Clinical trial NCT02593097
Conditions: Migraine
Sponsor: Mayo Clinic
Start date: 2016-02-01; Completion date: 2019-06-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The investigators will evaluate the safety and efficacy of metformin for preventive treatment of migraine in a randomized, double-blind, placebo-controlled, crossover trial.

Detailed description:
This will be a single-center, double-blind, randomized, placebo-controlled, crossover study. The investigators will enroll 40 subjects. Subjects will be recruited from the outpatient Mayo Headache Clinic, Mayo Women's Health Clinic, Mayo Community Internal Medicine, and the Mayo Clinic- Arizona State University Neurology Clinic. The Headache Clinic employs 6 headache specialists and 1 fellow which is sufficient staffing to support this study and recruitment of patients with migraine.

Before study enrollment, patients will undergo a 2-hour oral glucose tolerance test to confirm the absence of diabetes mellitus.

Subjects will then keep a headache diary for 4 weeks to establish baseline characteristics, including number of migraine days per month, number of moderate to severe headache days per month, and number of days per month of acute medication use. The 4-week baseline period will be followed by 2 treatment periods of 12 weeks each, separated by a washout period of 4 weeks (total study duration, 32 weeks). For the 12-week treatment periods, subjects will receive either metformin 500mg twice daily or matching placebo twice daily.

Subjects will have 7 study visits. Routine laboratory studies and a pregnancy test will be performed at enrollment and week 20. Abnormal kidney or liver function will exclude subjects. Pregnancy will exclude subjects. General and neurologic examinations will be performed during 3 of the 7 visits. At each visit, subjects will receive medication for the period until the next visit. A headache diary will be used for the trial. For every day that the subject has a headache of any type, she or he will record headache characteristics, associated features, and medications used.

Arms: arm 1: Subjects will be randomized into the Metformin group, treated for 12 weeks with a 4 week washout period in between treatments, then treated with matching placebo for 12 weeks. arm 2: Subjects will be randomized into the matching placebo group, treated for 12 weeks with a 4 week washout period in between treatments, then treated with Metformin for 12 weeks.
Interventions: intervention 1: Metformin intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Metformin 500mg twice daily intervention 2: Matching Placebo twice daily

Protocol documents:
Prot_SAP_000.pdf: 
 
 
METFORMIN FOR THE 
PREVENTION OF MIGRAINE: A 
RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, 
CROSSOVER STUDY 
 
NCT02593097 
 
1/12/2017 


MPEM Study 
 
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Revised 01/12/2017 
METFORMIN FOR THE PREVENTION OF MIGRAINE: A RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, CROSSOVER STUDY 
 
 
 
 
 
 
 
 
Funding Sponsor: 
 
Migraine Research Foundation 
 
Study Product: 
Metformin 
 
 
 
 
 
 
 
 
 
Initial version: [01/12/2017] Version (4.0)  
 
 


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Table of Contents 
 
STUDY SUMMARY ..................................................................................................................... 5 
1 
INTRODUCTION................................................................................................................. 7 
1.1 BACKGROUND ...................................................................................................................... 7 
1.2 INVESTIGATIONAL AGENT ................................................................................................... 8 
1.3 PRECLINICAL DATA ............................................................................................................. 8 
1.4 CLINICAL DATA TO DATE .................................................................................................... 9 
1.5 DOSE RATIONALE AND RISK/BENEFITS................................................................................ 9 
2 
STUDY OBJECTIVES ......................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................. 10 
3.1 GENERAL DESIGN .............................................................................................................. 10 
3.2 PRIMARY STUDY ENDPOINTS ............................................................................................. 12 
3.3 SECONDARY STUDY ENDPOINTS ........................................................................................ 12 
3.4 PRIMARY SAFETY ENDPOINTS............................................................................................ 13 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL .............................. 13 
4.1 INCLUSION CRITERIA ......................................................................................................... 13 
4.2 EXCLUSION CRITERIA ........................................................................................................ 13 
4.3 SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................. 13 
4.4 EARLY WITHDRAWAL OF SUBJECTS .................................................................................. 14 
4.4.1 When and How to Withdraw Subjects ....................................................................... 14 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ......................................... 14 
5 
STUDY DRUG .................................................................................................................... 14 
5.1 DESCRIPTION ..................................................................................................................... 14 
5.2 TREATMENT REGIMEN ....................................................................................................... 14 
5.3 METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................... 15 
5.4 PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................... 15 
5.5 SUBJECT COMPLIANCE MONITORING ................................................................................. 15 
5.6 PRIOR AND CONCOMITANT THERAPY ................................................................................ 15 
5.7 PACKAGING ....................................................................................................................... 16 
5.8 MASKING/BLINDING OF STUDY ......................................................................................... 16 
5.9 RECEIVING, STORAGE, DISPENSING AND RETURN.............................................................. 16 
5.9.1 Receipt of Drug Supplies .......................................................................................... 16 
5.9.2 Storage ...................................................................................................................... 17 
5.9.3 Dispensing of Study Drug ......................................................................................... 17 
5.9.4 Return or Destruction of Study Drug ........................................................................ 17 
6 
STUDY PROCEDURES .................................................................................................... 17 
7 
STATISTICAL PLAN ........................................................................................................ 18 
7.1 SAMPLE SIZE DETERMINATION .......................................................................................... 18 
7.2 STATISTICAL METHODS ..................................................................................................... 18 


