Clinical trial NCT04698525
Conditions: Migraine Headache
Keywords: Episodic MIgraine Memantine Valproate Efficacy Security MIDAS Prophylaxis
Sponsor: Universidad Autonoma de San Luis Potosí
Start date: 2019-02-15; Completion date: 2020-01-15
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Migraine is one of the three most disabling diseases worldwide. Constituted by recurrent episodes of headache, characterized by unilateral location, throbbing character, moderate or severe intensity, worsening with physical activity, and association with nausea or photophobia and/or phonophobia. There are two types of drug treatment: abortifacient and prophylactic. The American Academy of Neurology classifies sodium valproate as level A; however, some patients do not obtain a satisfactory response rate and/or have adverse effects. Therefore, the search for new pharmacological treatments continues. In 2015, a double-blind, randomized clinical trial with a placebo was carried out to assess Memantine's efficacy in the prophylactic treatment of migraine without aura, which reported a reduction of 2.3 migraine attacks per month compared to the placebo group. Memantine could be a new effective treatment alternative, which is why we will compare the efficacy of Memantine against sodium valproate as a prophylactic migraine treatment.

Main objective: To compare the efficacy of Memantine at a rate of 20mg divided into two doses a day against sodium valproate (VPA) at a rate of 1000mg divided into two doses a day prophylactic treatment of migraine for three months.

Study design: a prospective controlled, randomized, double-blind clinical trial. Inclusion criteria: Men and women aged 18 to 65 years with a diagnosis at least one year before the study must present at least 2 to 8 migraine attacks per month and less than 15 days with headache per month, which should not be receiving prophylactic treatment for migraine and sign an informed consent

Sample size calculation and statistical analysis:

It is calculated using the normal distribution model, where the recommended sample size is 196 participants. Since a pilot study will be conducted, 10% of the sample size will be taken to make it representative, a sample size of 20 participants is decided for each group.

Detailed description:
Migraine is a primary headache, currently one of the three most disabling diseases globally. It has an annual and lifetime prevalence of 18% and 33% in women, and 6 to 13% in men, respectively, with a predominance in women (3: 1). The age of onset with the highest prevalence is between 25 and 55 years.

Migraine is described by the International Headache Society (IHS) as recurrent episodes of headache lasting 4 to 72 hours, characterized by unilateral location, pulsatile character, moderate or severe intensity, worsening with physical activity, and association with nausea or photophobia and phonophobia. The IHS also classifies migraine based on the frequency of attacks: episodic migraine when the headache occurs on less than 15 days a month, and chronic migraine, when the headache occurs 15 or more days a month for three months and at least eight days a month with characteristics of migraine headache.

The subtypes of migraine concerning their clinical presentation are migraine with aura and without aura.4 Up to one-third of patients present migraine aura, with visual symptoms being the most frequent.

Four phases have been identified during a migraine: prodromal phase, aura, headache, and postdrome. The prodromal phase is characterized by premonitory symptoms hours before the headache, including difficulty concentrating, irritability, fatigue, repetitive yawning, stiff neck, and photophobia.

Recurrent episodes characterize the aura, lasting from 5min to 60min, with transient unilateral visual, sensory, or other CNS symptoms that develop progressively, usually precede headache and symptoms associated with migraine.4 The aura's genesis is activated by the NMDA (N-methyl-D-aspartate) receptor and disseminated cortical depression. Disseminated cortical depression is an extreme depolarization of the cell membranes of the glia and neurons that produce an alteration of the ionic gradient, an increase in extracellular potassium concentrations, glutamate release, and a transient increase followed by a decrease in cerebral blood flow.

The pain phase in migraine is due to the activation and sensitization of the trigeminovascular pain pathway, which innervates intracranial structures, including the eye, the dura mater, large braincases, and the venous sinuses. It has been shown to involve neuronal presynaptic activation by ID serotonin receptors (5-HT 1D), resulting in the release of the calcitonin gene (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP-38), which are neuroinflammatory peptides. The post-synaptic effect on the meninges includes the activation of the arachidonic acid cascade, which conditions inflammation and vasodilation, stimulates the nociceptive afference of pain first branch of the trigeminal nerve.

