Effectiveness and Tolerability of Repetitive Transcranial Magnetic Stimulation For Preventive Treatment Of Episodic Migraine: A Single Centre, Randomised, Double-Blind, Sham-Controlled Phase 2 Trial
Phase: NA
Conditions: Migraine
Sponsor: Universiti Putra Malaysia

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Study Title:  
Effectiveness and Tolerability of Repetitive Transcranial Magnetic Stimulation for 
Preventive Treatment of Episodic Migraine: A Single Centre, Randomised, Double-
Blind, Sham-Controlled Phase 2 Trial (Magnet-EM)   
 
 
Development phase: 2nd 
 
Date of protocol: 01st October 2019 
 
 
 
 
 
 
 

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1 SYNOPSIS 
 
Title of study: 
 
Effectiveness and Tolerability of Repetitive Transcranial Magnetic Stimulation for 
Preventive Treatment of Episodic Migraine: A Single Centre, Randomised, Double-
Blind, Sham-Controlled Phase 2 Trial 
 
Brief 
Title: 
Transcranial Magnetic Stimulation in Episodic Migraine (Magnet-
EM)   
 
Sponsor: Research Management Centre (RMC) Universiti Putra Malaysia 
 
Clinical Phase: 2 
 
 
Investigators: 
 
 
Investigators will be medical practitioner practicing in internal medicine and 
neurology. 
 
Main Principal Investigator 
Institutions 
A/P Dr Wan Aliaa Wan Sulaiman 
Universiti Putra Malaysia 
Name of Co-Investigators 
Institutions 
Dr. Liyana Najwa binti Inche Mat 
Universiti Putra Malaysia 
Prof. Dr. Hamidon Basri 
Universiti Putra Malaysia 
A/P Dr. Hoo Fan Kee 
Universiti Putra Malaysia 
Musmarlina Omar 
Universiti Putra Malaysia 
Nur Ain binti Amir 
Universiti Putra Malaysia 
Nabil Izzaatie binti Mohamad Safiai  
Universiti Putra Malaysia 
 
 
Study period: 3 years 
Planned date of first subject enrolment: 1st December 2018 
Planned date of last subject completed: 1st December 2020 
 
Objectives: 
 
• 
Primary objective: 
 
To evaluate the efficacy an of r-TMS in the adjunctive treatment of episodic migraine 
subjects  

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• 
Secondary objectives: 
 
 
1. To evaluate the safety of r-TMS in the treatment of migraine. 
2. To identify the factors that predicts good responses to TMS treatment. 
3. To determine the biochemical migraine biomarkers associated with pre and 
post r-TMS treatment.  
4. To determine the clinical neurophysiological parameters among patients with 
migraine pre and post r-TMS treatment. 
5. To examine the neuropsychological findings among patients with migraine pre 
and post r-TMS treatment. 
6. To determine the health-related quality of life (HRQOL) among patients with 
migraine pre and post r-TMS treatment. 
7. To determine the lifestyle factors associated with migraine patients. 
8.  To identify genetic polymorphism between migraine patients. 
8. To evaluate the patient satisfaction measures to TMS treatment. 
 
Hypothesis: 
Repetitive Transcranial Magnetic Stimulation as new preventive treatment of 
episodic migraine.  
 
 
Methodology: 
 
This is a single-centre, randomised, double blind, placebo controlled, parallel group 
design clinical trial. 
 
Number of patients: 
 
The sample size was calculated based on the expected differences in the primary 
outcome variable, headache days. “Hypothesis testing of two population means” 
formula was used. With 80% power, 5% level of significance, 30% of attrition 
calculated sample rate, the sample size for the study was 29 in each arm. 
Accounting for a drop-out rate of 30%, the sample size will be increased to 38 in 
each arm. The total sample size will be 76. 
 
 
 
Number of centres: 1 
 
 
Inclusion criteria:  
1. Males or females aged 18 to 60 years of age. 
2. Subjects fulfilling criteria for episodic migraine as per the Third Edition of The 
International Headache Society (ICHD-3) for at least 1 year. 
3. Frequency of migraine attacks 2-8 times per month with less than 15 
headache days per month for at least 3 months prior to screening. 
4. Demonstrated compliance with the headache diary during the run-in period by 
entry of headache data on a minimum of 24/30 days (80% compliance). 
5. A signed and dated informed consent document indicating that the subject 
has been informed of all pertinent aspects of the study including any known 
and potential risks and available alternative treatments. 

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Exclusion criteria: 
 
1. Patients with previous history of rTMS treatment. 
2. Onset of headache more than 50 years 
3. Headache with red flags symptoms that may suggest organic secondary 
headaches. 
4. Pregnant or lactating women. 
5. Patients with contraindications to TMS such as metallic implant and 
pacemaker based on the Screening 13-item Questionnaire for rTMS 
candidate. 
6. Patients with medical conditions such as severe hypertension, infections, 
malignancy, cardiovascular and cerebrovascular diseases, epilepsy 
degenerative central nervous system diseases, renal failure, hepatic failure, 
bleeding diathesis and serious mental illnesses. 
 
 
Test treatment, dose and mode of administration: TMS devices treatment, high 
frequency 20 Hz repetitive stimulation, non-invasive, external application on the 
scalp 
 
Duration of treatment with study medication: 2 weeks  
 
Criteria for evaluation: 
 
Primary Outcome Measure  
 
1. Change from baseline in mean monthly migraine days. The mean monthly 
migraine days will be calculated using the monthly migraine days from each of 
the month of the double-blind treatment phase. [Time frame: 4 months after 
the first session of r-TMS] 
 
Secondary Outcomes Measure 
 
1. Change from baseline in mean monthly migraine attacks. The mean monthly 
migraine attacks will be calculated using the monthly migraine attack from 
each of the month of the double-blind treatment phase. [Time frame: 4 months 
after the first session of r-TMS] 
2. Proportion of subjects with at least a 50% reduction from baseline in mean 
monthly migraine days. [Time Frame:  4 months after first session of r-TMS]. 
Change from baseline in mean monthly pain intensity of migraine attacks. The 
mean monthly pain intensity will be based on the record of the maximal pain 
intensity by means of a verbal scale (i.e. 0 =no headache; 1 = mild headache; 
2 = moderate headache; 3 = severe headache) prior to taking symptomatic 
medication. [ Time Frame: 4 months after first session of r-TMS] 
3. Frequency and severity of adverse events in response to r-TMS. [Time 
Frame:  4 months after first session of r-TMS]  
4. The DASS 21 score changes in migraine patients in response to r-TMS. [Time 

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Frame: 4 months after first session of r-TMS]. Mean score changes from 
baseline for depression, anxiety and stress category.  
5. The MIDAS score changes in migraine patients in response to r-TMS. [Time 
Frame: 4 months after first session of r-TMS]. Mean score changes from 
baseline. 
6. The MSQ score changes in migraine patients in response to r-TMS. [Time 
Frame:  4 months after first session of r-TMS]. Mean score changes from 
baseline. 
7. The EQ-5D score changes in migraine patients in response to r-TMS. [Time 
Frame: 4 months after the first session of r-TMS.  Mean score changes from 
baseline. 
8. The ABNAS score changes in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean score changes from baseline. 
9. The PSQI score changes in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean scores change from baseline. 
10. The FFQ score changes in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean score changes from baseline 
11. The IPAQ score change in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean score changes from baseline 
12. Transcranial Doppler (TCD) pattern changes in migraine patients in response 
to r-TMS. [Time Frame: Baseline and after treatment sessions (month 4).] Mean 
flow velocity (cm/s). 
13. Electroencephalography (EEG) pattern change in migraine patients in 
response to r-TMS. [Time Frame: Baseline and after treatment sessions (month 
4).] EEG pattern differences based on report. 
14. Serum serotonin level and DNA changes in migraine patients in response to r-
TMS. [Time Frame: Baseline and after treatment sessions (month 4)] Serum 
serotonin (ng/ml). 
15. Serum beta-endorphin level changes in migraine patients in response to r-TMS 
[Time Frame: Baseline and after treatment sessions (month 4)]. Serum beta-
endorphin (ng/ml). 
16. C-Reactive Protein (CRP) level changes in migraine patients in response to r-
TMS [ Time Frame: Baseline and after treatment sessions (month 4)] Serum 
CRP mg/dL 
17. Serum Calcitonin gene related peptide (CGRP) level and DNA changes in 
migraine patients in response to r-TMS. [Time Frame: Baseline and after 
treatment sessions (month 4)] Serum CGRP pg/mL 
18. Satisfaction measures of efficacy, tolerability, safety and expectations of r-TMS 
among the participants. A 5-point, Likert scale will be used to evaluate 
satisfaction with r-TMS in migraine prevention. [ Time Frame: 4 months after 
first session of r-TMS]  
 
 
 
 
 
 

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Statistical methods: 
 
Characteristics of the patients in each of the groups will be compared with 
parametric tests for normally distributed data using Paired T-test for univariate and 
ANCOVA within GEE for multivariate and with nonparametric tests if otherwise using 
Fried-Mann test for univariate and Kruskall-wallis for multivariate. For all outcome 
measures, treatment effects will be calculated for each subject by the differences 
between the baseline values before and after r-TMS stimulation using analysis of 
covariance (ANCOVA) test. Compliance with treatment in each group will between 
compared with Mann-Whitney tests. Frequencies of adverse events were compared 
with Fisher’s exact tests. All other endpoints will be evaluated using generalized 
estimating equations (GEE) models. GEE will be used to analyse correlated data, 
particularly when analysis of variance assumptions is not met. Two-tailed p values 
<0.05 were considered statistically significant. Post-hoc analysis will be performed 
with Bonferroni corrections. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 TABLE OF CONTENTS 
 
 
1  
SYNOPSIS 
 
1 
2  
TABLE OF CONTENTS 
6 
3  
                                                                                            LIST OF 
ABBREVIATIONS  
     9 
4  
GLOSSARIES OF TERMS 
10 
5  
ETHICS & REGULATORY CONSIDERATIONS 
11 
5.1 
 
ETHICAL CONDUCT OF THE STUDY 
 
11 
5.2 
 
INFORMED CONSENT AND SUBJECT INFORMATION 
 
11 
5.3 
 
PATIENT PROTECTION PROCEDURES 
 
13 
5.3.1 
PROCEDURES IN THE EVENT OF EMERGENCY  
 
13 
5.3.2 
PROCEDURES IN THE EVENT OF PREGNANCY 
 
14 
5.3.3 
PATIENT DATA PROTECTION  
 
14 
5.3.4 
INSURANCE  
 
15 
6  
 
INTRODUCTION AND BACKGROUND  
16 
6.1 
Potential risks 
16 
6.2 
Potential Benefits 
18 
7  
 
OBJECTIVES 
19 
7.1 
 
PRIMARY OBJECTIVE:  
19 
7.2 
 
SECONDARY OBJECTIVE(S): 
 