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7.3 SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................... 19 
8 
SAFETY AND ADVERSE EVENTS ................................................................................ 19 
8.1 DEFINITIONS ...................................................................................................................... 19 
8.2 RECORDING OF ADVERSE EVENTS ..................................................................................... 22 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................... 22 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB ......................................... 23 
8.4 UNMASKING/UNBLINDING PROCEDURES ........................................................................... 23 
8.5 STOPPING RULES ................................................................................................................ 24 
8.6 MEDICAL MONITORING ..................................................................................................... 24 
9 
DATA HANDLING AND RECORD KEEPING ............................................................. 24 
9.1 CONFIDENTIALITY ............................................................................................................. 24 
9.2 SOURCE DOCUMENTS ........................................................................................................ 25 
9.3 CASE REPORT FORMS ........................................................................................................ 25 
9.4 RECORDS RETENTION ........................................................................................................ 26 
10 STUDY MONITORING, AUDITING, AND INSPECTING ......................................... 26 
10.1 
STUDY MONITORING PLAN ............................................................................................ 26 
10.2 
AUDITING AND INSPECTING ........................................................................................... 27 
11 ETHICAL CONSIDERATIONS ....................................................................................... 27 
12 STUDY FINANCES............................................................................................................ 28 
12.1 
FUNDING SOURCE .......................................................................................................... 28 
13 PUBLICATION PLAN ...................................................................................................... 28 
14 REFERENCES .................................................................................................................... 28 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
 
 
 
 
 


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Study Summary 
Title 
Metformin for the Prevention of Migraine: A Randomized, Double-
Blind, Placebo-Controlled, Crossover Study 
Running Title 
MPEM 
Protocol Number 
 
Phase 
Clinical study phase II 
Methodology 
Randomized, double-blind, placebo-controlled, crossover design  
Overall Study 
Duration 
12 months 
Subject Participation 
Duration 
32 weeks 
Single or Multi-Site  
Single 
Objectives 
Metformin is a safe, well-tolerated AMPK activator that has 
demonstrated efficacy in preclinical animal models of migraine and 
chronic pain. The objective of the MPEM Study is to determine if 
metformin will reduce the number of migraine days per month in 
patients with high-frequency migraine. 
Number of Subjects 
40 
Diagnosis and Main 
Inclusion Criteria 
Age 18-65 years 
Diagnosis of migraine with or without aura according to the ICHD-IIIb 
(2013) 
5-25 migraine days per month 
Study Product, Dose, 
Route, Regimen 
Metformin 500mg twice daily orally x 11 weeks, the first week of each 
12 week treatment period, patients will receive metformin 250mg twice 
a day or matching placebo. At week 2, the dose will be increased to 
metformin 500mg twice a day or matching placebo. In case of 
intolerable side effects, the dose will be reduced to 250mg twice a day. 
 
Duration of 
Administration 
12 weeks 
Reference therapy 
Matching placebo 


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Statistical 
Methodology 
The primary end point is the number of migraine days per month during 
treatment with metformin vs placebo. The secondary end point is the 
percentage of patients with >50% reduction in migraine days per 
month (response rate). Mean 4-week migraine frequency for patients 
receiving metformin vs placebo treatment will be assessed by using the 
Hills-Armitage method. Response rate will be assessed by using the 
McNemar test. 
 
 
 


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1 
Introduction 
This is a clinical research protocol for a human research study. This document is a protocol for a 
human research study. This study will be carried out in accordance with the applicable United 
States government regulations and Mayo Clinic research policies and procedures.  
 