The diagnosis of migraine is clinical and must meet the criteria of the IHS International Classification of Headaches (ICH-3), which are for migraine without aura:

At least five crises that meet criteria B-D. A. Headache episodes are lasting 4 to 72 hours (untreated or unsuccessfully treated).

B. The headache has at least two of the following four characteristics:

1. Unilateral location.
2. Pulsatile character.
3. Pain of moderate or severe intensity.
4. Made worse by or conditions the abandonment of habitual physical activity (e.g., walking or climbing stairs).

C. At least one of the following during the headache:

1. Nausea and vomiting.
2. Photophobia and phonophobia. D. No better explanation by another diagnosis of ICHD-III.

The non-pharmacological treatment of migraine goes hand in hand with the pharmacological one; one is to avoid the triggers of the migraine attacks and carry out the lifestyle modifications. Pharmacological treatment is divided into acute (administered at the time of headache) and prophylactic (administered daily to reduce the chances of migraine episodes).

The objective of prophylactic treatment is to reduce the frequency, duration, and severity of migraine attacks, improve the response to acute treatment, improve functionality, and reduce disability.

The American Academy of Neurology recommends initiating prophylactic treatment in patients with migraine with one or more of the following characteristics9

1. Recurrent migraine, which interferes with the patient's daily life and quality of life.
2. Frequent headaches.
3. That they have an inadequate response or contraindication to abortive treatment.
4. Adverse events to abortion treatment.
5. Uncommon migraine conditions: ophthalmoplegic migraine, basilar migraine, hemiplegic, prolonged aura, migraine infarction.

The IHS defines the response to treatment as a decrease equal to or greater than 50% in the frequency of migraine attacks compared to the baseline situation.

The American Academy of Neurology guideline for the prophylactic drug treatment of episodic migraine classifies divalproex sodium, valproate sodium (VPA), topiramate, metoprolol propranolol as level A (Drugs with established efficacy ).

Valproic acid (2-propylpentaenoic acid) was first synthesized in 1882 as an analog of valeric acid, naturally found in valerian. Anyone of Valproic acid, sodium valproate, or a mixture of the two (sodium valproate) has a mechanism of action characterized by increasing or improving GABA neurotransmission, blocking voltage-gated sodium channels, and T-type calcium channels. In 2013, Cochrane conducted the review: Valproate for the prophylaxis of episodic migraine (Linda et al.), where they evaluated ten clinical trials. Two crossover clinical trials for sodium valproate demonstrated a significant reduction in headache frequency than placebo (MD -4.31 95% CI -8.32 to -0.30), which shows us in clinical terms an approximate reduction of four headaches for every 28 days. Jensen 199413 showed that sodium valproate is superior to placebo (OR 4.67; 95% CI 1.54 - 14.14), suggesting that patients are three times more likely to present a reduction equal to or greater than 50% in the frequency of headaches compared to placebo. The recommended dose for migraine headaches is 500-1000mg per day. The most common adverse effects are asthenia, fatigue, dizziness/vertigo, nausea, tremor, and weight gain.

In recent years, interest has increased in glutamate receptor antagonists for migraine prophylaxis, such as memantine. Within the pathophysiology of migraine, glutamate is implicated in disseminated cortical depression, trigeminal-vascular activation. Other studies corroborate its role by reporting elevated glutamate levels in the cerebrospinal fluid in patients with chronic migraine in the ictal period and elevated serum levels in migraine patients. Besides, after experimental stimulation in the dura and the ventral-posteromedial thalamic nucleus structures, elevated levels of glutamate in the trigeminal-cervical complex have been evidenced. fifteen

In 2008 Bigal and colleagues conducted the first open clinical trial, a pilot study to evaluate memantine's efficacy and safety as a prophylactic treatment in patients diagnosed with refractory migraine. A sample of 28 participants who had a baseline frequency of headache days of 21.8 days per month received memantine from 10mg to 20mg per day for three months. A decrease in the frequency of headache days was obtained to 16.1 (P \<0.01). Therefore, the authors concluded that memantine as a prophylactic treatment is safe and effective in refractory migraines. In 2015, Noruzzadeh and colleagues conducted the first randomized, double-blind, placebo-controlled clinical trial to evaluate memantine's efficacy as a prophylactic treatment of migraine without aura With a sample of 52 participants, 25 with memantine (10 mg/day) and 27 with placebo. The memantine group had a more significant reduction in the frequency of migraine attacks compared to placebo, which was a difference of 2.3 attacks per month with a P \<0.001.14

