine, etc…) if 
applicable  
 Data completion on the CRFs including source data verification (SDV).  
The monitor will review the relevant CRFs for accuracy and completeness and will ask the site 
staff to adjust any discrepancies as required.   
The monitor will provide to the Sponsor a recommendation regarding continuation, termination 
or other modifications of the study based on the cumulative experience, including the observed 
adverse effects of the treatment under study.   
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be 
allowed access to source data for source data verification in which case a review of those parts 
of the hospital records relevant to the study will be required.   
 
7.3.2 Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements regulatory agencies 
may conduct a regulatory inspection of this study. Such audits/inspections can occur at any time 
during or after completion of the study. If an audit or inspection occurs, the investigator and 
institution agree to allow the auditor/inspector direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings 
and any relevant issues.  
 
8. INTERVENTION DISCONTINUATION  
8.1 Criteria for subject discontinuation  
In accordance with the Declaration of Helsinki, the Investigator must explain to 
the subject that they have the right to withdraw from the study at any time, and 
that this will in no way prejudice their future treatment. As stated in 6.1.9, if the 
patient contact the study personal for such withdrawal, and it is natural, they will 

27 
 
be asked if they want to take part in a final visit or meeting with a representative 
from the study group. If so, AEs and the reason for withdrawal can be noted and 
recorded in the CRF.   
Included study participant is regarded as a screening failure if:   
• Incorrect inclusion i.e., the participant does not meet the required inclusion/exclusion criteria 
for the study in the baseline period. (See 4.2 and 4.3)  
• Patient’s non-compliance to completing the Headache Diary during the baseline period;   
• Patients starting on novel headache prophylactic medication    
Included study participant may also be discontinued at any time for the following reasons:   
• Patient lost to follow-up   
• Withdrawal   
Patient found to not qualify in accordance to the study inclusion and exclusion criteria or lost 
for other reasons in the baseline period, are excluded from the study as screening failures. 
Otherwise, patients are included in the intention-to-treat analysis, but not the per protocol 
analysis.   
  
8.2 Procedures for Discontinuation   
If possible, a final assessment shall be made (end of study visit). As states in section 4.3.4 of the 
ICH E-6 Good Clinical Practice: Consolidated Guidance “Although a subject is not obliged to give 
his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a 
reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.“ Thus, if 
possible, the reason for discontinuation shall be recorded.   
 
8.3. The role of the Data Safety Monitoring Committee   
An indepedent Data Saftey Monitoring Committee (DSMC) may give advice that the trial should 
be temporary or permanently discontinued based on accumulated safety data. The final 
decision will be made by the Sponsor in collaboration with regulatory authorities.  
 
9. STATISTICAL CONSIDERATIONS  
9.1 Hypotheses  
The study has mainly been powered to answer the following hypothesis:  
H1: Alternative hypothesis: Atorvastatin 40 mg per day results in significantly fewer migraine 
days /4 weeks than placebo 
H2: Null hypothesis: There is no difference in change from baseline in mean migraine days/4 
weeks during the treatment period between the Atorvastatin 40 mg and placebo 
In addition, it is also an aim of the study to evaluate several secondary hypotheses: 

28 
 
H3: Atorvastatin 40 mg results in significantly fewer headache days /4 weeks 
than placebo 
H4: Atorvastatin 40 mg results in significantly fewer doses of analgesics of any 
type /4 weeks than placebo 
H5: Atorvastatin 40 mg results in significantly fewer days with sick leave /4 weeks 
than placebo 
H6: There are more responders (reduction in migraine days with more than 50% 
compared to baseline) in the Atorvastatin 40 mg mg group than in the placebo 
group 
 
9.2 Determination of sample size  
This trial has a confirmatory statistical strategy that pre-specifies just one single 
hypothesis (See 9.1: H1) relating to the primary endpoint. The study is powered 
to answer whether this hypothesis (Atorvastatin 40 mg daily is superior to 
placebo) should be rejected. 
A reduction of 1 headache day per month is considered as clinically meaningful 
reduction for patients with episodic migraine (6, 7). In a similar way this may be 
clinically meaningful also for chronic migraine. Using data from our previous 
studies for migraine (6, 7), with the same inclusion/exclusion criteria and primary 
efficacy variable (days with migraine per 4 weeks) quite similar to the ones in the 
present study, it was calculated that a sample of 123 in each group was needed 
(alpha 0.05, 80 % power) to detect a reduction in mean frequency of migraine 
days per month of 1 day (from 19.0 to 18.0 (SD 2.8) evaluated by using a 
parametric t-test . Expecting a dropout rate of maximum 20 % (38), 150 patients 
will have to be included in each group for the primary ITT analysis. With two 
treatment arms, that is 300 patients altogether. 
 