1.1 
Background 
Migraine is the third most prevalent disease in the world (Vos, 2012). Preventive treatment is 
indicated in about 40% of individuals with migraines. Although 4 treatments are FDA-approved 
for prevention of migraine, none were designed to prevent migraine, efficacy is modest, and all 
have significant adverse-event profiles. As a result, less than 1/3 of migraine sufferers with who 
are candidates for prevention receive drug treatment and of those who are treated, more than 
85% have discontinued the preventive drug within one year.   . Medications designed to prevent 
migraine by addressing disease pathophysiology likely will have improved efficacy and 
increased tolerability compared with currently available therapies. 
 
Migraine pain is associated with the activation and sensitization of peripheral meningeal 
nociceptors. As a result, approximately 75% of patients with migraine will have cephalic 
allodynia during an attack. mTORC1/MAPK are involved with the sensitization of nociceptors, 
resulting in chronic pain (Price, 2012). AMPK is a negative modulator of the mTORC1/MAPK 
pathways (Price, 2012) and therefore may be a novel target for the preventive treatment of 
migraine.  
 
Metformin is a widely available, safe drug used to treat diabetes mellitus; it also is a powerful 
activator of AMPK. Preclinical data demonstrates efficacy of metformin in animal models of 
migraine, suggesting that it blocks hyperalgesia and the transformation to chronic pain.   
 
Metformin has been studied in oncologic research as a novel anticancer drug for many types of 
cancers including prostate, breast, ovarian, and endometrial cancer. Many studies of metformin 
in nondiabetic patients with cancer have shown tolerability and lack of hypoglycemia at 
therapeutic doses up to 1,500 mg daily (Dilokthornsakul, 2013; Laskov, 2014). 
 


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Micromedex and prior studies as documented in the protocol, metformin alone does not cause 
hypoglycemia. 
 
 
Micromedex:  
             Hypoglycemia has not been reported at usual doses in monotherapy. Hypoglycemia may occur if 
             caloric intake is insufficient, if strenuous exercise occurs without adequate intake of calories, if 
             other glucose lowering agents are used concurrently, or in combination with ethanol use. 
 
We will instruct patients regarding eating well and not using any other glucose lowering agents or drink 
ethanol during the study. 
 
1.2 
We will educate patients on the symptoms of hypoglycemia including sweating, weakness, 
tachycardia, tremor, and feelings of nervousness and/or hunger. If they experience these 
symptoms, the patient can take 4 oz (120 mL) fruit juice; 6 ounces of non-diet soda; or a 
tablespoon (15 mL) of honey or table sugar. This process may be repeated in 10 to 15 minutes. If 
there is no improvement, they will be advised to seek immediate medical help. Investigational 
Agent 
Metformin is a widely available, safe drug used to treat diabetes mellitus; it also is a powerful 
activator of AMPK. Preclinical data demonstrates efficacy of metformin in animal models of 
migraine, suggesting that it blocks hyperalgesia and the transformation to chronic pain.   
 
Metformin has been studied in oncologic research as a novel anticancer drug for many types of 
cancers including prostate, breast, ovarian, and endometrial cancer. Many studies of metformin 
in nondiabetic patients with cancer have shown tolerability and lack of hypoglycemia at 
therapeutic doses up to 1,500 mg daily (Dilokthornsakul, 2013; Laskov, 2014). 
 
1.3 
Preclinical Data 
Preliminary experiments in the laboratories of Drs. Greg Dussor and Ted Price have shown that 
application of the proinflammatory cytokine interleukin-6 (IL-6) to the dura of rats produces 
allodynia that lasts for 24 hours and is resolved by 48 hours (Figure 1) (Yan, 2012). However, 
they remain sensitive to normally nonnoxious stimuli such as small changes in pH (here, the 
application of a pH 6.8 solution to the dura). As shown in Figure 1, only rats that received IL-6 
responded to subsequent pH 6.8 stimulation, even though they were all free from allodynia. This 
shows that an initial headache-like event in rats can prime the nociceptive system to subsequent, 


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normally subthreshold events. Mechanisms that mediate priming of the dural-afferent 
nociceptive system in rats may similarly sensitize the analogous system in humans and 
contribute to the pain of migraine. This could promote development of headaches in response to 
events that would be considered nonnoxious in those without headaches. Next, rats were given 
metformin (200 mg/kg, saline vehicle, administered intraperitoneally) the day before and the day 
of the IL-6 injection. Metformin administration attenuated the initial allodynia due to IL-6, but 
more importantly, it prevented development of the primed state (Figure 2). Rats treated with 
metformin did not have allodynia with pH 6.8 stimulation at the 72-hour time point. These data 
suggest that metformin treatment may have efficacy against individual headache attacks and that 
it may treat sensitization of the dural-afferent nociceptive system present between migraine 
attacks. 
 