Arms: arm 1: This is a well know antiepileptic drug with efficacy as a preventive tic treatment in episodic migraine arm 2: This is a possible preventive treatment in episodic migraine
Interventions: intervention 1: Valproate Sodium intervention 2: Memantine
Intervention descriptions: intervention 1: Comparison between two actives intervention 2: Memantine

Protocol documents:
ICF_002.pdf: 
INFORMED CONSENT DOCUMENT FOR THE PATIENT 
CENTRAL HOSPITAL "DR. IGNACIO MORONES PRIETO" CENTRAL HOSPITAL 
NEUROLOGY DEPARTMENT    
ID:74-19 
NCT04698525 
Study Protocol document date: February 15, 2019; Statistical Analysis Plan 
document date: October 20, 2020; Informed Consent Form document date: 
February 5, 2019. 
 
 
  
 
 
 
 
ADULT PATIENT 
TITLE OF THE RESEARCH PROTOCOL 
"Efficacy of memantine compared with sodium valproate in the prophylactic treatment of 
migraine". The randomized controlled clinical trial" 
 
REGISTRATION NUMBER OF THE 
PROTOCOL AUTHORIZED BY THE 
RESEARCH 
 
ETHICS COMMITTEE PERIOD OF 
EXECUTION OF THE AUTHORIZED 
PROTOCOL 
____________ 
___/___/____ - ___/___/____ 
 
PRINCIPAL INVESTIGATOR AND PERSON 
IN CHARGE AT THE HOSPITAL  
 
ASSIGNMENT OF THE PRINCIPAL 
INVESTIGATOR 
Dr. Ildefonso Rodríguez Leyva 
 
Department of Neurology  
Internal Medicine Division  
Dr. Ignacio Morones Prieto" Central 
Hospital 
Autonomous University of San Luis Potosí  
Professional license 763163 
CO-INVESTIGATOR 
CO-INVESTIGATOR ASSIGNMENT 
Dra. Damaris Daniela Vazquez Guevara 
Neurology Department   
Internal Medicine Division  
Dr. Ignacio Morones Prieto" Central 
Hospital 
Autonomous University of San Luis Potosí 
Professional license 10045226 
 
DATE OF PRESENTATION OF 
INFORMED CONSENT 
 
 
PATIENT IDENTIFICATION NUMBER  
 
 
 
The Neurology Department of the Central Hospital, Dr Ignacio Morones Prieto, is 
conducting a research study to compare the efficacy of Memantine versus sodium 


valproate in the prophylactic treatment of Migraine.  This study will include 40 patients for 
three months, each participant, from July 08 to October 30. It will be conducted in the 
Outpatient Referral, Emergency Outpatient and Neurology services of the Central 
Hospital "Dr Ignacio Morones Prieto".  
 
Information for the patient 
Migraine is a neurological disease characterized by headaches with variable duration, 
usually located in the middle of the head. However, it can also be found in the forehead 
or the whole head. Most patients report that the pain is throbbing (like a heartbeat) and 
often accompanied by nausea, vomiting, discomfort, intolerance to light and noise. Some 
patients are warned of Migraine before the headache with particular symptoms such as 
blurred vision, flashes of light or stars, tunnel vision, known as aura.  
 
To know if your headache is a Migraine, you should be evaluated by a doctor, because 
migraine headaches are very intense, Migraine becomes incapacitating causing missed 
work, school or not being able to perform activities of daily living, is one of the reasons 
why you should go to a neurologist who will make the diagnosis and assess whether you 
are a candidate for treatment. The treatment of Migraine is divided into two types: acute, 
which is given at the time of the migraine attack, and prophylactic, which is given to 
prevent new migraine attacks and reduce their intensity. The complication of Migraine is 
that it becomes a chronic disease, which implies migraine attacks more than 15 days a 
month.  
 
You have been invited to participate in this study because you have been diagnosed with 
Migraine and are candidates for prophylactic treatment. In this research study, we will 
compare the efficacy of two types of treatment, one known as sodium valproate, already 
known as a treatment for Migraine and another that could be a new treatment for Migraine, 
which is Memantine.   
 