9.3 Interim analyses   
An interim analysis of efficacy will not be performed. However, throughout the study, safety 
data will be reviewed by the DSMC as described in section 7.3.1. The study will be stopped 
temporarily or permanently if the Sponsor, based on the recommendations from the DSMC, 
finds that the risk of participation for the patients is greater than the expected benefit of the 
study; or if the regulatory authorities decides this.  
 
9.4 Procedure for statistical analyses  
The main statistical analysis will be performed when the planned number of patients have been 
included , when all included patients have either finalized their last assessment or is withdrawn 
according to protocol procedures, and when all data have been entered, verified and validated 
according to the data management plan.  

29 
 
Prior to the main statistical analysis, the data base will be locked for further entering or altering 
of data.   
Deviation from the original statistical plan will be described and justified in the Clinical Study 
Report. Amendments to plan can be done until the day of database lock.  
 
9.5 Data Analyses   
In addition to the summarized analysis plan outlined below, a separate statistical analysis plan 
(SAP) will provide further details on the planned statistical analyses. The SAP will be finalized, 
signed and dated prior to database lock.   
We plan to let the statistician be blinded as to which treatment each group has been given. This 
can be achieved by letting our data manager break the randomisation code and make groups 
labelled A or B on which the statistical tests are run. In this way we will obtain a statistician-
blinded study. 
The primary population for ITT analysis will include all randomized participants whether they 
receive treatment or not (intension-to-treat strategy). The null hypothesis to be tested is that 
there is no difference in change from baseline in mean monthly headache days during the 
treatment period between the active treatment and the control group (See 9.1, H1).  
The primary endpoint will be analyzed using parametric method with t-test. Differences 
between analyzed groups is defined as statistically significant using two-side test at a p-value 
<0.05. Supplementary sensitivity analyses will be done for per protocol completers (defined as 
registration of at least 90% of days (i.e. 76 days) in the Headache Diary during the treatment 
period (weeks 5 – 16). We may expect that 80% of the participants complete per protocol, 
based on our experiences with four previous performed RCTs with preventive treatment in 
migraine patients (38). Included patients with chronic migraine would have baseline headache 
frequency between 15-30 headache days/months. We may expect that more Individuals have 
15-17 days/month than higher values (Poisson distribution), and parametric model evaluating 
treatment effect from generalized linear mixed models presented using odds ratios and 
associated 95% confidence. This method allows adjustments for known confounders, in 
particular age, gender distribution, years lived with migraine, and number of previous 
preventive treatment attempts if they differ between the two groups at baseline. In the 
generalized linear mixed models, potential difference in dropouts caused by e.g. side effects 
could be considered. It should be mentioned that such difference was not found in our previous 
four performed RCTs with preventive medical treatment in migraine patients. The overall 
dropout rate was 10% (38) and caused by several different reasons, including pregnancy, co-
occurrence of other diseases needing treatment, hospitalization needing unblinding, or by 
unspecified reasons. Demographics and baseline characteristics, including known confounders, 
will be presented separated by treatment arms (i.e. active treatment and placebo) using 
descriptive statistics.  
This trial has a confirmatory statistical strategy that pre-specifies just one single null hypothesis 
relating to the primary variable. Secondary hypotheses are considered non-confirmatory. It is 

30 
 
not considered necessary to adjust for multiplicity when there is a single primary outcome, as 
findings for secondary outcomes in this study will be considered subsidiary and exploratory, 
rather than confirmatory. This is in line with “Guideline on multiplicity issues in clinical trials 
EMA/CHMP/44762/2017”. Rather than adjust for multiplicity or applying fixed sequence or 
gatekeeping approaches, the trial explores a number of secondary endpoints. Their analysis will 
be pre-specified in the statistical analysis plan (SAP). We argue that this approach will enable us 
to generate hypothesis on potential treatment benefit and inform future study designs in this 
patient population, even in the event of a negative study (this study not meeting its primary 
endpoint).   
Any change to the data analysis methods in the protocol will require an amendment only if it 
changes a principal feature of the protocol. Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
clinical study report.  
 
10 DATA COLLECTION AND QUALITY ASSURANCE  
10.1 Data collection forms  
The Sponsor will supply the centres with web-based Case Report Forms (Viedoc) specific for the 
particular trial. Site personnel will be trained in how to complete the Viedoc. The Viedoc will be 
designed with special focus to fulfil the requirements for completeness, accuracy, reliability and 
consistency with the intended trial. A personal log-in will be provided for all responsible 
personnel to allow for an audit trail relating to the study data to be maintained.   
Completed paper version (if used),  as well as the informed consent declarations, participant 
list, prescreening lists and a paper version of the CVs of study personnel, will be kept at the 
study centres until the end of the study and before estimated study end date is 31/12/2028.  A 
sponsor representative will collect the originals.  
   