19 
8  
 
STUDY DESIGN  
19 
8.1 
 
OVERALL STUDY DESIGN  
19 
8.1.1 
 
SCHEMATIC DIAGRAM OF STUDY DESIGN: 
. 
20 
8.1.2 
 
DISCUSSION OF STUDY DESIGN  
 
21 
8.1.3 
 
STUDY POPULATION 
  
23 
8.1.3.1 
INCLUSION CRITERIA 
  
23 
8.1.3.2 
EXCLUSION CRITERIA  
 
23 
8.1.3.3 
SUBJECT WITHDRAWAL & DROP-OUT 
 
23 
8.1.3.4 
PROCEDURES FOR HANDLING WITHDRAWAL 
24 

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8.1.3.5 
DEALING WITH DROP-OUTS 
24 
 
8.1.4 
ENROLMENT 
 
24 
8.2 
FUTURE PLAN STUDY 
25 
9 
TREATMENT AND STUDY PROCEDURES 
 
25 
9.1   
DESCRIPTION OF STUDY INTERVENTION 
 
25 
9.2 
Comparator Intervention 
 
26 
9.3  
Dosage and Administration 
26 
9.4 
Investigational Product Supply and Handling 
27 
9.4.1 
Supply, Packaging and Labelling 
27 
9.4.2 
Storage 
27 
9.4.3 
Accountability 
27 
9.5 
Concomitant Medication/Treatment 
27 
9.6 
Treatment Allocation and Randomization 
27 
9.7 
Blinding & Emergency Unblinding Procedures 
28 
9.8 
Baseline Assessment and Laboratory Tests  
29 
9.9 
Primary Outcome Measure ( Assessment of Efficacy) 
29 
9.10   
SECONDARY OUTCOMES MEASURE 
29 
10 
ADVERSE EVENTS  
31 
10.1 
REPORTING SAE  
 
31 
11 
STUDY CONDUCT  
31 
11.1 
                                                                    STUDY VISITS AND PROCEDURES 
 
31 
11.1.1 
Screening Visit 
31 
11.1.1.1 
Definition 
32 
11.1.2 
Baseline Visit 
33 
11.1.3 
Randomisation 
35 
11.1.4 
Study Treatment and Visits 
37 
11.1.5 
Study visits schedule and procedures 
38 
11.1.6 
Assessment of efficacy 
39 
11.2 
Criteria for stopping subject treatment 
39 
11.3 
Sample handling and analysis 
39 
11.3.1 
Collection 
39 
11.3.2 
Labelling  
39 
11.3.3 
Analyses 
39 
12 
Data management 
40 
13 
Statistical methods 
41 
13.1 
Sample size and power considerations 
41 
13.2 
Randomisation 
42 
13.3 
Analyses 
42 
13.3.1 
Analysis sets 
42 
13.3.2 
Baseline comparability 
42 
 
13.3.3 
Efficacy analysis 
42 
13.3.4 
Safety analysis 
42 
13.3.5 
Handling of missing, unused and spurious data 
43 
13.3.6 
Planned interim analysis 
43 
14 
Administrative matters 
43 
14.1 
Notification of regulatory authority(ies) 
43 
14.2 
Notification of primary care physician 
43 

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14.3 
Study initiation 
43 
14.4  
Protocol deviation 
43 
14.5 
Study documentation 
44 
14.5.1 
Essential documents 
44 
14.5.2 
Source documents 
44 
14.6 
Patient identification list/enrolment log 
44 
14.7 
Curriculum vitae 
45 
14.8 
Site signature/authorization log 
45 
14.9 
Retention of documents 
45 
14.10 
Finance  
45 
14.11 
Study termination and site closure 
45 
14.12 
Confidentially  
46 
14.13 
Anticipated subject accrual and duration of the study 
46 
 
REFERENCES  
47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 LIST OF ABBREVIATIONS 
 
5-HT 
5-Hydroxytryptamine 
 
ACE 
Angiotensin I-Converting Enzyme 
(ACE) 
 
AE 
Adverse Event 
 
 
BLAST 
Basic Local Alignment Search Tool 
 
BMI 
Body Mass Index 
 
BLS 
Basic Life Support 
 
CGRP 
Calcitonin  
 
CRF 
Case Report 
Form 
 
 
CV 
Curriculum Vitae 
 
 
DNA 
Deoxyribonuclease 
 
EDTA 
Ethylenediaminetetraaacetic Acid 
 
EEG 
Electroencephalography 
 
EQ-5D 
Euroqol 5 Dimension Questionnaire  
 
FFQ 
Food Frequency Questionnaire 
 
GCP 
Good Clinical Practice 
 
GEE 
Generalized Estimating Equations. 
 
HRQOL 
Health-Related Quality of Life  
 
ID 
Identification 
 
 
IPAQ 
International Physical Activity 
Questionnaire 
 
MA 
Migraine with Aura 
 
MeSH 
Medical Subject Headings 
 
MIDAS 
Migraine Disability Assessment 
mmHg 
Millimetre 
Mercury 
 
MO 
Migraine Without Aura 
 
MSQ v2.1 
Migraine Specific Quality of Life Questionnaire Version 2.1 
PSQI 
Pittsburgh Sleep Quality Index 
r-TMS 
Repetitive Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event 
 
SMI 
Structure Migraine Interview 
 
TCD 
Transcranial Doppler 
 
TMS 
Transcranial Magnetic Stimulation 
 
TNF 
Tumour Necrosis Factor 
 
VNTR 
Variable Number Tandem Repeats 
 
 
 
 
 
 
 
 
 

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4 GLOSSARIES OF TERMS 
 
(Comprehensive list of commonly used terms is found in Malaysian Guidelines 
for GCP) 
 
 
Eligible 
 
 
Qualified for enrolment into the study 
based on strict adherence to inclusion 
and exclusion criteria. 
 
Evaluable 
 
Meeting all eligibility criteria, 
complying with the procedures 
defined in the protocol and 
therefore included in analysis. 
 
Investigator 
 
Treating physician 
 
Monitor 
 
An individual assigned by JKEUPM 
who is responsible for assuring proper 
conduct of a clinical study. 
 
Protocol amendment 
 
Any change in a study protocol which 
affects the safety of subjects, the 
scope, 
design, 
assessments 
or 
scientific 
validity 
of 
the 
clinical 
investigation. 
 
Subject(s) 
 
Individuals enrolled in the clinical study. 
 
 

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5 
ETHICS & REGULATORY CONSIDERATIONS 
 
 
5.1  
Ethical conduct of the study 
 
The study will be conducted in compliance with the protocol and JKEUPM standard 
operating procedures. These are designed to ensure adherence to the ethical 
principles that have their origin in the "World Medical Association Declaration of 
Helsinki", "Malaysian Guidelines for Good Clinical Practice" and applicable regulatory 
Requirements.  Applicable government regulations and Universiti Putra Malaysia 
research policies and procedures will also be followed. 
  
This protocol and any amendments will be submitted to the JKEUPM for formal 
approval to conduct the study.  The decision of the JKEUPM concerning the conduct 
of the study will be made in writing to the investigator. All subjects for this study will be 
provided a consent form describing this study and providing sufficient information for 
subjects to make an informed decision about their participation in this study.  This 
consent form will be submitted with the protocol for review and approval by the 
JKEUPM.  The formal consent of a subject, using the JKEUPM -approved consent 
form, will be obtained before that subject is submitted to any study procedure.  This 
consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent. 
 
 
5.2 
Informed consent and subject information 
 
Informed Consent Process 
 
Informed consent is a process initiated prior to an individual agreeing to participate in 
a study and continues throughout the individual’s participation. Informed consent is 
required for all patients participating in this study. In obtaining and documenting 
informed consent, the investigator should comply with applicable regulatory 
requirements and should adhere to GCP and to the ethical principles that have their 
origin in the Declaration of Helsinki. Discussion of objectives, risks and 
inconveniences of the study and the conditions under which it is to be conducted are 
to be provided to patients by staff with experience in taking consent and who are 
familiar with the study. All potential participants will be given a patient information 
sheet (PIS). Upon reviewing the PIS, the investigator will explain the research study 
to the patient and answer any questions that may arise. The investigator will inform 
every subject in detail about the nature of the study, its purpose, the treatments and 
the probability of random assignment to treatment groups, those aspects of the study 
that are experimental, the procedures involved and the discomfort they may entail, the 
possible risks including to an embryo, foetus or nursing infant where applicable, the 
reasonably expected benefits the expected duration and the approximate number of 
subjects involved and the subject's responsibilities. 
 
A contact point where further information about the study may be obtained will be 
provided. The patient should have the opportunity to discuss the study with their 
surrogates and think about it prior to agreeing to participate. A copy of the informed 
consent document will be given to the patient and/or consultee for their records. 
Consent will be obtained for the participants name and address to be provided to the 

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co-ordinating centre and a copy of the consent form, participant detail form and 
enrolment form will be kept there. The patient or consultee may withdraw from the 
study at any time by revoking the informed consent. The rights and welfare of the 
patients will be protected by emphasising to them that the quality of medical care will 
not be adversely affected if they decline to participate in this study. 
 
Study subjects will be informed that: 
 
1. Participation in this study is voluntary and that he/she may withdraw from 
this study at any time for any reason and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating 
physician. 
2. They will be notified in a timely manner if information becomes available that 
may be relevant to their willingness to continue participation in the study. 
3. Alternative procedures or treatments that may be available and the 
important potential benefits and risks of these available alternative 
procedures or treatments. 
4. Any compensation for additional costs and/or injury caused to a subject 
attributable to participation in the study. 
5. Financial expenses, if any, to the subject for participating in the study as 
well as prorated payment, if any, to the subject for participating in the study. 
6. Any foreseeable circumstances and/or reasons under which the subject's 
participation in the study may be terminated. 
7. The person(s) to contact for further information regarding the study and 
whom to contact in the event of study related injury. 
 
Written consent will be obtained from each subject involved in the study. If written 
consent is not possible, oral consent can be obtained if witnessed by a signed 
statement from one or more persons not involved in the study, stating why the patient 
was unable to sign the consent form. The informed consent form used to document 
written or oral consent in the study must be received prior to approval from the IEC. If 
the subject and his/her parent/guardian are unable to read, the investigator or 
designee must explain to the subject the content of the Patient Information Sheet and 
Consent Form point by point in the presence of an impartial witness. The witness 
should personally sign and date the consent form. The potential study subject and/or 
his/her parent/guardian should be given the opportunity to ask questions and time for 
consideration. 
 
A copy of the Patient Information Sheet and signed Consent Form should be given to 
the subject. The original must be filed by the principal investigator in the Investigator's 
Study File. A sample of the Patient Information Sheet and Consent Form can be found 
in the Appendix of this protocol. 
 