To realize this research, the participants who can be included will be separated into two 
randomized groups, and each group will have 20 participants. One group will receive 
sodium Valproate, and the other will receive Memantine. However, neither you nor the 
physician must know which pharmacological treatment you will be receiving for three 
months.  
 
Procedures the patient will undergo 
Your participation in this research study is entirely voluntary. If you agree to participate, 
we will ask you to read this informed consent document carefully and to ask all the 
necessary questions to the responsible research physician, Dr Ildefonso Rodriguez 
Leyva, so that he can resolve your doubts. When you no longer doubt what will be done 
in this study, we will ask you to sign your acceptance to participate at the end of this 
document. We will also ask you to provide us with general information such as your name, 
age, weight, height, and medical history; in an interview of approximately 45 minutes, Dr 
Damaris Daniela Vazquez Guevara will conduct the outpatient area of this hospital. So it 
will not be necessary to review your clinical record. At the end of this first medical 
assessment, you will be given a migraine diary to record your migraine attacks and their 


characteristics.  To keep your data anonymous, you will be assigned a code by which 
only the research physicians participating in this study will be able to know your identity. 
 
Medical evaluations will be performed every four weeks on five occasions at the 
Neurology outpatient clinic of the Central Hospital by Dr Damaris Daniela Vazquez 
Guevara. From the second visit, she will be asked again about the frequency of migraine 
attacks, if she tolerates the medication and possible adverse effects. In addition, at visits 
2, 3, and 4, the research team will provide you with the drug at no cost randomly assigned 
for four weeks, and at each visit, you will be given a new migraine diary which will be 
collected at the next visit. At all visits, you will be given a survey to assess the intensity of 
your migraine attack pain. While you are receiving the drugs, you will be monitored by the 
team for possible adverse effects. 
 
Dr Vazquez has explained to you in detail what your disease consists of and the 
importance of having a prophylactic treatment with the goal of decreasing the frequency 
of your migraine attacks.  
 
Benefits to the patient: 
You may benefit by having a favourable response to treatment and decreasing the 
frequency of migraine attacks. However, you will be collaborating with the research area 
of the Neurology Department of the Central Hospital, "Dr Ignacio Morones Prieto", and 
we will not know which medication you will be receiving.  This study is intended to evaluate 
a new prophylactic treatment for Migraine that seems to be well tolerated by patients.  
 
Benefits to society: 
This research study will help to evaluate a new drug for the prophylactic treatment of 
Migraine. Although there are already have medications indicated for Migraine sometimes, 
patients do not tolerate it or have no response, which is why this new drug is proposed.  
 
Potential risks for the patient: 
The potential risks involved in your participation are minimal as it is an interventional 
study. However, you may experience side effects from the drugs such as nausea, 
vomiting, weight gain, tremor, hair loss.  
 
However, in the remote case that you feel any other discomfort generated by the research 
drug, it is necessary to notify Dr Damaris Daniela Vazquez Guevara immediately. She will 
provide the necessary care, which will not create any cost to you.  
 
You should know that if you present a side effect or adverse reaction to the medications 
and require hospitalization or treatment, the principal investigator will cover the expenses.  
 
We must comment that you will not receive any payment for participating in the study. 
However, you will be given a copy of this informed consent document signed by the 
responsible investigators. 
 
Confidentiality: 


The personal and medical information obtained from you in this study is confidential and 
will be used only by the research team of this project to analyze and complement the 
results obtained and will not be available for any other purpose.  This information will be 
combined with that of other participants to carry out the present study. To maintain 
anonymity, you will be assigned a code for the use of your data.  
 
If you so choose, the investigators responsible for this study may inform your treating 
physician that you have agreed to participate in this study so that the information obtained 
may be included in your medical record. For this purpose, we will ask you to indicate 
whether or not you agree to the above at the end of this document. 
 
The results of this study may be published for scientific purposes in special journals 
directed to medical personnel, nurses, chemists and researchers related to the health 
area to make them aware of the possibility of a new prophylactic treatment for Migraine. 
The results of this study may also be presented at scientific meetings where new findings 
obtained from this and other studies related to the health and treatment of patients with 
the same diagnosis are discussed. The clinical data of all participants will be presented 
anonymously and in such a way that you or any of the patients participating in this study 
cannot be identified. 
 