  
10.2 Data Management   
The five centers are responsible for collecting and safe storing of all relevant documents, signed 
informed consent in paper version and prescreening lists included. They are encouraged to 
enter data in the Viedoc in a timely manner. Only certified persons using two-factor login 
procedure have access to VieDoc. The data will be stored in a dedicated and secured area in a 
server system. The database server is located securely behind a firewall and is not accessible 
through the web. All included patients have to fill in an electronic headache diary during the 
baseline period, the 12 weeks treatment period, and the four-week follow-op period (in total 21 
weeks). The patients have to log on with a personal code in a study version of BrainTwin with 
data transferred as deidentified data at a secured approved server located in Stavanger 
administrated by Microsoft Azure Norway. Headache diary data will be later be transferred to a 

31 
 
secured area of HUNT Cloud. After this process, the headache diary data stored at Microsoft 
Azure Norway will be delated.  
 
10.2.1 Data Management Plan  
The Data Management Plan (DMP) is included in a separate document (R2_Data Management 
Plan 2022-502177-42-02). The DMP describe the main elements of the data management policy 
for the project. It describes the responsibilities of institutions, how data are to be collected and 
stored. In addition to an evaluation of issues related to protection of privacy.   
  
10.3 Quality Assurance   
10.3.1 Training   
There will be a meeting with all investigators at all centers before start of the study. In addition, 
all study personnel at each site will be trained in the study procedures and use of the Viedoc 
and electronic headache diary.   
 
10.3.2 Documentation of study personnel deviations   
All deviations from the protocol and standard operation procedures shall be assessed by the 
principal investigator and documented as a “Note to file” to be stored in the Investigator Site 
File (ISF). All five centers will store all relevant updated documents in the ISF.  The trial master 
file (TMF) kept by the sponsor contain a log with “note to file” from all participating sites. The 
national coordinating Investigator (NCI) shall be informed by e-mail in the event of a deviation 
and ensure that the deviation is documented in the TMF. In the case of severe deviations, the 
NCI decides how to proceed with the participant. Data in the TMF will be stored for 25 years for 
archiving proposes according to CTR article 58.  
All deviations from the protocol and standard operation procedures shall be assessed by the 
local primary investigator, central primary investigator and the monitor. 
 
10.3.3 Monitoring   
A monitoring plan specific to this study is held separately to the protocol. The monitoring plan 
will outline the level of monitoring to be performed for the trial and how this will be carried out. 
The level of monitoring will be based on the phase of the trial and any perceived risks identified 
by the risk assessment. Monitoring visits will commence after the Sponsor approves the plan. 
Clinical study monitors will be assigned, and will visit the investigator in a regular basis 
according to the monitor plan.  
We envisage that the Clinical Research Unit at ST. Olavs Hospital/NTNU in Trondheim will serve 
as the lead monitor in Norway, and that other centers will be monitored from here or by 
monitors in the NorCrin network. The trial will be monitored regularly according to ICH-GCP. 
On-site initiation visits will be performed at each study site before the inclusion of the first 

32 
 
patient to ensure that all requirements are met. Regular on-site monitoring visits and close-out 
visits will be performed during the trials and after the last visit by the last participant. See also 
section 7.3.   
 
10.3.4 Source Data   
Source data are specified in a source data list. Variables included directly into the eCRF are 
considered source data if specified in the source data list.   
The medical records for each participant should contain information which is important for the 
participant’s safety and continued care, and to fulfil the requirement that critical study data 
should be verifiable.   
To achieve this, the medical records of each participant should clearly describe at least:   
• That the patient is participating in the study, e.g. by including the enrolment number and the 
study code or other study identification;   
• Results of all assessments confirming a patient’s eligibility for the study;   
• Diseases (past and current; both the disease studied and others, as relevant);   
• Surgical history, as relevant;   
• 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)   
• Date of, and reason for, withdrawal from study;   
• Additional information according to local regulations and practice.   
Worksheets provided by the Sponsor can be used to collect relevant information from the 
participant. The information will be entered from the worksheet into the CRF.   
The following data can be considered source data and can be recorded directly in the CRFs:   
• Questionnaires  
• Extraction of headache Diary data. The electronic diary can be monitored by using a digital 
code.   
• Baseline characteristics and medical history not required in the medical records   
 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review   
The study will be conducted in accordance with the Fortaleza 2013 amendment to the 
Declaration of Helsinki 1964.   