1.4 
Clinical Data to Date 
This will be the first clinical data exploring the use of metformin in high-frequency migraine. 
 
1.5 
Dose Rationale and Risk/Benefits 
Metformin is a widely available, safe drug used to treat diabetes mellitus; it also is a powerful 
activator of AMPK. Preclinical data demonstrates efficacy of metformin in animal models of 
migraine, suggesting that it blocks hyperalgesia and the transformation to chronic pain.   
 
Metformin has been studied in oncologic research as a novel anticancer drug for many types of 
cancers including prostate, breast, ovarian, and endometrial cancer. Many studies of metformin 
in nondiabetic patients with cancer have shown tolerability and lack of hypoglycemia at 
therapeutic doses up to 1,500 mg daily (Dilokthornsakul, 2013; Laskov, 2014). 
 
2 
Study Objectives 
Study Objective 1: To compare the reduction in the number of migraine days per month during 
12 weeks of treatment with metformin vs placebo (primary end point). 
 
Hypothesis: Metformin treatment will significantly reduce the number of migraine days per 
month compared with placebo. 


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Study Objective 2: To compare the response rate (percentage of patients with a >50% reduction 
in migraine days per month) during 12 weeks of treatment with metformin vs placebo (secondary 
end point). 
 
Hypothesis: The response rate to metformin will be significantly greater than the response rate to 
placebo. 
 
Study Objective 3: To determine the safety and tolerability of metformin in patients with 
migraine. 
 
Hypothesis: Metformin treatment will be safe and well tolerated, with limited adverse effects. 
 
3 
Study Design 
3.1 
General Design 
We will obtain approval from the Mayo Clinic Institutional Review Board, and all patients will 
provide written, informed consent before study enrollment. 
 
This will be a single-center, double-blind, randomized, placebo-controlled, crossover study.  
 
After study enrollment, patients will be randomized to the Metformin study drug group or the 
placebo group.  The Principal Investigator or patient can’t choose the study group. The patient 
will have an equal chance of being assigned to the Metformin group. Neither the patient or the 
Principal Investigator will know which study group they are participating in.  In case of an 
emergency, this information will be available.   
 
 Patients will undergo a 2-hour oral glucose tolerance test to confirm the absence of diabetes 
mellitus. Subjects will then keep a paper headache diary for 4 weeks to establish baseline 
characteristics, including number of migraine days per month, number of moderate to severe 
headache days per month, and number of days per month of acute medication use. The 4-week 
baseline period will be followed by 2 treatment periods of 12 weeks each, separated by a 


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washout period of 4 weeks (total study duration, 32 weeks).  During the washout period, we will 
washout the study drug x 4 weeks.  
 
For the 12-week treatment periods, subjects will receive either metformin 500mg twice daily or 
matching placebo twice daily. During the first week of each 12 week treatment period, patients 
will receive metformin 250mg twice a day or matching placebo. At week 2, the dose will be 
increased to metformin 500mg twice a day or matching placebo. In case of intolerable side 
effects, the dose will be reduced to 250mg twice a day. 
 
Subjects will have 7 clinic visits. Routine laboratory studies and a pregnancy test will be 
performed at enrollment and week 20. Abnormal kidney or liver function will exclude subjects. 
Pregnancy will exclude subjects. General and neurologic examinations will be performed during 
2 of the 7 visits. At each visit, subjects will receive medication for the period until the next visit. 
A paper headache diary will be used for the trial. For every day that the subject has a headache of 
any type, she or he will record headache characteristics, associated features, and medications 
used. 
 
The Screening Visit, visit #1, week 0, will be 60 minutes.  During this visit, we will do some 
tests and procedures to confirm study subjects are eligible to take part in this research study such 
as: review medical history, physical exam, including height, weight, and “vital signs” (blood 
pressure, temperature, heart and breathing rates), draw a blood sample, 2 hour glucose tolerance 
test, urine pregnancy test, provide the study subject instructions for completion of the headache 
diary and provide headache diary. 
 