 
 
 
 
 
 
 
 
 

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5.3 
Patient protection procedures 
 
5.3.1 Procedures in the event of emergency 
 
The investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the study. An emergency may 
constitute an SAE. A medical emergency is an acute, unplanned event that has the 
potential for serious harm or death. This includes anaphylaxis and cardiorespiratory 
arrest. 
 
Responsibilities  
 
1. Clinical staff, including nurses, doctors and research technicians, are 
responsible for the identification of medical emergencies, mobilising the 
resuscitation team and providing initial treatment to address the emergency.  
2. Research nurses and technicians are responsible for ensuring that emergency 
equipment is available and is in good working order.  
3. Non-clinical staff are responsible for assisting in the management of 
emergencies, mobilising the resuscitation team when asked to do so and 
facilitating emergency procedures. 
4. Clinical staff are responsible for ensuring that BLS (Basic Life Support) training 
is up-to-date, as appropriate to their role. 
5. The CRF Manager/Lead Research Nurse is responsible for arranging any 
additional training and for arranging regular emergency simulation training.  
 
Procedures  
 
1. Maintenance of equipment: Resuscitation trolleys (Adult) are located in the 
medical lab. Trolleys are checked weekly by study staff to ensure that all drugs 
and equipment are in-date and functional. Contents are checked against the 
checklist, which is kept on the trolley.  
2. Staffing: Whenever there are study participants in the headache research clinic, 
two members of staff should usually be present to ensure that an emergency 
can be managed as safely as possible. At least one member of staff should be 
a member of the study clinical team.  
3. Procedure in the event of a life-threatening emergency: In the event of an acute 
deterioration or collapse of any person in the study, study clinical staff will 
perform an ABCDE assessment in accordance with the current Resuscitation 
Council guidelines. A member of staff should collect an arrest trolley. If cardiac 
or respiratory arrest has occurred, staff should initiate cardiopulmonary 
resuscitation and defibrillation in line with Resuscitation Council guidance 
(Figure 2). Staff caring for the patient must call activate emergency alarm. On 
hearing the emergency alarm all available staff must attend immediately.  A 
member of clinical or non-clinical staff will contact the resuscitation team on 999 
stating ‘adult cardiac arrest’ and give the location. A member of staff should go 
to the nearest entrance to facilitate access for the resuscitation team. Once the 
resuscitation team arrive, a member of study clinical staff will hand over to the 
resuscitation team using a structured handover technique, such as Situation, 
Background, Assessment and Recommendation (SBAR). Study staff should 
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the resuscitation team may be unfamiliar with the layout of the study site. The 
patient will be send to the nearby emergency department of Hospital Serdang 
and an emergency physician who is also sub investigator of this study will be 
alerted. 
4. Procedure in the event of a non-life threatening emergency: In the event of mild 
adverse event such as headache, dizziness, nausea and vomiting, study 
clinical staff will perform an ABCDE assessment and will direct the person to a 
treatment room with a bed located at the study site. Symptomatic treatment will 
be provided to the person. Patient should bring their own medicines prescribed 
for their acute headaches and the rescue medicine will be administered. Study 
staff should remain on hand to assist the patient. Patient who has persisting 
symptoms will be referred to the emergency department in Hospital Serdang. 
An emergency physician who is also sub investigator of this study will be alert 
for further assessment.  
5. Procedures in the event of seizure: During the event of seizure, patient will be 
put into left lateral position, immediately be given initial assessment and initial 
first aid for seizure as well as monitoring in the first five minutes. The onset of 
seizure should be noted. Intramuscular midazolam will only be given to the 
patient if the seizure persists more than 2 minutes. The dosage of 5mg 
midazolam will be given stat, and the maximum dose given will not exceed 10 
mg. The time of midazolam taken by the patient and the time of seizure stop 
should be noted and recorded. 
6.  A collaboration with Pusat Pengimejan Diagnostik Nuklear (PPDN) was done 
to handle intramuscular midazolam for usage during emergency. During the 
emergency situation, one of the research staff will run to PPDN immediately 
and collect midazolam vials from PPDN staff according to procedures set up by 
PPDN. 
 
5.3.2 Procedures in the event of pregnancy 
 
The subject must be instructed to inform the investigator if she becomes 
pregnant during the study and seek advice regarding continuation of the study 
treatment. The investigator should follow up the pregnancy until the outcome is 
known. 
 
5.3.3 Patient data protection 
 
1. The investigator must assure that the anonymity of the subjects will be 
maintained and that the confidentiality of records and documents that 
could identify subjects will be protected, respecting the privacy and 
confidentiality 
rules 
in 
accordance 
with 
applicable 
regulatory 
requirements. 
 
2. Subjects must be identified only by their assigned identification number 
and initial on all CRFs and other records and documents submitted to 
JKEUPM and sponsor. 
 
3. The investigator will keep a Patient Identification List with complete 
identification information (name, address, contact number, IC#) on each 
subject. 
 

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4. Documents not for submission to JKEUPM such as subject's written 
informed consent form, should be maintained by the investigator in strict 
confidence. Monitors and auditors from JKEUPM and sponsor, and 
representatives of IEC or other regulatory agencies will be granted direct 
access to subject medical records and other study documents for 
verification of study procedures and data without violating the 
confidentiality of the subject. The subject should be informed that by 
signing a written informed consent form, the subject or his/parent or 
guardian is authorizing such access. 
 
 
All electronic data processed at JKEUPM will be identified by patient 
numbers only, thereby ensuring that patients' identity remains unknown 
to JKEUPM and the sponsor. In the event that the study is discontinued 
all samples and data already received will be kept anonymised 
/pseudonymised and analysed where possible. 
 
 
5.3.4 Insurance 
 
With respect to any liability directly or indirectly caused by the investigational 
products in connection with this study, the sponsor assumes liability by law on 
behalf of the investigator and his/her staff for possible injury to the subject, 
provided the investigator and his/her staff have followed the instructions of the 
sponsor in accordance with this protocol and any amendments thereto, that the 
investigational products administered to the subject in this study have been 
supplied by the sponsor and that the investigator and his/her staff have in 
general performed this study in accordance with scientific practice and currently 
acceptable techniques and know how. 
 
 

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6 
INTRODUCTION AND BACKGROUND 
 
Migraine is a common chronic debilitating disease with an estimated global prevalence 
of 14.7% (Steiner 2013). Medications such as propranolol or topiramate, have an 
important role in abortive and prevention of attacks but are limited in effectiveness 
while carrying side effects. Transcranial magnetic stimulation (TMS), is a non-invasive 
neuromodulation procedure for people with migraine that has been proved to be safe 
and effective option of a non-pharmacological migraine treatment. TMS is given using 
a table-top or handheld device that delivers a predetermined level of magnetic pulses 
to the head. Based on the theory that repetitive TMS alters brain excitability and 
neurotransmitter activity, several studies that examined TMS as a preventive migraine 
treatment and some had shown positive results. However, there is still uncertainty of 
the extend of efficacy of TMS and we are lacking information to identify patient that 
will benefit from TMS (Lan 2017). Therefore, its role as an effective and safe non-
pharmacological treatment for migraine need to be further determined especially 
among our population. 
 
Besides all the environmental factors, studies also suggest migraine basically caused 
by genetic factors. First-degree relatives or family suffers from migraine with aura (MA) 
are prone to inherit the genetic and hold almost four-fold enhancement risk to suffers 
while for Migraine without aura (MO) have two-fold increased risk (Kowalska et al., 
2015). There are many studies associated between genes candidates and their 
variation with different populations (Guler et al., 2014). The finding of epigenetic 
changes in migraine will assess the role of environmental risk factors that may reduce 
or enhance the risk of migraine. B endorphin is suggested by Misra et al, 2013 
associated with migraine headache as it is found that level of B endorphin was 
significantly lower in migraine (4.35 2.29 ng/ml) compared to controls (6.68 2.93 
ng/ml). Interestingly, the improvement in migraine after r-TMS was associated with 
increase in B endorphin level (Misra et al. 2013).  
There are many outstanding issues and unanswered questions about r-TMS for 
migraine prevention treatment, mainly on identifying the responders and non-
responders to this treatment. 
This current study is planned to produce outcome data needed for evidence-based 
use of r-TMS in migraine.
 
 
6.1 
 
Potential Risks 
 
 
(i) Potential adverse reactions 
 
Potential adverse reactions to TMS (e.g. seizures, syncope, migraines) TMS is widely 
considered to be a safe technique, however, has induced brief seizures in a small 
number (<20) of individuals worldwide. As a result of these reported incidents, 
guidelines were published specifying safe operating parameters for stimulation with 
respect to intensity, frequency and duration (Wassermann, 1998). Since 1998, 
seizures due to TMS have occurred, but mostly in studies operating outside the safe 
limits previously defined. Incidents of seizures in studies operating within the safe 
parameters occurred in subjects using pro-epileptogenic medication. Considering the 
very large number of subjects who have participated in TMS studies since 1998 and 
the small number of seizures, the risk of TMS inducing seizures is considered to be 

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very low (Rossi et al., 2009). Because of these potential risks, all researchers carrying 
out TMS must do so due so according to the parameters for intensity, frequency and 
duration described in the international guidelines (Wasserman 1998; Rossi et al., 
2009). To further ensure that risks are minimised, subjects are also required to fill out 
a TMS safety screening form before participating to rule out other contraindications to 
participation. These include: family history of epilepsy, a history of neurological or 
psychiatric conditions or transient lowering of seizure thresholds e.g. as a result of 
lack of sleep, high consumption of alcohol, caffeine, or through taking anti-malarial 
medication. Please refer to the enclosed TMS Safety Screening Questionnaire for a 
complete list of contraindications (Appendix 5). The guidelines on how often a subject 
can participate in a TMS study are unclear. Many studies are using TMS to treat 
disorders (e.g. psychiatric disorders). TMS can cause syncope, or fainting in some 
participants. This reaction is often caused by situations of anxiety and psycho-physical 
discomfort and is a more common adverse reaction to TMS than a seizure. Screening 
prior to stimulation will not reliably rule out any predisposition to fainting, so to avoid 
inducing syncope it is important to ensure that participants are fully informed and 
comfortable with the procedure before beginning. Researchers should monitor a 
subject‘s ongoing reactions to TMS and will avoid stimulating if the subject appears to 
be uncomfortable. Researchers undergo basic life support training so they are able to 
ensure the participant‘s safety and comfort in the event of syncope.  
 