According to the General Law of Protection of Personal Data in Possession of Obligated 
Subjects and the Law of Protection of Personal Data of the State of San Luis Potosi, your 
data may not be processed, transferred or used for purposes not expressly described in 
this document. For this reason, it is strictly necessary for the exercise and fulfilment of the 
powers and obligations expressly provided in the rules governing the actions of the 
researchers responsible for the study. Furthermore, it complies with a legal mandate; it is 
necessary for public safety, public order, public health or safeguarding the rights of third 
parties. 
 
For the use of your data or analysis or handling of your samples and results of the studies 
described in this document must be informed and requested with due justification to the 
Research Ethics Committee. This entity will determine the pertinence of the request and, 
if applicable, authorize a different use for your data, samples and products derived from 
your models and results. All processes will comply with national and international 
legislative guidelines and norms and benefit and protect the integrity of the participating 
actors. 
 
There are Mexican institutions or organizations such as the Ministry of Health, the Federal 
Commission for the Protection against Health Risks (COFEPRIS), the National Bioethics 
Commission (CONBIOETICA) or even the Research Ethics Committee (CEI) of this 
hospital, which are responsible for monitoring the proper handling of personal and 
medical data. Therefore, you and other patients have been authorized to be used in the 
conduct of research studies such as this one. Furthermore, these institutions or 
organizations may request from the researchers to review the procedures that are 
performed with your information and results. For example, those to verify that correct and 
ethical use of them; may have access to this information that has been previously 


assigned with an identification code when is required. 
 
Participation or withdrawal: 
Your participation in this study is voluntary. However, you have been invited to participate 
due to the characteristics of your disease, to be a candidate to receive prophylactic 
treatment for Migraine.   
 
You are free to refuse to participate in this research study, but if you decide to join at any 
time and without explanation, you may revoke or cancel the consent you now sign. Your 
decision whether or not to participate will in no way affect the medical treatment you 
receive at the institution for your illness. Suppose you decide to terminate your 
participation in this study. In that case, you must communicate it to Dr Damaris Daniela 
Vazquez Guevara. She will provide you with a straightforward document (format) in which 
you will put some of your data and indicate that you no longer wish to participate in the 
study. Again, your decision to participate or not will not affect in any way the medical 
treatment you receive in the institution for your disease.  
 
You will be given a copy of this informed consent form which includes the contact 
information of the person responsible for this study and the Research Ethics Committee 
of this hospital to clarify any doubts that may arise.  
 
Ethical Considerations: 
This study is considered higher than minimal risk as it is an interventional study. In 
addition, you will be randomized between 2 interventions because the investigators 
responsible for this study will be making decisions regarding your treatment for three 
months.  
 
We will not ask for your authorization to review your clinical record. Instead, we will only 
ask you some questions, as we have explained previously. 
 
You will be given a copy of this informed consent, signed by the responsible investigator, 
including their contact information and the contact information of the Research Ethics 
Committee of this hospital to clarify any doubts that may arise. 
Commitment to answer questions and doubts: 
To ask any question, doubt or clarification about this the study of the Double-Blind 
Randomized Clinical Trial to compare the efficacy of Memantine against Sodium 
Valproate in the prophylactic treatment of Migraine, or about any adverse reaction related 
to the medication that you are taking as treatment and that has been indicated by your 
treating physician, and you can contact: 
 
Dr. Ildefonso Rodriguez Leyva 
Department of Neurology   
Central Hospital "Dr. Ignacio Morones Prieto". 