            Visit #2, week 4, will take about 30 minutes.  At this visit we will: review the headache 
diary and provide the participant with a new supply of study drug. 
 
Visit #3, week 10, will be a phone visit and will take about 15 minutes.  At this phone visit we 
will: Review the headache diary. 
 


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Visit #4, week 16, will take about 30 minutes.  At this visit we will: Review the headache diary 
and collect any unused study drug.  
 
Visit #5, week 20, will take about 30 minutes.  At this visit we will: review interim medical 
history, conduct a physical exam including height, weight, and “vital signs” (blood pressure, 
temperature, heart and breathing rates), collect blood sample, pregnancy test, review the 
headache diary and provide a new supply of study drug. 
 
            Visit #6, week 26, will be a phone visit and will take about 15 minutes to review the 
headache diary. 
 
Study Closeout Visit 
 
Visit #7, week 32, will take about 30 minutes.  At this visit we will: review and collect the 
headache diary, and collect any unused study drug. The primary end point is the number of 
migraine days per month during treatment with metformin vs placebo. The secondary end point 
is the percentage of patients with >50% reduction in migraine days per month (response rate). 
Adverse events will be recorded. Mean 4-week migraine frequency for patients receiving 
metformin vs placebo treatment will be assessed by using the Hills-Armitage method. Response 
rate will be assessed by using the McNemar test.  
 
The statistician will create Web-based case report forms using REDCap. Study coordinators will 
record data using REDCap forms. 
 
3.2 
Primary Study Endpoints 
The primary end point is the number of migraine days per month during treatment with 
metformin 500mg BID vs placebo for 12 weeks. 
 
3.3 
Secondary Study Endpoints 
The secondary end point is the percentage of patients with >50% reduction in migraine days per 
month (response rate). 


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3.4 
Primary Safety Endpoints 
To determine the safety and tolerability of metformin in patients with migraine. 
Hypothesis: Metformin treatment will be safe and well tolerated, with limited adverse effects. 
 
4 
Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
Inclusion criteria are as follows: 1) age 18-65 years, 2) a diagnosis of migraine with or without 
aura for >1 year according to the International Classification of Headache Disorders-IIIb (2013), 
and 3) 5-25 migraine days per month on average during the preceding 3 months. Women of 
reproductive ability must use a reliable form of contraception beginning 3 months before study 
enrollment, throughout the study, and for at least 1 month after study completion.  
 
4.2 
Exclusion Criteria 
Exclusion criteria are as follows: 1) a diagnosis of diabetes mellitus or polycystic ovarian 
syndrome, 2) overuse of acute migraine treatments, 3) failure to respond to 3 or more previous 
preventive drug treatments, 4) change in dose of migraine-preventive medication within 2 
months of beginning the baseline diary phase, 5) initiation of cranial nerve blocks within 2 
months of beginning the baseline diary phase,  6) initiation of Botox within 12 months of 
beginning the baseline diary phase, 7) significant somatic or psychiatric disease, 8) known 
alcohol or other substance abuse, and 9) pregnant or breastfeeding. 
 
4.3 
Subject Recruitment, Enrollment and Screening 
Subjects will be recruited from the outpatient Mayo Headache Clinic, Mayo Women’s Health 
Clinic, Mayo Community Internal Medicine, and the Mayo Clinic- Arizona State University 
Neurology Clinic. The Headache Clinic employs 6 headache specialists and 1 fellow which is 
sufficient staffing to support this proposal and recruitment of patients with high-frequency 
migraine within 6 months. 


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4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects may withdraw from the study prior to that subject completing all of the study related 
procedures for the following reasons: 
 Subject safety issues 
 Failure of subject to adhere to protocol requirements 
 Subject decision to withdraw from the study (withdrawal of consent) 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Even though a subject has withdrawn from the study, it may be important to collect some follow-
up or survival data on such subjects throughout the protocol defined follow-up period. Such data 
is important to the integrity of the final study analysis since early withdrawal could be related to 
the safety profile of the study drug.  If a subject withdraws consent to participate in the study, for 
subject safety reasons, we will make every effort to obtain permission to collect follow up 
information.  
 
5 
Study Drug  
5.1 
Description 
The study drug will be a tablet containing metformin 250mg or matching-placebo.  The first 
week of the 12 week treatment period a tablet containing metformin 250mg will be used or 
matching placebo, 1 tablet twice daily. After the first week, 2 tablets of metformin 250mg (total 
of metformin 500mg) or 2 tablets of matching placebo twice daily x 11 weeks.  
 