(ii) Discomfort  
 
A loud clicking sound is produced each time the stimulator discharges. Since the coil 
is usually held in close proximity to the ears, subjects are given earplugs during 
stimulation. TMS causes localised tapping sensations on the scalp at the point of 
stimulation. Stimulation of motor cortical regions may also cause localised motor 
discharges, which manifest as muscle twitches. Neither of these effects should be 
unpleasant but may become uncomfortable when stimulating at high intensities and 
for long periods. Subjects are encouraged to let the researcher know if TMS is causing 
undue discomfort. Sometimes, muscles on the head or peripheral facial nerves are 
stimulated directly causing muscle contractions, jaw movements or eye blinks. Whilst 
these are not dangerous, and many subjects tolerate them comfortably, some of these 
reactions have potential to cause discomfort. Again, subjects are encouraged to make 
the researcher aware if they are at all uncomfortable. Researchers minimise these 
reactions through monitoring the state of the participant and adjusting coil position and 
output intensity accordingly. Headaches have been reported as a side effect of 
participation in brain stimulation studies. This risk can be minimised by ensuring 
participants are physically comfortable and take regular breaks if necessary. 
Participants are made aware from the start that a headache is a potential minor risk 
of TMS and that these usually respond well to over-the-counter analgesics (e.g. 
paracetamol). 
 
(iii) No device-related serious adverse events were reported in the RCT of 164 
patients. The incidence of adverse events was similar between the sTMS group (14%, 
14/102) and sham group (9%, 9/99) within 48 hours after treatment. All events 
(headache, migraine, sinusitis and paraesthesia) were mild or moderate with the 
exception of severe nausea (n=1 in each group), severe migraine (n=1, sTMS group) 
and severe headache (n=1, sTMS group) (Lipton 2010). Slight ‘unsustained’ dizziness 
(n=1) drowsiness (n=1) and tiredness (n=2) were reported in the case series of 42 
patients after treatment with low- or high-intensity TMS. None of these events recurred 

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or needed medical attention (Clarke 2006). Sleepiness (n=1 in each group), 
uncomfortable or long-lasting sitting (n=1 in each group), headache (n=2 in sham 
group) and uncomfortable assessment of visual motor threshold (n=5 in r-TMS group; 
n=4 in sham group) were reported during treatment in the case series of 27 patients. 
Amyostasia (muscle tremor causing difficulty in standing), irritability (n=1 in each 
group), ‘vigorous dreams’ and phonophobia (n=1 each in r-TMS group) were reported 
after r-TMS treatment in this study (Teepker 2010). Other risk for acute adverse events 
including neck pain, seizure, scalp burns, hearing impairment, impaired cognition, 
trouble 
concentrating 
and 
acute 
mood 
changes. 
 
(iv) Loss of confidentiality 
 
Other risks include loss of confidentiality. Good Clinical Practice should ensure this 
does not happen. Physical risks are limited to those of the extra venepuncture 
including bruising. The extra blood tests will, where possible be done at the same time 
as routine venepuncture to minimise this risk. The clinical care is directed by the 
responsible physician. There may be psychological risks as participants recall the 
impact their illness has had on their quality of life. 
 
 
 
6.2 
 
Potential Benefits 
 
An RCT of 11 patients comparing r-TMS (n=6) against sham treatment (n=5) 
showed a significant reduction in the outcome measures (attack frequency, 
headache index and medication use) during and 1 month after r-TMS treatment 
compared with baseline (p<0.0005). No significant differences in the outcome 
measures were observed in the sham group (Brighina 2004). 
 
A case series of 27 patients with migraine comparing low-frequency r-TMS (n=14) 
against sham stimulation (n=13) for prevention reported no significant differences 
between groups for all reported outcomes (including number and duration of 
migraine attacks, mean pain intensity and use of analgesics). The ‘within-group’ 
findings from this study showed a significant decrease in the number of migraine 
attacks during 8 weeks within the r-TMS group from 9.36±2.82 attacks to 6.79±4.28 
attacks (p=0.007), and a non-significant decrease within the sham group (numbers 
not reported; p=0.216). There was a significant reduction in migraine days during 8 
weeks in both r-TMS and sham groups (from 17.69±11.63 days to 13.15±9.27 days 
[p=0.012] and from 14.36±5.07 days to 9.50±6.80 days [p=0.006] respectively). The 
r-TMS group showed a significant reduction in migraine hours during 8 weeks from 
125.93±80.31 hours to 85.36±72.27 hours, p=0.035; the difference was not 
significant in the sham group (numbers not reported; p=0.080) (Teepker 2010). 
  
Mean pain intensity changed from 6.26±1.33 to 6.11±1.26 (p=0.455) in the r-TMS 
group; and from 5.52±1.72 to 5.17±2.51 (p=0.839) in the sham group. Differences 
between the r-TMS and sham groups were not significant (p=0.942). The intake of 
analgesics changed from 14.21±10.13 pills to 12.50±14.65 pills (p=0.232) in the r-
TMS group; and from 15.15±11.24 pills to 11.81±9.89 pills (p=0.094) in the sham 
group. Differences between the r-TMS and sham groups were not significant 
(p=0.577) (Teepker 2010).Overall, there will be future benefits in gaining more 
knowledge on r-TMS treatment as well as important biochemical and genomics work 
in migraine. 

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7 
OBJECTIVES 
 
 
7.1 
Primary objective: 
 
 
To evaluate the efficacy an of r-TMS in the adjunctive treatment of episodic migraine 
subjects  
 
 
7.2 
Secondary objective(s): 
 
 
 
1. To evaluate the safety of r-TMS in the treatment of migraine. 
2. To identify the factors that predicts good responses to TMS treatment. 
3. To determine the biochemical migraine biomarkers associated with pre and 
post r-TMS treatment.  
4. To determine the clinical neurophysiological parameters among patients with 
migraine pre and post r-TMS treatment. 
5. To examine the neuropsychological findings among patients with migraine pre 
and post r-TMS treatment. 
6. To determine the health-related quality of life (HRQOL) among patients with 
migraine pre and post r-TMS treatment. 
7. To determine the lifestyle factors associated with migraine patients. 
8.  To identify genetic polymorphism between migraine patients. 
8. To evaluate the patient satisfaction measures to r-TMS treatment. 
 
 
 
 
8 
STUDY DESIGN 
 
 
8.1 
Overall study design 
 
 
The overall study design is a randomized, sham controlled, double-blind, parallel 
clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
 

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8.1.1 Schematic diagram of study design: 
 
 
Design of a randomized, controlled, double-blind clinical trial 
 
 
Figure 1: Study design of r-TMS clinical trial 
 
 
 
 
                
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Conceptual Framework (r-TMS in patients with episodic migraine)   
 
 
 
 
 
8.1.2 Discussion of study design 
 
 
Single-centre, randomized, sham-controlled double-blind study. 
 
The centre for this study is the clinical neurophysiology medical laboratory which is 
currently providing TMS treatment for migraine patients mainly from Hospital 
Serdang. A headache research clinic will be set up in this laboratory to cater the 
logistic for this clinical study. Investigators involved are UPM medical lecturers. 
Every PI and sub investigator involved have current GCP status. The RCT design 
will follow the CONSORT 2010 protocol. 
 
 
 
 
 
 

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CONSORT 2010 FLOW DIAGRAM 
 
 
 
Figure 2: Consort diagram for r-TMS clinical trial 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.1.3 Study population 
 
 
Patients with migraine in the community as well as staff and students of UPM 
attending community screening programme. 
 
Patients with migraine attending UPM primary care facilities (PKU) and private 
general practitioner (GP) clinics are also eligible for enrolment.  
 
In addition, this study will be advertised to the general public via formal and informal 
media. Interested subjects will be directed to the headache research clinic and will 
be recruited if they meet trial study criteria for clinical trial participants.  
 
The subjects will undergo pre-screening to identify whether or not they meet the 
inclusion and exclusion criteria before enrolment to the clinical trial. Consent forms 
will be prior to the screening result. If the subjects not meet the inclusion criteria, the 
subjects will be considered screening failures. 
 
8.1.3.1 Inclusion criteria 
 
1. Males or females aged 18 to 60 years of age. 
2. Subjects fulfilling criteria for migraine as per the Third Edition of The 
International Headache Society (ICHD-3) for at least 1 year. 
3. Frequency of migraine attacks 2-8 times per month with less than 15 
headache days per month for at least 3 months prior to screening. 
4. Demonstrated compliance with the headache diary during the run-in period by 
entry of headache data on a minimum of 24/30 days (80% compliance). 
5. A signed and dated informed consent document indicating that the subject 
has been informed of all pertinent aspects of the study including any known 
and potential risks and available alternative treatments. 
 
8.1.3.2 Exclusion criteria 
 
1. Patients with previous history of rTMS treatment. 
2. Onset of headache more than 50 years 
3. Headache with red flags symptoms that may suggest organic secondary 
headaches. 
4. Pregnant or lactating women 
5. Patients with contraindications to TMS such as metallic implant and 
pacemaker based on the Screening 13-item Questionnaire for rTMS 
candidate. 
6. Patients with medical conditions such as severe hypertension, infections, 
malignancy, cardiovascular and cerebrovascular diseases, epilepsy 
degenerative central nervous system diseases, renal failure, hepatic failure, 
bleeding diathesis and serious mental illnesses. 
 
8.1.3.3 Subject withdrawal & drop-out 
 
Subjects are free to withdraw from the study at any time for any reason. In consenting 
to the study, patients are consented to study follow-up and data collection. If voluntary 
withdrawal occurs, the patient should be asked to allow continuation of scheduled 

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evaluations and complete an end-of-study evaluation. Subjects may withdraw from the 
study or follow up at any time. Data already collected will still be used in the final 
analysis unless otherwise requested by the participant/consultee. Two written 
attempts and one phone call will be made to follow up patients before a patient is 
defined as lost to follow up. Methods to motivate compliance (check-ups, pamphlets, 
education) and monitor compliance will be used. 
 
Subjects may also be withdrawn from the study at any time at the discretion of the 
investigator based on these possible reasons: 
 
 
1. Adverse event(s) 
2. Protocol violation (e.g., incorrectly enrolled or randomised) 
3. Subject requires use of unacceptable concomitant medication 
4. Subject not compliant with protocol procedures 
5. Subject develops a condition during the study that violates the 
inclusion/exclusion criteria 
6. Lost to follow-up 
7. Death 
 
 
8.1.3.4 Procedures for handling withdrawal 
 
Patients who withdraw from the study for other reasons have previously consented to 
follow-up in the study. Data up to this time can be included in the study if anonymised. 
Subjects who withdraw or are withdrawn from the study should: 
 
1. Have the reason(s) for their withdrawal recorded 
2. Be asked about the presence of any AEs and if so should be followed up by 
regular scheduled visits, telephone contact, correspondence or home visits until 
satisfactory clinical resolution of AEs is achieved. 
3. Be seen by an investigator and all final assessments will be performed and 
recorded in the Termination page of CRF. 
4. Be encouraged to continue coming for regular visits and assessments 
5. Have at least one follow-up contact (scheduled visit, telephone contact, 
correspondence or home visit) for safety evaluation during the 30 days 
following the last administration of study treatment 
6. In the event of pregnancy, the subject should be monitored until conclusion of 
the pregnancy and the outcome of pregnancy reported. 
 