Av. Venustiano Carranza 2395, Col. Zona Universitaria, San Luis Potosí, S.L.P., C.P. 
78290, Tel. 6643759438   
 
Dr. Damaris Daniela Vazquez Guevara 
Neurology Department   
Central Hospital "Dr. Ignacio Morones Prieto". 
Av. Venustiano Carranza 2395, Col. Zona Universitaria, San Luis Potosí, S.L.P., C.P. 
78290, Tel. 6643759438   
 
If you have any questions regarding your rights as a participant in the research study, you 
may also contact a person not involved with the research team of this study: 
 
Dr Emmanuel Rivera Lopez 
President of the Research Ethics Committee 
Central Hospital "Dr. Ignacio Morones Prieto", Venustiano Carranza Ave. 
Venustiano Carranza Av. 2395,  
Col. Zona Universitaria, San Luis Potosí, S.L.P., C.P. 78290,  
Tel (52-444) 8 34 27 01, Ext. 1710 
 
 
Acceptance of the Informed Consent Document 
If you wish to participate in this research voluntarily, please provide your name, signature 
and date of this document in the spaces provided below. Your signature means that you 
agree to the following: 
 
1. I have been given complete and adequate information verbally and in writing about the 
purpose of the study, have had it explained to me that the risks are more significant than 
minimal because it is an intervention study and the benefits of participating in clear 
language. 
2. I have been informed that I may withdraw my consent and terminate my participation 
in this study at any time without affecting my right to medical care. 
3. It is my responsibility to ask questions to clarify any points I do not understand regarding 
my participation in this study. I have asked all questions of the person conducting the 
consent process and have received satisfactory answers. 
4. I have not concealed or misrepresented any current medical condition or medical 
history related to my health. I have answered all questions regarding my health accurately 
and truthfully. 
5. I am of legal age and legally capable of giving this consent.  
6. I agree to participate in this study voluntarily without being pressured or coerced. I 
understand that my refusal to participate or discontinuation of participation at any time will 
not result in penalty or loss of benefits to which I am otherwise entitled. 


7. I understand and agree that the information obtained from the present study may be 
used to publish these results for academic purposes as part of scientific dissemination 
and in support of clinical practice. But that at all times, and we will be assigned code that 
will be used to maintain my anonymity and the confidentiality of my data. 
8. It has been explained to me that the personal and clinical information that I have 
consented to provide will preserve my privacy and will be used only for purposes arising 
from this study.  
9. The investigators participating in this project have agreed to provide me with updated 
information obtained during the study when I request it and give me a copy of this 
informed consent document. 
 
I, at this moment, agree to participate in the medical study entitled "Efficacy of memantine 
compared to sodium valproate in the prophylactic treatment of migraine". A randomized 
controlled clinical trial on a free and voluntary basis. 
 
Authorization for the use of clinical data 
 
You are asked to indicate your agreement or disagreement so that the investigators 
responsible for this project can use the clinical data anonymously to realize this research 
protocol. All the objectives and procedures have been explained to you, and that you 
have freely and voluntarily provided the; mark with an X your answer:  
 
____Yes, I give my authorization to the investigators participating in this project to use 
the clinical data that I have provided to them in the research that they have explained to 
me.  
 
____I do not give my permission to the investigators participating in this project to use the 
clinical data that I have provided to them in the research that they have explained to me.  
Authorization to inform my treating physician of my participation in this research study 
and include my results in my clinical record. 
 
You are requested to indicate your agreement or disagreement with the investigators 
responsible for this research study to inform your treating physician. Dr  
___________________________________________, 
that 
you 
have 
agreed 
to 
participate in this study with the registration number ___________ before the IRB of this 
hospital and for the results obtained from the measurements of blood flow in the arteries 
of your brain, which you have consented to be performed, to be included in your clinical 
record so that they can be used as a reference for your treatment by your treating 
physician. Please mark your answer with an X:  
 
____Yes, I give my authorization to the investigators to inform my treating physician of 
my participation in this research study and to have my results included in my file, following 
the above and as explained to me.  


____ I, at this moment, give my permission to the investigators to inform my treating 
physician of my participation in this research study and to include my results in my file, 
following the above and as explained to me. 
 
I, at this moment, agree to participate in the research study entitled "Efficacy of 
memantine compared to sodium valproate in the prophylactic treatment of migraine". A 
randomized controlled clinical trial in a free and voluntary manner. 
 