5.2 
Treatment Regimen 
The study drug will be a tablet containing metformin 250mg or matching-placebo.  The first 
week of the 12 week treatment period a tablet containing metformin 250mg will be used or 
matching –placebo, 1 tablet twice daily. After the first week, 2 tablets of metformin 250mg (total 
of metformin 500mg) or 2 tablets of matching placebo twice daily x 11 weeks.  


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 This will be followed by a 4 week washout period following which the patients will be crossed 
over to the other arm taking either of metformin or matching placebo x 12 weeks. The first week 
of the 12 week treatment period a tablet containing metformin 250mg will be used or matching –
placebo, 1 tablet twice daily. After the first week, 2 tablets of metformin 250mg (total of 
metformin 500mg) or 2 tablets of matching placebo twice daily x 11 weeks. 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
A statistician will create a randomized treatment allocation schedule by using a computerized 
random-number generator. The randomized treatment allocation schedule will be stored using 
the REDCap randomization module.  
 
5.4 
Preparation and Administration of Study Drug 
The Mayo Clinic Pharmacy will allocate patients to the metformin-placebo sequence or the 
placebo-metformin sequence in a 1:1 ratio. Study drug, both metformin and matching-placebo 
will be prepared and distributed to subjects. Pharmacy would not be blinded. 
The study drug will be stored and dispensed from the Research Pharmacy 
 
 
 
5.5 
Subject Compliance Monitoring 
Subject compliance with study drug regimen will be monitored during study visits. 
 
5.6 
Prior and Concomitant Therapy 
A list of all current medications will be recorded for all subjects including preventive headache 
medications and as needed headache medications. 
 
Subjects are allowed to use preventive headache medications during the study, however, there 
must have been no change within 2 months of beginning the baseline diary phase. In addition, 
subjects that have failed to respond to 3 or more previous preventive drug treatments will be 
excluded. 


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Subjects are allowed to use as needed headache medications for rescue treatment. However, 
subjects may not overuse these medications. Overuse is defined by the ICHD-3b criteria for 
medication overuse. 
 
5.7 
Packaging 
 The study drug and any comparator agent will be compounded into capsules 
 Bottles containing 336 capsules 
 Study drug will NOT be shipped.  
 The study drug or comparator will be labeled with drug name, Lot #, preparation date, 
quantity and statement 
 Study drug or comparator will be labeled "Caution: Existing Drug--Limited by Federal 
(or United States) law to investigational use." 
 
 
5.8 
Masking/Blinding of Study  
Patients will be allocated to the metformin-placebo sequence or the placebo-metformin sequence 
at random in a 1:1 ratio. The statistician will create the randomized treatment allocation schedule 
by using a computer random number generator. The randomized treatment allocation schedule 
will be concealed by storing it on the REDCap Randomization Module. The Mayo Clinic 
Pharmacy will allocate patients to treatments using the REDCap Randomization Module.  
 
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
The drug will be obtained or delivered from Cardinal Health or PCCA to the pharmacy at each 
investigative site. 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out by the person accepting the shipment.  It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipping 


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invoice. Any discrepancies, damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. The investigator must be notified immediately 
of any discrepancies, damaged or unusable products that are received. 
 
5.9.2 Storage 
No special handling requirements 
 
5.9.3 Dispensing of Study Drug 
The Mayo Clinic Pharmacy will allocate patients to the metformin-placebo sequence or the 
placebo-metformin sequence in a 1:1 ratio. 
 
Regular study drug reconciliation will be performed to document drug assigned, drug dispensed, 
drug returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, and signed and dated by the study team. 
 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
dispensed, drug returns, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be documented and 
investigated, prior to return or destruction of unused study drug.  Drug destroyed on site will be 
documented in the study files. 
 
6 
Study Procedures 
After study enrollment, patients will undergo a 2-hour oral glucose tolerance test to confirm the 
absence of diabetes mellitus. Subjects will then keep a headache diary for 4 weeks to establish 
baseline characteristics, including number of migraine days per month, number of moderate to 
severe headache days per month, and number of days per month of acute medication use. The 4-
week baseline period will be followed by 2 treatment periods of 12 weeks each, separated by a 
washout period of 4 weeks (total study duration, 32 weeks). For the 12-week treatment periods, 
subjects will receive either metformin 500mg twice daily or matching placebo twice daily. 