8.1.3.5 Dealing with drop-outs: 
 
Dealing with dropouts will be considered from the start during the calculation of 
sample size in addition to dealing with missing values using GEE. 
 
8.1.4 Enrolment 
 
Screening criteria  
 
a) Males or females 18 to 60 years of age suspected of migraine 
Patients will be screened from community screening programme when they have 
suspected migraine (see definitions). They will be allocated a screening number. 
They can be considered for inclusion in the study by the research study teams (on 

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clinical suspicion of migraine), or by self-diagnosis (based on the SMI criteria). Only 
episodic migraine with or without aura will be included. Chronic migraine will be 
excluded from this study. 
 
E.g.  
Screening point 1:  
A clinician identifies a patient that meets the inclusion criteria and refer patient to the 
headache research clinic.  
 
Screening point 2:  
A patient self-identified as probably having the diagnosis for migraine from the public 
adverts and self-referred to the headache research clinic. 
Enrolment should occur within the first screening visit if they fulfil the requirements. 
A screening register or log will be required at the site and reasons for non-inclusion 
will be listed in the screening log. Screening log will be kept at site. 
 
Screening failures 
 
Patients who fail to meet the inclusion and exclusion criteria are defined as screening 
failures. The investigator will maintain a Screening Log which includes screen failures. 
The log will document the subject number, subject initials, demographics and the 
reason(s) for excluding the patient from the study. This log will be kept in the 
Investigator's Study File.  
 
 
8.2 
 
Future Plan Study 
 
This genetic and biochemical study can be further explored by analysing candidate 
genes related to different metabolism, conducting exome sequencing, DNA 
methylation study and possible other genome-wide association study (GWAS) 
associated with loci region and traits.  
 
 
9 
TREATMENT AND STUDY PROCEDURES 
9.1 
 
Description of study intervention 
At baseline, all participants will have blood tested for CGRP, serotonin, and endorphin. 
Questionnaires will be administered to assess patient’s medical history, lifestyle, 
neuropsychological assessment and HRQOL. Patients will also undergo the EEG test. 
Patients then will be given headache diary to prospectively collect baseline information 
of the headache attacks and days during the 1-month run-in phase. 
 
After baseline (run-in) period, patients will be randomised into the active intervention 
r-TMS group and sham r-TMS group. For the active intervention, Repetitive TMS (r-
TMS) using Magstim Rapid-2 (Whiteland, Walsh, UK) with an air-cooled figure- eight 
coil of 7 cm diameter will be administered to the scalp of the patients from visit 1 to 8. 
A total of 5 sessions will be done in every day for three consecutive days per week in 
the first week and 2 consecutive days in 2nd week. Then patients will be followed up 

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at month 2, 3 and 4. The r-TMS treatment will be administered by a trained technician 
under the responsibility of the PI. 
 
TCD and EEG will be done on patient at month 1 and 4. The blood tests will be 
repeated at month 4 during follow-up phase. The neuropsychological and HRQOL 
assessment will be repeated at month 4. Patients are required to fill the headache 
diary monthly for 4 months. Patient satisfaction measures will be assessed at the 
completion of the study. 
 
9.2   
Comparator intervention 
 
The sham stimulation will be given in the same manner using a sham coil. The sham 
coil is a Magstim Rapid-2 (Whiteland, Walsh, UK), 70mm Double Air Film Sham Coil. 
Motor threshold measurement was not done in the sham stimulation group. The 
Magstim Air Film sham coil is identical in all but stimulation output. Patient assigned 
to sham coil will undergo similar procedures with the r-TMS coil. The sham treatment 
will be administered by a trained technician under the responsibility of the PI. 
 
9.3   
Dosage and administration 
 
The stimulator will be placed antero-posteriorly parallel to midline on the left 
dorsolateral prefrontal cortex (Brighina et al,2004) corresponding to the hot spot of the 
right abductor digiti minimi (7 cm lateral and 5 cm anterior to the inter- aural line). For 
stimulation, 80 % of the motor threshold was used. The motor threshold was 
determined at the hot spot of the right abductor digiti minimi as the minimum stimulus 
intensity able to elicit 5 or more motor-evoked potentials of 50 IV out of 10 consecutive 
stimuli. Each session of r-TMS consisted of 2000 pulses. The impulses will be given 
in 40 trains, each train duration is 5s consisting of 50 pulses at 20 Hz with intertrain 
interval of 25s. Adverse events during stimulation and follow-up will be monitored.  
 
 
 

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9.4   
Investigational product supply and handling 
 
9.4.1 Supply, packaging and labelling 
 
Each study coil will be labelled with the following information: 
 
1. Sponsor identification 
2. Manufacturer's identification 
3. Protocol number 
4. Caution statement 
5. 'For Clinical Trial Use Only' statement 
6. Investigational product identification (name/treatment no.) and batch number 
7. Storage conditions 
 
 
9.4.2 Storage 
 
The investigational product must be stored in accordance with the manufacturers' 
instructions. Required conditions for storage will be printed on the label.  
 
Investigational product should be kept under adequate security by the investigator and 
only accessible to authorised study personnel. 
 
9.4.3 Accountability 
 
The investigator or designee must maintain current and accurate record of the receipt, 
inventory and dispensing, including shipping invoices, of all study supplies. The 
Investigational Product Accountability Log must include: 
 
1. Date received 
2. Delivery order (D.O.#) reference number and amount received and placed     
in storage 
3. Name of study coil 
4. Amount currently in storage area 
5. Label ID number or batch number/Lot number 
6. Name and initial of person responsible for each investigational treatment 
 
7. Amount transferred to another area for storage 
8. Non-study disposition (e.g. Lost, wasted, broken) 
9. Amount returned to sponsor or JKEUPM 
10. Amount destroyed at study site 
 
9.5 
 
Concomitant treatment 
 
No concomitant treatment will be provided. Patient is allowed to take their acute 
abortive medicine for their acute migraine attacks. 
 
 
9.6 
 
Treatment allocation and randomization 
 
Patients’ randomisation is done by an independent statistician using a random number 
generating programme www.randomizer.org. into two groups (intervention and sham 
controlled group) using mixed block randomization technique at the ratio of 1:1 i.e. 

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group A and group B. The independent statistician will then code the active TMS coil 
and the sham coil into group A and group B.  
 
The written allocation of assignment for each participant with an identification number 
(code) was sealed in a brown opaque envelope.  This envelope will be opened by the 
researcher on recruitment of a participant. The key coding to the allocation will be 
revealed by the independent statistician at the completion of the study. The r-TMS and 
sham treatment will be administered by a trained technician under the responsibility 
of the PI. The sham r-TMS are an exact replication of the active r-TMS but with a 
different serial number. An independent statistician will label the active r-TMS and 
sham r-TMS as either treatment ‘A’ or treatment ‘B’.    
 
The participants are assigned to either an r-TMS intervention or a sham control arm 
in a parallel intervention mode. The principle of random allocation is employed to 
assign the participants to an intervention and a control arm. To achieve an unbiased 
comparison group and to have a balanced randomization, permuted block 
randomization with a varying block size is used for the study. The sample size 
estimated for the study is 76. Hence, there are ten blocks with a block size of four 
participants each and ten blocks with a block size of two participants each. One-to-
one allocation ratio is used. 
 
Random sequence generation is done with the help of a Research Randomizer, an 
online random number generator (Urbaniak & Plous, 2014). An external member, who 
is not directly involved in the study, generates the sequence. To have a strict 
implementation of the generated random sequence, the concealed allocation is 
achieved 
using 
sequentially 
numbered, 
opaque 
and 
sealed 
envelopes 
(SNOSEs). 
An 
aluminium 
foil 
is 
kept 
inside 
the 
envelope to prevent from possible chances of deciphering. An external member, who 
is not directly involved in the study, would prepare the SNOSEs. 
  
The final code is only known to the statistician and the document will be stored in a 
secure locked safe. The following information will be recorded during the 
randomization; study ID (assigned during the study initiation), investigator password 
(assigned during the initiation), subjects screening status, date of informed consent 
signed by subject, subject’s ID no (e.g. Last 4 digits of IC), upon successful 
randomization, the subjects will be assigned randomization number and treatment. 
Documents the subject’s ID no. and randomization no. on the Patient Enrolment Log 
and Patient Identification List. 
 
 
9.7 
 
Blinding & emergency unblinding procedures 
 
The participants and outcome assessor of the study is blinded about the allocation 
status of the participants. In the event that an AE or pregnancy occurs for which 
knowledge of the identity of the test drug is necessary to manage the subject's 
condition, the sealed emergency code key for that subject may be broken and the test 
drug identified by the medical monitor. The medical monitor will have a set of sealed 
emergency code keys (one for each subject) kept in a secured location and he/she 
will be accessible at all times by telephone. Should emergency unblinding be required, 
the investigator will call the medical monitor who will break the emergency code key 
for that subject, identify the test coil and inform the investigator. A detailed report with 
the date and reason for identifying the study drug will be prepared by the medical 
monitor and attached to the CRF. This report must be signed by the medical monitor 

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and the investigator. All unused sealed code keys will be accounted for at the end of 
the study. 
 
Except in the case of emergency, the treatment blind will be maintained until all 
subjects have completed the treatment and the database has been cleaned and 
locked. Any broken code will be clearly justified and explained by a comment on the 
case report form, along with the date on which the code was broken. 
 
 
9.8   
Baseline assessment and laboratory tests 
 
1. Social demographics 
2. Medical history and clinical examination 
3. Laboratory blood test (CGRP, Serotonin, CRP, B-Endorphins, Gene studies) 
4. Headache diary 
5. Lifestyle questionnaire (PSQI, IPAQ, FFQ) 
6. Neuropsychological assessment (ABNAS, DASS-21,) 
7. HRQOL assessment (MIDAS, MSQ, EQ-5D) 
8. Clinical neurophysiology assessment (EEG, TCD) 
 
 
9.9 
 
Primary Outcome Measure (Assessment of efficacy) 
 
1. Change from baseline in mean monthly migraine days. The mean monthly 
migraine days will be calculated using the monthly migraine days from each 
month of the double-blind treatment phase. [Time frame: 4 months after the 
first session of r-TMS]. 
 