33 
 
The Protocol and the Patient Information Sheet / Informed Consent Form will be approved by 
the relevant Competent Authorities and Ethics Committees, and possibly other public bodies 
according to local requirements before commencement. If a protocol amendment is necessary, 
this will be prepared with the agreement of the Principal Investigator, and signed by the 
relevant parties. If the amendment is considered to be substantial, it will be submitted to the 
Competent Authorities and Ethics Committees, and possibly other public bodies according to 
local requirements for review and approval. The protocol amendment will not be implemented 
before the required approvals are obtained. Minor amendments which do not affect the safety 
or physical or mental integrity of the clinical trial participants or the scientific value of the trial 
(i.e. non-substantial amendments) will not be submitted to Competent Authorities or Ethics 
Committees.   
SUSAR reports and Periodic Safety Reports will be sent to Competent Authorities according to 
international regulations.   
 
11.2 Informed Consent Forms   
The information about the study and the Informed consent Form (ICF) should be given by an 
independent qualified study personal without depended relationship as a treating physician. 
The independent qualified study personal will explain the details of the study and will hand out 
the Study Information.  The participant can read the ICF and consider to participate, and can re-
consider by seeing the ICF during the study period. Patients will have sufficient time to read the 
Study Information and Consent Form and to ask questions. They can take time to think about 
their participation and to discuss it with family members and friends if they wish.    
Because of the use of electronic diary (explained in Norwegian only), the process with multiple 
blood samples and pregnancy tests, only patients who understand the Norwegian language will 
be included. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. Copies will be given to each participant and 
this fact will be documented in the participant’s record.   
 
11.3 Participant Confidentiality   
The Investigator must ensure that subject’s confidentiality will be maintained. The eCRFs or 
other documents submitted to the sponsor should only identify subjects by their initials and 
study number. The Investigator should keep a separate log of subject codes and names in the 
Investigator site file (ISF) stored at a safe place locked with a key. Documents not for submission 
to the Sponsor, e.g., subject’s completed Consent Forms, should be retained by the Investigator 
in strict confidence.   
 
11.4 GCP   

34 
 
The study will be managed and conducted according to the latest International Conference on 
Harmonization (ICH) guidelines for Good Clinical Practice (GCP). A copy of these guidelines can 
be found in the Investigator Site File (ISF).   
 
11.5 Study Discontinuation   
Regular Trial Termination   
The end of the trial is defined as the last visit of the last subject included in the trial. Within 90 
days of the end of the trial, the Sponsor will notify Competent Authorities and Ethics 
Committees the regular termination of the of the study as required according to national law 
and regulations.   
 
Premature Trial Termination  
For safety reasons, this trial may be terminated prematurely at any time by the sponsor, the 
Principal investigator, DSMC or competent authorities. If the sponsor decides to terminate the 
trial for any other reason, the investigator, ethics committee and competent authority will be 
informed about the reason(s) for stopping the study.   
 
11.6 Insurance and Liability   
Liability insurance in contention with clinical trials of drugs will be paid by the sponsor to the 
Norwegian Liability insurance company “Norsk legemiddelansvarsforeningen”.   
 
11.7 Study report   
A clinical study report (CSR) will be prepared covering clinical and statistical aspects and 
summarizing all findings of the clinical study. The study report will be sent to the Investigators, 
and the Competent Authorities and Ethics Committees.  
 
12. SAFETY DATA  
The safety of atorvastatin have been described in the RCTs (16-18). Part of the aim of the 
inclusion and exclusion criteria is to minimize the risk of these complications.  
 
13. ETHICAL CONSIDERATIONS   
13.1 Individual patient risks and benefits   
The current study will be performed in otherwise relatively healthy patients with chronic 
migraine, and with study medicines has been on the market for more than three decades and 
has been used by hundreds of thousands of patients, by many over several years. Hence, the 
safety profile of the drug is well known, and the contraindications and hazards are reflected in 

35 
 
the exclusion criteria (See 4.3). In the earlier migraine studies, there were relatively few side 
effects related to the drugs. Therefore, with the proposed doses, we foresee little risk to the 
patients, provided patients with serious medical conditions and risk of pregnancy are avoided.   
Patients should be thoroughly informed of the possibility of not having an effect of the 
medicine, and the possible side effects. Patient must not feel pressured to participate and also 
be given sufficient time to consider.  
 
13.2 Challenges of study design   
The study design is close to clinical real-life practice. In a clinical setting, the majority of the 
study medicines has been well tolerated. One practical problem may be with recruitment of 300 
participants. However, chronic migraine patients who are candidates of preventive drugs are 
frequently remitted to neurological departments.  
 
14. PUBLICATION OF RESEARCH FINDINGS   
The results of this trial will be published in international open access medical 
journals, or such access will be purchased. In addition, the results will be 
presented at international conferences and in news media.  The active part of 
the study will end before 31/12/2028.  The analyses and publication process will 
start soon after and will be expected to be finished before 31/12/2031.   
 
 
 
 
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