PATIENT'S NAME 
PATIENT'S SIGNATURE OF 
ACCEPTANCE 
 
 
 
 
 
DATE INFORMED CONSENT OBTAINED 
 
 
 
NAME OF LEGAL REPRESENTATIVE (if necessary) 
SIGNATURE 
OF 
ACCEPTANCE 
OF 
LEGAL REPRESENTATIVE 
 
 
 
 
DATE INFORMED CONSENT WAS OBTAINED 
RELATIONSHIP 
 
 
ADDRESS / CONTACT PHONE NUMBER 
 
 
 
 
NAME OF WITNESS 1 
SIGNATURE OF WITNESS 1 
 
 
 
 
DATE 
RELATIONSHIP 
 
 
ADDRESS / CONTACT PHONE NUMBER OF WITNESS 1 
 
 
 
 
 
NAME OF WITNESS 2 
SIGNATURE OF WITNESS 2 
 
 
 
 
DATE 
RELATIONSHIP 
 
 
ADDRESS / CONTACT TELEPHONE NUMBER OF WITNESS 2 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr. Ildefonso Rodríguez Leyva 
  
 
 
 
Dra. Damaris Daniela Vazquez 
Guevara 
PRINCIPAL INVESTIGATOR AND 
RESPONSIBLE 
OF THE RESEARCH PROTOCOL 
Department of Neurology  
Universidad Autonoma de San Luis Potosí  
PROFESSIONAL LICENSE 763163  
 
CO-INVESTIGATOR 
Department of Neurology 
Universidad Autónoma de San Luis Potosí  
CÉDULA PROFESIONAL 10045226 
 
 
 
 
 
Dr. Damaris Daniela Vazquez Guevara 
(name and signature of the person obtaining the 
informed consent) 
INVESTIGATOR PARTICIPATING IN THE 
PROTOCOL 

Prot_003.pdf: 
"Efficacy of memantine compared with sodium valproate in the prophylactic 
treatment of migraine" Randomized controlled clinical trial. 
 
NEUROLOGY DEPARTMENT 
ID:74-19 
NCT04698525 
Study Protocol document date: February 15, 2019; Statistical Analysis Plan 
document date: January 15, 2020; Informed Consent Form document date: 
February 5, 2019. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
1 
                                                    
 
 
 
SAN LUIS POTOSÍ AUTONOMOUS UNIVERSITY 
 
MEDICAL SCHOOL 
 
CENTRAL HOSPITAL "DR. IGNACIO MORONES PRIETO" CENTRAL HOSPITAL 
 
 
 
 
 
Thesis to obtain the diploma in the specialty of Neurology. 
"Efficacy of memantine compared with sodium valproate in the prophylactic 
treatment of migraine" Randomized controlled clinical trial. 
 
 
 
 
Damaris Daniela Vazquez Guevara  
 
 
 
 
ASSESOR 
Dr. Ildefonso Rodríguez Leyva 
 
 
CO - CONSULTANTS 
Dr. Alejandro Orozco Narváez   
Juan Manuel Shiguetomi Medina, M.D. 
 
 
 
 
 
 
San Luis Potosí January 15, 2020 
 
 
 


 
2 
 
SUMMARY 
 
Objectives 
To compare the efficacy of Memantine versus sodium Valproate as a prophylactic 
treatment of episodic migraine for three months. Evaluating efficacy (measured in 
reduction in the number of migraine attacks per month) and safety (measured in 
frequency and severity of adverse events), as well as response rate. 
 
Subjects and methods 
The prospective, randomized, double-blind, controlled clinical trial was conducted 
with patients who attended the outpatient clinic, either by referral or by the 
Emergency Department of the Neurology Service of the Central Hospital. 
Participants were randomized into two groups, the Memantine group received doses 
of 10 mg twice a day and the Sodium Valproate group received 500 mg twice a day, 
both groups for 3 months.   
 
Results 
A total of 33 patients were included in the study, 27 of them concluded the study; 14 
in the Memantine group and 13 in the Sodium Valproate group. The Memantine 
group with mean number of migraine attacks per month prior to treatment of 5.31 
(SD + 1.54) and after three months of treatment, mean number of migraine attacks 
per month 0.93 (SD + 1.49) with a decrease of 4.21 (SD+1.76) migraine attacks p 
<<0.001. In the VPA group the mean number of migraine attacks before treatment 
was 5.35 (SD + 1.11) migraine attacks per month and after three months of treatment 
the mean number of migraine attacks per month was 0.77 (SD + 1.16), with a 
decrease of 4.5 (SD + 1.39) migraine attacks p <<0.001. All 27 patients had a good 
response rate. Adverse effects were infrequent in both groups and of minimal 
severity. 
 