9.10  Secondary Outcomes Measure 
1. Change from baseline in mean monthly migraine attacks. The mean monthly 
migraine attacks will be calculated using the monthly migraine attack from 
each of the month of the double-blind treatment phase. [Time frame: 4 months 
after the first session of r-TMS] 
2. Proportion of subjects with at least a 50% reduction from baseline in mean 
monthly migraine days. [Time Frame:  4 months after first session of r-TMS]. 
Change from baseline in mean monthly pain intensity of migraine attacks. The 
mean monthly pain intensity will be based on the record of the maximal pain 
intensity by means of a verbal scale (i.e. 0 =no headache; 1 = mild headache; 
2 = moderate headache; 3 = severe headache) prior to taking symptomatic 
medication. [ Time Frame: 4 months after first session of r-TMS] 
3. Frequency and severity of adverse events in response to r-TMS. [Time 
Frame:  4 months after first session of r-TMS]  
4. The DASS 21 score changes in migraine patients in response to r-TMS. [Time 
Frame: 4 months after first session of r-TMS]. Mean score changes from 
baseline for depression, anxiety and stress category.  
5. The MIDAS score changes in migraine patients in response to r-TMS. [Time 
Frame: 4 months after first session of r-TMS]. Mean score changes from 
baseline. 

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6. The MSQ score changes in migraine patients in response to r-TMS. [Time 
Frame:  4 months after first session of r-TMS]. Mean score changes from 
baseline. 
7. The EQ-5D score changes in migraine patients in response to r-TMS. [Time 
Frame: 4 months after the first session of r-TMS.  Mean score changes from 
baseline. 
8. The ABNAS score changes in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean score changes from baseline. 
9. The PSQI score changes in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean scores change from baseline. 
10. The FFQ score changes in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean score changes from baseline 
11. The IPAQ score change in migraine in response to r-TMS. [Time Frame: 4 
months after first session of r-TMS]. Mean score changes from baseline 
12. Transcranial Doppler (TCD) pattern changes in migraine patients in response 
to r-TMS. [Time Frame: Baseline and after treatment sessions (month 4).] Mean 
flow velocity (cm/s). 
13. Electroencephalography (EEG) pattern change in migraine patients in 
response to r-TMS. [Time Frame: Baseline and after treatment sessions (month 
4).] EEG pattern differences based on report. 
14. Serum serotonin level and DNA changes in migraine patients in response to r-
TMS. [Time Frame: Baseline and after treatment sessions (month 4)] Serum 
serotonin (ng/ml). 
15. Serum beta-endorphin level changes in migraine patients in response to r-TMS 
[Time Frame: Baseline and after treatment sessions (month 4)]. Serum beta-
endorphin (ng/ml). 
16. C-Reactive Protein (CRP) level changes in migraine patients in response to r-
TMS [ Time Frame: Baseline and after treatment sessions (month 4)] Serum 
CRP mg/dL 
17. Serum Calcitonin gene related peptide (CGRP) level and DNA changes in 
migraine patients in response to r-TMS. [Time Frame: Baseline and after 
treatment sessions (month 4)] Serum CGRP pg/mL 
18. Satisfaction measures of efficacy, tolerability, safety and expectations of r-TMS 
among the participants. A 5-point, Likert scale will be used to evaluate 
satisfaction with r-TMS in migraine prevention. [ Time Frame: 4 months after 
first session of r-TMS]  
  
 
 
 
 
 
 
 
 

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10 
ADVERSE EVENTS 
 
10.1  
Reporting SAE 
 
Information about all SAE will be recorded on the Serious Adverse Event Page of the 
CRF. All events documented in the SAE Form must be reported within 24 hours to the 
(JKEUPM)/sponsor by fax (see below for contact person and fax no.). The investigator 
should not wait to receive additional information to fully document the SAE before 
notifying (JKEUPM). A fax SAE form detailing relevant aspects of the SAE in question 
should follow telephone report of SAE. The investigator should also comply with the 
applicable regulatory requirements related to the reporting of unexpected serious drug 
reactions to the regulatory authorities. Where applicable, information from relevant 
medical records and autopsy reports should be obtained. 
 
Any death or congenital abnormality, if brought to the attention of the investigator 
within 6 months after cessation of study treatment, whether considered treatment 
related or not, should be reported to (JKEUPM). 
 
Study contact for reporting SAE: 
 
Name: Prof Madya Dr Wan Aliaa Wan Sulaiman 
Department: Medicine, Faculty of Medicine and Health Science, UPM 
Tel: 03-8946 6000  
Fax: 03-8609 2980 
E-mail: wanaliaa@upm.edu.my 
Mobile phone: +60134888405 
 
24-hour contact information for patients and their attending medical practitioners will 
be provided prior to study initiation. 
 
 
11 
STUDY CONDUCT 
 
11.1  
Study visits and procedures 
 
Any deviation from the study procedures described below will be noted in the 
CRFs and the sponsor and (JKEUPM) will be notified. 
 
 
11.1.1 Screening visit 
 
1. A pre-screening information sheet will be given to all potential subjects. 
2. A written informed consent for pre-screening will be obtained from subject. 
3. The following screening tests are one: pre-screening questionnaires to 
assess subject for eligibility to enter study according to the inclusion and 
exclusion criteria. In addition, a headache diary will be given to the 
patients to be completed during the run-in period. 
4. Women of child-bearing potential must declare that they are not pregnant 
and should be on reliable contraception methods. 
5. For subjects enrolled into the study, another informed consent will be 
obtained and relevant section/page of CRF will be completed. 

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6. Record all screened subjects in the Screening Log regardless of whether 
or not the subject has been enrolled in the study. 
 
If a patient is keen to participate, a pre-screening information sheet will be given and 
informed consent form will be obtained to assess eligibility. Once eligible, the subject 
will be given a patient information sheet (PIS). Informed consent will be taken after 
the patient has had time to read the PIS and ask any questions. Written consent will 
be taken by a member of the research team. 
 
The participant contact detail form, consent form and enrolment form will be filled in 
at site. The patient’s screening number will be used on all these forms. Once the 
enrolment form is received, a subject ID number will be allocated. Once the subject 
ID has been allocated the CRF can be completed.  
 
The clinical care of the patient will be under the direction of the responsible clinician 
and involvement in the study will not alter that.  
 
Two written attempts and one phone call will be made to follow up patients before a 
patient is defined as lost to follow up. 
 
11.1.1.1 Definitions 
Migraine without aura diagnostic criteria: 
A. At least five attacks fulfilling criteria B-D 
B. Headache attacks lasting 4-72 hr (untreated or unsuccessfully treated) 
C. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g., 
walking or climbing stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 
Migraine with aura diagnostic criteria: 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
 
C. At least three of the following six characteristics: 

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1. at least one aura symptom spreads gradually over ≥5 minutes 
2. two or more aura symptoms occur in succession 
3. each individual aura symptom lasts 5-60 minutes 
4. at least one aura symptom is unilateral 
5. at least one aura symptom is positive 
6. the aura is accompanied, or followed within 60 minutes, by headache 
 
D. Not better accounted for by another ICHD-3 diagnosis. 
11.1.2 Baseline visit 
 
At baseline, all participants will have blood tested for CGRP, serotonin, endorphin, 
CRP. Questionnaires will be administered to assess patient’s medical history, lifestyle, 
neuropsychological assessment and HRQOL. Patients will also undergo EEG test. 
Patients then will be given headache diary to prospectively collect baseline information 
of the headache attacks and days during the 1-month run-in phase. 
 
After baseline (run-in) period, patients will be randomised into the active intervention 
r-TMS group and sham r-TMS group. For the active intervention, Repetitive TMS (r-
TMS) using Magstim Rapid-2 (Whiteland, Walsh, UK) with an air-cooled figure- eight 
coil of 7 cm diameter will be administered to the scalp of the patients. A total of 5 
sessions will be done in every day for 3 consecutive days in 1st week and 2 
consecutive days in 2nd week. Then will be continued for follow-up at month 2, 3 and 
4.  
 
TCD and EEG will be done on patient at baseline and repeated at visit 10. The blood 
tests will be repeated at visit 10, after 4 months of the intervention. The 
neuropsychological and HRQOL assessment will be repeated at visit 10. Patients are 
required to fill the headache diary monthly for 5 months, from run-in period until 
completion of the study. Patient satisfaction to treatment will be assessed at the end 
of the study. 
 
The following data will be collected at baseline: 
 
1. Subject's demography: date of birth/age, gender, race, marital status, level of 
education and occupation. 
 
2. Background and medical history which includes the cause and trigger points of 
migraine, any diagnosed medical conditions within the previous 12 months, 
history of medication and medical procedures within the previous 30 days of 
entry into the study. 
 
3. Physical examination: 
a. Complete physical examination, performed by a licensed physician, will 
include examination of general appearance, skin, and neurological 
examination. 
b. Body weight (kg) and height (cm), no shoes in light clothing 
c. Body mass index (BMI) 
d. Waist circumference (cm) 
e. Neck circumference (cm) 

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4. Vital signs 
a. The following vital signs assessments will be performed: 
 Blood pressure and pulse rate. 
 
 
5. Questionnaires assessment 
The following self-administered questionnaires will be done:  
 
a. Monthly headache diary whereby the migraine attacks and days need to 
be recorded in the baseline rune in period. 
b. Lifestyle questionnaire will be adapted from a previously validated 
questionnaire on migraine patients (Nazari et. al. 2010) which consisted 
of 9 questions about current disease history and 59 questions about 
lifestyle factors including diet and eating habits, physical activities and 
exercise, rest and sleep, medication, smoking and stress which was 
rated using the Holmes and Rahe Stress Scale. The measurement scale 
used in the section on lifestyle for most of the questions was designed 
based on a Likert scale (always, sometimes, never). The scoring method 
varied according to the type of questions (dichotomous positive/negative 
questions) so that in positive questions, “always” or “yes” had the highest 
score while in negative questions “never” or “no” were the lowest. In the 
end, total scores were divided into 3 groups: not good, average, and 
good. 
c. ABNAS- Neuropsychological function will be assessed with the ABNAS 
(Aldenkamp and Baker Neuropsychological Assessment Schedule). 
This is a patient completed assessment of cognitive impairment and 
function based on everyday activities, that takes approximately 5 
minutes to complete (26). This has been used in epilepsy, meningitis 
and a range of other conditions with neuropsychological impairment, and 
has normative data available, but has not been used previously in 
migraine. 
d. DASS-21- The DASS-21 is a set of three self-report scales designed to 
measure the negative emotional states of depression, anxiety, and 
stress. The 21-item instrument asks respondents to rate the relevancy 
of each of the three negative affective states over the past week on a 
four-point scale ranging from: (0) not at all, (1) some of the time, (2) a 
good part of the time, and (3) most of the time. Scores range from 0 to 
21 in each of the three domains, and are then multiplied by two to 
produce a possible score of 0 to 42 in each of the three domains. 
Validated cut-offs were used to categorize DASS scores: minimal (score 
0–9), mild (score 10–13), moderate (score 14–20), and severe (score 
≥21) depressive symptoms on the DASS Depression subscale. The 
corresponding cut-offs for the DASS Anxiety subscale were minimal 
(score 0–7), mild (score 8–9), moderate (score 10–14), and severe 
(score ≥15). The corresponding cut-offs for the DASS Stress subscale 

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were minimal (score 0–14), mild (score 15–18), moderate (score 19–25), 
and severe (score ≥26).  
e. MIDAS- Disability induced by migraine can be measured with MIDAS 
questionnaires developed and validated in headache/ migraine patients 
with good psychometric properties. 
f. MSQ v.21- Among the migraine specific questionnaires, the most used 
were Migraine-Specific Quality-of-Life Questionnaire (MSQ). This 
disease-specific questionnaires are specifically designed to assess 
HRQOL associated with a single disease or treatment, and are more 
likely to be sensitive to changes after specific treatment interventions. 
g. EQ-5D- The EQ-5D will be used for expressing the health outcomes as 
cost per Quality Adjusted Life Years (QALY). Patients and carers will be 
asked to answer a socio-economic questionnaire to assess the costs 
incurred by them (non-medical direct costs, indirect costs, and 
accompany person costs). 
h. FFQ- Food Frequency Questionnaire will be used to measure dietary 
intake among the participants. Patients will be asked to complete a 
validated food frequency questionnaire to determine dietary pattern. 
There are 13 food type included in the questionnaire. 
i. PSQI- Pittsburgh Sleep Quality Index will be used to measure quality of 
sleep among migraine patient 
j. Patient satisfaction measures of efficacy, tolerability, safety and 
expectations of r-TMS among the participants. A 5-point, Likert scale (1= 
very dissatisfied, 2 = somewhat dissatisfied; 3 = neither satisfied nor 
dissatisfied, 4 = somewhat satisfied, 5 =very satisfied) will be used to 
evaluate satisfaction with r-TMS in migraine prevention.  
 