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During the first week of each 12 week treatment period, you will receive metformin 250mg twice 
a day or matching placebo. At week 2, the dose will be increased to metformin 500mg twice a 
day or matching placebo. In case of intolerable side effects, the dose will be reduced to 250mg 
twice a day. 
 
 
Subjects will have 7 clinic visits. Routine laboratory studies and a pregnancy test will be 
performed at enrollment and week 20. Abnormal kidney or liver function will exclude subjects. 
Pregnancy will exclude subjects. General and neurologic examinations will be performed during 
2 of the 7 visits. At each visit, subjects will receive medication for the period until the next visit. 
 
7 
Statistical Plan 
7.1 
Sample Size Determination 
This will be a single-center, double-blind, randomized, placebo-controlled, crossover study. 
Crossover designs have been used successfully in migraine trials (Olesen, 1981). Prior migraine 
trials have suggested that a sample size of 34 patients has 80% power to detect a mean reduction 
in migraine days of 1.25 days per month, with =0.05[Q1] (σ 2.5, ρ 0.5; Hauge, 2009; 
Silberstein, 2004; Sorensen, 1986). We will enroll 40 subjects to account for an estimated 15% 
dropout rate.  
 
7.2 
Statistical Methods 
The primary end point is the number of migraine days per month during treatment with 
metformin vs placebo. The secondary end point is the percentage of patients with >50% 
reduction in migraine days per month (response rate). Mean 4-week migraine frequency for 
patients receiving metformin vs placebo treatment will be assessed by using the Hills-Armitage 
method. Response rate will be assessed by using the McNemar test. The frequency of adverse 
events during metformin treatment will be compared to that during placebo treatment by using 
the McNemar test.  
 
                                                     
 


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Descriptive Statistics 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate for 
all variables.   
 
Handling of Missing Data 
Patients will be included in the primary analysis on the basis of intention to treat. Migraine 
frequency will be calculated using all available follow-up data and converted to units of 
frequency per four weeks. 
 
Multiplicity 
There is a single primary outcome measure. If the primary analysis is statistically significant, the 
secondary outcome measure will be assessed in order to facilitate interpretation of clinical 
importance.  
 
Interim Analysis 
There will be no interim analysis for early stopping due to efficacy.  
 
7.3 
Subject Population(s) for Analysis 
All-treated population:  Any subject randomized into the study that received at least one dose of 
study drug employing an intention-to-treat analysis. 
 
8 
Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
 Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
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publications, interim findings, product labeling change) that in the opinion of the local 
investigator may adversely affect the rights, safety, or welfare of the subjects or others, or 
substantially compromise the research data, AND 
 Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
 Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
 death 
 life threatening adverse experience 
 hospitalization 
 inpatient, new, or prolonged; disability/incapacity 
 persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
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Adverse Event Reporting Period 
For this study, the study treatment follow-up period is defined as 32 weeks following the 
initiation of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report, to the investigator, any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if active 
management necessary requiring a change of dosage, or dosing schedule, discontinuation of 
study treatment or additional follow-up. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
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this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported for 
diagnostic or elective surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs after the study period and is considered to 
be at least possibly related to the study treatment or study participation should be recorded and 
reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The investigator will evaluate the event and determine the necessary follow-up and 
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8.3.1 Investigator reporting: notifying the Mayo IRB 
The investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs according to 
the Mayo IRB Policy and Procedures. 
 
According to Mayo IRB Policy any serious adverse event (SAE) which the Principal Investigator 
has determined to be a UPIRTSO must be reported to the Mayo IRB as soon as possible but no 
later than 5 working days after the investigator first learns of the problem/event. 
 
Adverse events will be reported in an adverse event worksheet to be entered in the research 
database:  
 Subject’s name:  
 Medical record number:  
 Disease/histology (if applicable):  
 The date the adverse event occurred:  
 Description of the adverse event:  
 Relationship of the adverse event to the research (drug, procedure, or intervention):  
 If the adverse event was expected:  
 The severity of the adverse event: (use a table to define severity scale 1-5) 
 If any intervention was necessary:  
 Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
 Date of Resolution:  
 
The investigator will review all adverse event reports to determine if specific reports need to be 
made to the IRB and FDA.  The investigator will sign and date the adverse event report when it 
is reviewed.  For this protocol, only directly related SAEs/UPIRTSOs will be reported to the 
IRB. 
 