6. Laboratory evaluations 
i. The following laboratory evaluations will be done:  
1. Biochemical analysis 
2. Clinical neurophysiology test 
ii. Biochemical analysis will be done by the respective laboratory services 
such as PATHLAB for biochemical parameters. While genetic analysis will 
be done in Nutrition Lab and Molecular Lab, Faculty of Medicine and 
Health Sciences, UPM 
iii. Refer to Section 11.3 for instructions regarding collection and transport of 
samples. 
iv. Clinical neurophysiology test will be done by the member of the research 
team at the study site. The EEG and TCD machines are available at the 
study site which is the neurology lab of UPM. 
 
7. Complete relevant section/page of the CRF. 
 
 
11.1.3 Randomisation 
 
1. Complete the Randomization Sheet 
 
100 subjects randomized into blocks of 

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36 
 
4 6 6 6 6 6 4 4 4 4 4 4 6 6 6 4 4 6 6 4 
www.randomization.com To reproduce this plan, use the seed 8180 
along with the number of subjects per block/number of blocks and (case-   
sensitive) treatment labels as entered originally. Randomization plan created on 
24/07/2018, 07:17:38 
 
2. Description for randomization process 
 
Patients’ randomisation is by an independent statistician using a random number 
generating programme www.randomizer.org. into two groups (intervention and 
sham controlled group) using block randomization technique at the ratio of 1:1 i.e. 
group A and group B. The independent statistician will then code the active TMS 
coil and the sham coil into group A and group B. The sequence was concealed 
until interventions were assigned. 
 
The written allocation of assignment for each participant with an identification 
number (code) was sealed in a numbered brown opaque envelope.  This envelope 
will be opened by the researcher on recruitment of a participant. The key coding to 
the allocation will be revealed by the independent statistician at the completion of 
the study. The r-TMS and sham treatment will be administered by a trained 
technician under the responsibility of the PI. The sham r-TMS are an exact 
replication of the active r-TMS but with a different serial number. An independent 
statistician will label the active r-TMS and sham r-TMS as either treatment ‘A’ or 
treatment ‘B’.    
 
The participants are assigned to either an r-TMS intervention or a sham control 
arm in a parallel intervention mode. The principle of random allocation is employed 
to assign the participants to an intervention and a control arm. To achieve an 
unbiased comparison group and to have a balanced randomization, permuted 
block randomization with a varying block size is used for the study. The sample 
size estimated for the study is 76. Hence, there are ten blocks with a block size of 
four participants each and ten blocks with a block size of two participants each. 
One-to-one allocation ratio is used. 
 
Random sequence generation is done with the help of a Research Randomizer, 
an online random number generator (Urbaniak & Plous, 2014). An external 
member, who is not directly involved in the study, generates the sequence. To 
have a strict implementation of the generated random sequence, the concealed 
allocation 
is 
achieved 
using 
sequentially 
numbered, 
opaque 
and 
sealed envelopes (SNOSEs). An aluminium foil is kept inside the envelope to 
prevent from possible chances of deciphering. An external member, who is not 
directly involved in the study, would prepare the SNOSEs.  
 
The final code is only known to the statistician and the document will be stored in 
a secure locked safe. The following information will be recorded during the 
randomization; study ID (assigned during the study initiation), investigator 
password (assigned during the initiation), subjects screening status, date of 
informed consent signed by subject, subject’s ID no (e.g. Last 4 digits of IC), upon 
successful randomization, the subjects will be assigned randomization number and 
treatment. Documents the subject’s ID no. and randomization no. on the Patient 
Enrolment Log and Patient Identification List. 
 

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37 
 
3. The following information will be recorded during randomization: 
 
1) Study ID (assigned during study initiation) 
2) Investigator password (assigned during study initiation) 
3) Subject's screening status 
4) Date of informed consent signed by subject 
5) Subject's ID no. (e.g. Last 4 digits of IC) 
6) Upon successful randomization, the subject will be assigned a 
randomization number and treatment. Document the subject's ID no. 
and randomization no. on the Patient Enrolment Log and Patient 
Identification List. 
 
 
11.1.4 Study treatment and visits 
 
Study visits will occur from the first to the final month for efficacy and safety 
assessments for the total 4 months duration of the study.  The r-TMS will be 
administered on the first month. There will be a total of 8 visits.  
 
The investigator will perform the following procedures at each visit where applicable: 
 
1) Medical history taking 
2) Record any concomitant medication 
3) Record any change of dose administration of study treatment 
4) Perform physical examination including vital signs 
5) Administer questionnaires 
6) Obtain blood sample for lab evaluations 
7) Perform EEG or TCD test 
8) Record monthly headache diary  
9) Record any AE or SAE 
10) Complete relevant section/page of CRF 
11) Dispense study treatment 
 

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38 
 
11.1.5 Study visits schedule and procedures are summarised in the table 
below: 
 
 
Screenin
g& Run in 
period 1 
month 
(VISIT 1) 
VISIT 
2 
VISIT 
3 
VISIT 
4 
VISIT 
5 
VISIT 
6 
VISIT 
7 
VISIT 
8 
VISIT 
9 
VISIT 
10 
  
M0 
M1 
 
M1 
T1 
M1 
T2 
 
M1 
T3 
 
M1 
T4 
 
M1 
T5 
M2 
M3 
M4 
Check 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
X 
 
 
 
 
 
 
 
 
 
Patient   
demographic
s      Medical 
history 
Clinical 
examination 
 
X 
X 
X 
 
 
 
 
 
 
 
Questionnair
es 
X 
X 
 
 
 
 
 
 
 
X 
Randomisati
on 
 
 
X 
 
 
 
 
 
 
 
Lab. Test 
(Biochemical 
Analysis) 
 
 
X 
 
 
 
 
 
 
X 
Lab. Test 
(Genetic) 
X 
 
 
 
 
 
 
 
 
 
Efficacy 
assessment 
 
 
 
 
 
 
 
X 
X 
X 
Report AE and 
SAE 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
EEG 
 
 X 
  
  
  
  
 
 
 
X 
TCD 
 
X 
 
  
  
  
 
 
 
X 
Study 
treatment 
(rTMS) 
 
 
X 
X 
X 
X 
X 
 
 
 
Table 1 : Study visits and schedule. M= month, W=week and D=Day 
 
 
 
 
 

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39 
 
11.1.6 Assessment of efficacy 
 
Assessment of efficacy will be assessed repeatedly from month 1 to month 4 of the 
study. Patient will complete their monthly headache diary and will submit it during 
their visit 10 to be assessed. 
 
Table below shows the summary of the assessment of efficacy. 
 
 
Month 
1 
2 
3 
4 
Frequency of 
migraine attack 
 
 
 
 
 
Migraine Days 
 
 
 
 
 
Table 2: Effecticness of r-TMS treatment was assessed and summarised in the 
table. 
11.2  
Criteria for stopping subject treatment 
 
1. Severe and serious adverse event(s) 
2. Protocol violation (e.g. incorrectly enrolled or randomised) 
3. Subject requires use of unacceptable concomitant medication 
4. Subject not compliant with protocol procedures 
5. Subject develops a condition during the study that violates the 
inclusion/exclusion criteria 
6. Lost to follow-up 
7. Death
 
11.3  
Sample handling and analysis 
 
11.3.1 Collection 
 
11.3.2 Labelling 
 
1. The standard labels provided by central lab should be used to label each 
sample. 
2. Any hand-written additions to the labels should be made using indelible ink. 
3. Labels should not be attached to caps. 
 
11.3.3 Analyses 
 
 
# 
Test 
Method 
1 
Biochemical Analysis 
Elisa Kit, Collection of blood, Extraction 
of peptide from plasma,  
2 
 
 
 
TCD test 
 
 
 
An ultrasound probe will be used non-
invasively on the scalp to find the main 
cerebral blood vessels and blood flow 
velocities will be measured with a pulsed 

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40 
 
 
 
 
 
Doppler effect probe, which graphs 
velocities over time. 
 
3 
EEG Test 
A conventional scalp EEG, the recording 
is obtained by placing electrodes on the 
scalp with a conductive gel based on the 
International 10–20 system. 
 
 
 
12 
DATA MANAGEMENT 
 
Data management will be conducted using appropriate database and validation 
programmes. Accurate and reliable data collection will be assured by verification and 
cross-check of 100% of the CRFs against the investigator's records (source document 
verification). The data collected will be entered into a computer database and subject 
to quality assurance procedures as dictated by Standard Operating Procedures of 
Malaysian GCP. 
 
 
1. Data entry 
All the data will be recorded into the computer programs using the 
Microsoft Excel 2013 
2. Data validation and Data Query 
Data will be abstracted retrospectively from computerized medical records 
by a database query for the identified patients. These data will be 
validated and augmented by abstracting data from the patients’ paper 
records. 
3. Clean File and Database Lock 
The missing data will be managed by running standard data-cleaning 
reports, which identify missing values or missing records. Once all the data 
collected during the visits have been transferred and captured in the 
database, cleaning, reconciliation, and verification activities will be formed 
for smooth database lock.  
 
Relevant bodies such as JKEUPM and RMC UPM would also have access to the 
study data. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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41 
 
13 
STATISTICAL METHODS 
 
13.1  
Sample size and power considerations 
 
The number of patients to be involved in this study is calculated by using hypothesis 
testing method. The null hypothesis defined is that frequency of migraine (primary 
outcome) is not different among group with r-TMS treatment. Alternative hypothesis 
defined is that the frequency of migraine is different among group with r-TMS 
treatment.  
 
The sample size calculation is given below: 
 
n= 
2  𝜎²[z1-α/2 +z1-β]2 
    
 
  (µ1-µ2) ² 
Where; 
 
z1-α/2 =1.96 at 𝛼 =0.05  
z1-β =0.842 at 1-β = 0.80 
𝜎²=4.9 
n=29 
 
Title  
Power 
Number 
of 
groups 
Number 
of 
measurement
s 
Sample 
Size 
High-rate repetitive 
transcranial magnetic 
stimulation in migraine 
prophylaxis: a 
randomized, placebo-
controlled study 
0.8 
2 
4 
29/arm 
 
The satisfying figure of power test in biomedical researches statistics is 80%, while 
above 80 Statistical power will give good study design, therefore, the power test is 
80% has been selected in this study and significance level for rejecting a Null 
hypothesis is 5%. Therefore, the target number of participants per group is 29 with the 
total number of participants being 76 allowing 30% dropout rate to detect frequency 
between active treatment and sham.  
 
Characteristics of the patients in each of the groups at baseline will be compared 
using independent t-test or Mann Whitney test for numerical variables, depending on 
the normality test for the variable. Chi-square or Fisher's exact will be used to 
compare categorical variables between the groups. For primary and other outcome 
measures, treatment effects will be examined based on within group effect, between 
group effect and within-between group effect. Repeated measure Analysis of 
Covariance (ANCOVA) will be used for the analysis. Compliance with treatment in 
each group will between compared using independent t-test or Mann Whitney test 
depending on the normality of the data. Frequencies of adverse events will be 

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42 
 
compared using Chi-square or Fisher’s exact test. All analysis will be done at 
significance level 0.05. 
 
Assistance with analysis will be given by Dato’ Professor Dr Lye Mun San, Senior 
Lecturer in Public Health and Epidemiology. 
 
 
13.2  
Randomisation 
 
The participants are assigned to either an r-TMS intervention or a sham control arm 
in a parallel intervention mode. The principle of random allocation is employed to 
assign the participants to an intervention and a control arm. To achieve an unbiased 
comparison group and to have a balanced randomization, permuted block 
randomization with a varying block size is used for the study. The sample size 
estimated for the study is 76. Hence, there are ten blocks with a block size of four 
participants each and ten blocks with a block size of two participants each. One-to-
one allocation ratio is used. 
 
13.3  
Analyses 
 
13.3.1 Analyses Sets 
 
All randomised subjects will be included in the analysis. 
13.3.2 Baseline Comparability 
 
True randomisation, concealed location and adequate sample size planned for this 
study will ensure enough baseline comparability between groups (r-TMS and sham). 
Additionally, a table of baseline characteristics of participants in each group, without 
between-group statistical comparisons will be included. The study team will analyse 
this table to decide whether any characteristics were imbalanced enough to have 
influenced the outcomes of the study. 
 
13.3.3 Efficacy Analysis 
 
Analyses were performed on an intent-to-treat basis with the last observation carried 
forward.  The primary treatment comparisons of benefit include all eligible patients, 
regardless of the amount of TMS treatment sessions received. Both eligible and 
ineligible patients are included in the analyses and compared by treatment assignment 
when an intent-to-treat analysis is specifically indicated.  
 
13.3.4 Safety Analysis 
 
The summaries of adverse events include all patients who received any study 
treatment; those who did not receive study treatment are not included in these 
summaries. The safety population comprised all randomized patients who received 
at least one treatment dose and was based on the actual treatment received. 
 
 
13.3.5 Handling of missing, unused and spurious data 
 

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43 
 
All available data will be included in the data listings and tabulations. Where appropriate, 
imputations of values for missing data for primary and secondary efficacy analyses will 
be performed as specified in the Statistical Analysis Plan. All data recorded on the CRF 
will be included in the data listings that will accompany the clinical study report. 
Missing data will be described, for example, by presenting the number and percentage 
of individuals in the missing category and will be dealt with GEE.  No data will be 
considered spurious in the analysis since all data will be checked and cleaned before 
analysis 
 
13.3.7 Planned Interim Analysis 
 
There will be no interim analysis done in this study. 
 
 
14 
ADMINISTRATIVE MATTERS 
 
14.1  
Notification of regulatory authority(ies) 
 
All necessary arrangements for the registration and approval of this study with the 
responsible authorities and the disposition of the required data and document will be 
undertaken by the Principal Investigator. 
 
 
14.2  
Notification of primary care physician 
 
Investigators should ask patients if they wish for their general practitioner or primary 
care physician to be notified about their involvement in this study. This is so that if the 
patients need to see their own physician for any reason, the physician will be aware 
that they are taking a study drug, 
 
 
14.3  
Study initiation 
 
Investigators involved in this study must not enrol any patient prior to completion of a 
formal meeting conducted by the Clinical Research Associate of (JKEUPM). This 
meeting will include an inventory of study supplies, a detailed review of the protocol 
and CRF, training on study procedures and other procedures required of GCP. 
Investigators who are not GCP certified will undergo GCP training during the study. 
 
 
14.4  
Protocol deviation 
 
Any protocol deviation will be documented by the (JKEUPM) monitor with rectification 
as soon as possible. The investigator should be notified immediately. With the 
exception of emergency situations, no changes or deviations in the conduct of this 
protocol will be permitted without the prior approval from (JKEUPM). In the event of 
any emergency, the investigators will institute any medical procedures deemed 
appropriate. All such procedures must be promptly reported to (JKEUPM). 
 

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14.5  
Study documentation 
 
14.5.1 Essential documents 
 
These are documents that permit evaluation of the study and the quality of the data 
produced. The Essential Documents are: 
 
1. Signed protocol amendments 
2. Sample CRFs 
3. JKEUPM approval letter, including a dated list of JKEUPM membership 
and members' affiliation 
4. Informed consent form 
5. CV of investigator and co-investigator 
6. Correspondences with sponsor and (JKEUPM)  
7. Interim reports to JKEUPM 
8. Investigational product accountability and shipping records 
9. Site signature log 
10. Monitor visit log 
11. Other appropriate documents in accordance with GCP guidelines. 
 
The investigator will maintain an Investigators Study File. This file will be used to 
facilitate and ensure filing of all relevant and Essential Documents during and after the 
study. The investigator will be responsible for keeping the Investigator's Study File 
updated and ensuring that all required documents are filed. The file will be inspected 
during monitoring visits. 
 
 
14.5.2 Source documents 
 
These are original hospital records, clinical charts, subject screening checklist, original 
laboratory reports, memoranda, recorded data from automated instruments, 
transcriptions certified after verification as being accurate, microfiches, photographic 
negatives, microfilm, magnetic or electronic media, x-rays, subjects' files, and records 
kept at the pharmacy, at the laboratories and at medico-legal departments involved in 
the study. 
 
The investigator must maintain source documents for each patient in the study. All 
information on CRFs must be traceable to these source documents: 
 
1. Patient identification list 
2. Curriculum vitae 
3. Site signature/authorization log 
 
 
14.6  
Patient identification list/Enrolment log 
 
The investigator has to maintain a list of all enrolled patients containing the full 
name, date of birth, date of enrolment, and the randomization number. The
list must show an unequivocal study identification number. The list will be filed in the 
Investigator's Study File on site. 
 
 
 

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45 
 
14.7  
Curriculum vitae 
 
The investigator will provide curriculum vitae showing his/her experience in the area 
of the proposed study. These should be filed at (JKEUPM) as well as in the 
Investigator's Study File on site. 
 
14.8  
Site signature/authorization log 
 
The investigator must maintain a Signature Log to document signatures and initials of 
all staff authorized to make entries and/or corrections on CRFs and other study related 
records or documents. The log will be filed in the Investigator's Study File. 
 
14.9  
Retention of documents 
 
The investigator shall arrange for the retention of all study documents and records, 
including subject records, CRFs, drug inventory/accountability log, signed informed 
consent forms and the patient identification list for at least 3 years after completion or 
discontinuation of the study. 
 
If the investigator moves or retires, he/she must nominate someone in writing to be 
responsible for archiving. Archived data may be held in microfiche or electronic record, 
provided a backup exists and a hard copy can be obtained from it if required. 
 
If the investigator cannot guarantee this archiving requirement at the study site for any 
or all the documents, special arrangements must be made with the sponsor or 
(JKEUPM) to store these in a sealed container(s) outside of the site so that they can 
be returned sealed to the investigator in case of a regular audit. Where source 
documents are required for the continued care of the subject, appropriate copies 
should be made for storage outside of the site.
 
For the biospecimens, patients will be asked for informed consent for future study of 
the samples for other indications. A separate informed consent will be signed for 
patients who agree for the future biospecimens testing. Another ethical board approval 
will be obtained for any other test. Samples will be stored securely at the Universiti 
Putra Malaysia and will be destroyed after 5 years of storage. 
 
14.10 
Finance 
 
UPM Putra Grant from the Research Management Centre (RMC) UPM (Grant id: 
GPB/2017/9585500) will support the work of the investigator and supply the required 
investigational product for the study. 
 
14.11 
Study Termination and Site Closure 
 
The sponsor and (JKEUPM) reserve the right to terminate this study and remove all 
study materials from the study site at any time. Reasons that may require termination 
of the study include: 
 
1. It becomes apparent that patient enrolment is unsatisfactory with respect 
to quality or quantity. 
2. Date recording is inaccurate and/or incomplete 
3. Deliberate violation of the signed protocol 

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46 
 
4. The incidence and/or severity of adverse events in this or other studies 
indicate a potential health hazard caused by the treatments under trial. 
 
Should (JKEUPM) or the sponsor decide to terminate the study, the investigator will 
complete the CRFs as far as possible. The completed CRFs and any study material 
will then be collected by (JKEUPM). 
 
14.12 
Confidentially 
 
The investigator agrees that all information communicated to him/her is the exclusive 
property of the Sponsor or (JKEUPM), and ensure that the same will be kept strictly 
confidential by the investigator or any person connected with the work and shall not 
be disclosed to any third party without the prior written consent of the sponsor and 
(JKEUPM). 
14.13 
Anticipated subject accrual and duration of the study 
 
This study is expected to start in December 2018.The projected study timetable for 
the study is as follows: 
 
1. First patient enrolled is expected in January 2019 
2. Last patient enrolled is expected in December 2019 
3. The last patient enrolled is projected to complete the study period in April 
2020. 
 
These accrual rates are based on reasonable planning expectations. The 
investigator should however continually compare the actual and expected 
accrual rates, and make every effort to ensure that they are as closely matched 
as possible. If the investigator anticipates major problems with recruitment, or 
delay in the expected completion date, he/she should discuss this with the 
(JKEUPM) staff as early as possible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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