8.4 
Unmasking/Unblinding Procedures 
If unmasking/unblinding of the study drug is needed for subject safety, this will be performed. 
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placebo versus active drug. This will be documented in the research database. In most cases, the 
unmasking/unblinding will be part of managing an SAE, and will be reported with the SAE.  
However, in cases where unmasking/unblinding was not associated with an SAE, such actions 
should be reported in a timely manner.   
 
8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
9 
Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 


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9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
9.3 
Case Report Forms 
The statistician will create Web-based case report forms using REDCap. Study coordinators will 
record data using REDCap forms. The study case report form (CRF) is the primary data 
collection instrument for the study.  All data requested on the CRF must be recorded.   
 
Data Management 
The statistician will create Web-based case report forms using REDCap. Study coordinators will 
record data using REDCap forms. 
 
Data Processing 
The REDCap project will be hosted on the Mayo Clinic intranet. The study coordinators will 
record the data on the REDCap forms. The statistician will download the data from the REDCap 
server. 
 
Data Security and Confidentiality 
All study data will be collected by the research team, reviewed by the PI, and stored in secure, 
locked files and/or databases in order to protect it from inadvertent loss or improper access. All 
laboratory specimens, evaluation forms, reports, and other records will be identified by coded 
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linked to the subject's identity will not be released to anyone other than the investigators, the 
subject and the subject's physician. All the information obtained in connection with these studies 
will remain confidential as far as possible within state and federal law. The results of these 
studies will be published in scientific journals without identifying the subjects by name. 
 
Data Quality Assurance 
Source document verification will be performed to ensure that the database accurately reflects 
data on the CRFs.  
 
Data Clarification Process 
9.4 
Records Retention 
The investigator will maintain records and essential documents related to the conduct of the 
study.  These will include subject case histories and regulatory documents. There will be a 
subject code master list that will be stored so as to protect subjects’confidentiality. Case Report 
Forms will be coded. There will be no subject names or other directly identifiable information 
will not appear on any reports, publications, or other disclosures of clinical study outcomes. 
 
The investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717   
Whichever is longer 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 


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all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
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 IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
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12 Study Finances 
12.1 Funding Source 
This study is financed through a grant from the Migraine Research Foundation.  
 
13 Publication Plan 
The primary investigator, Amaal Starling, MD, holds the primary responsibility for publication 
of the result of the study. The trial will be registered on ClinicalTrial.gov prior to subject 
recruitment and enrollment. We will post the results of the study within 12 months of final data 
collection for the primary outcome.  
 
Link to protocol registration site for ClinicalTrials.gov:  https://register.clinicaltrials.gov/ . 
 
14 References 
1. Headache Classification Subcommittee of the International Headache Society. (2013) 
The 
international classification of headache disorders, 3rd edition (beta version). Cephalalgia, 
33(9):629-808. 
2. Dilokthornsakul et al. (2013) The effects of metformin on ovarian cancer: a systematic 
review. Int 
J Gynecologic Cancer, 23(9):1544-51. 
3. Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J. (2009) Effects of 
tonabersat on 
migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet 
Neurol 8(8):718-23. 
4. Laskov et al. (2014) Anti-diabetic disease of metformin decrease proliferation markers in 
tumors 
of patient with endometrial cancer. Gynelcolgic Oncology, 8:4C. 
5. Price TJ, Dussor G (2013). AMPK: An emerging target for modification of injury-
induced pain 
plasticity. Neuroscience Letters, S0304-3940(13), 607-1. 


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6. Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan, J, Lark A, Khoutorsky A, 
Johnson J, 
Peebles KA, Lepow T, Sonenberg N, Dussor G, Price TJ. (2011). Targeting adenosine 
monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential 
mechanism for the treatment of neuropathic pain. Molecular Pain, 7:70. 
7. Olesen et al. (1981) Methodological aspects of prophylactic drug trials in migraine. 
Cephalalgia,1:127-41. 
8. Silberstein et al. (2004) Topiramate in migraine prevention: results of a large controlled 
trial. Arch 
Neurol, 61:490-95. 
9. Sorensen et. al. (1986) A placebo-controlled, double-blind, cross-over trial of flunarizine 
in 
common migraine. Cephalalgia, 6:7-14. 
10. Vos et al. (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 disease and 
injuries 
1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 
380:2163-2196. 
11. Yan J, Melemedjian OK, Price TJ, Dussor G. (2012) Sensitization of dural afferents 
underlies 
migraine-related behavior following meningeal application of interleukin-6 (IL-6). Molecular 
Pain 
8:6. 
 
 
 
 
 
 
 
 
 


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