Conclusions 
Memantine could be a new prophylactic treatment option in migraine, the study 
showed that there was no inferiority of Memantine compared to sodium Valproate 
as a prophylactic treatment for episodic migraine. 
   
 
 
 
 
 
 
 
 
 
 
 


 
3 
 
 
 
INDEX 
         Page 
Summary ........................................................................................ 3 
 
Index ............................................................................................. 4 
 
List of tables ............................................................................... 6 
 
List of figures ................................................................................. 7 
 
List of abbreviations ......................................................................... 8 
 
List of definitions ........................................................................... 9 
 
Dedications .................................................................................... 10 
 
Background .................................................................................... 11 
 
Justification .................................................................................... 15 
 
Hypothesis ........................................................................................ 16 
 
Objectives ........................................................................................ 16 
 
Subjects and methods ............................................................................ 17 
 
Statistical analysis ............................................................................ 20 
 
Ethics .............................................................................................. 20 
 
Results ..................................................................................... 21 
 
Discussion ....................................................................................... 25 
 
Limitations ........................................................ ............................ 26 
 
Conclusions .................................................................................. 26 
 
Bibliography .....................................................................................   27 
 
Annex 1 (Informed consent) ................................................ 29 
 
Annex 2 ( Inclusion and exclusion criteria ) ........................................ 39 


 
4 
 
Annex 3 (Migraine diary) ............................................................... 40 
 
 
Annex 4 ( MIDAS ) ........................................................................... 41 
 
Annex 5 (Medicine donation letter) ...................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
5 
 
 
LIST OF TABLES 
 
         
Page 
Table 1. (Baseline characteristics of both groups. ) .............................. 20 
 
Table 2. ( Side effects ) ......................................................... 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
6 
 
 
LIST OF FIGURES  
         
Page 
Figure 1. (Frequency of migraine attacks in the Memantine group) ......... 21 
 
Figure 2. (Frequency of migraine attacks in the sodium valproate group). 22 
 
Figure 3. (Frequency of migraine attacks pre- and post-treatment in both groups) 
......................................................................................................... 23 
 
Figure 4. (Days with migraine pre- and post-treatment in both groups) .............. 23 
 
Figure 5. (MIDAS pre- and post-treatment in both groups) ............................ 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
7 
 
 
LIST OF ABBREVIATIONS AND SYMBOLS 
 
 
- 
IHS: International Headache Society 
 
- 
NMDA: (N-methyl-D-aspartate)   
 
- 
5-HT 1D: Serotonin I ReceptorsD 
 
- 
CGRP: Calcitonin gene 
 
- 
PACAP-38: Pituitary adenylate cyclase activating polypeptide. 
 
- 
ICHD-III: III edition of the International Classification of Headaches  
 
- 
AAN: American Academy of Neurology 
 
- 
VPA: Sodium Valproate  
 
- 
GABA - γ-aminobutyric acid 
 
- 
MIDAS: Migraine Disability Assessment 
 
- 
VAS: visual analog scale 
 
 
 
 
 
 
 
 
 


 
8 
 
LIST OF DEFINITIONS 
 
 
- 
Episodic migraine: the presence of migraine < 14 days per month.   
 
- 
Prophylactic treatment of migraine: preventive treatment of migraine 
attacks with the purpose of reducing the frequency, intensity and 
duration of migraine attacks. 
 
- 
Frequency of migraine attacks: the number of migraine attacks during 
the month.  
 
- 
Treatment response rate: a decrease equal to or greater than 50% in 
the frequency of days with migraine compared to baseline. 
 
- 
Migraine disability: defined numerically according to the MIDAS 
(Migraine Disability Assessment) survey, (where 0-5=no disability, 6-10 
points mild disability, 11-20 points moderate disability, and >21=severe 
disability).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
9 
 
DEDICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
10 
 
BACKGROUND 
 
Migraine is a primary headache, currently one of the three most disabling diseases 
worldwide. 1 It has an annual and lifetime prevalence of 18% and 33% in women, 
and 6 to 13% in men respectively, with a predominance in women (3:1). 2 The age 
of onset with the highest prevalence is 25 to 55 years 3 
  
Migraine is described by the International Headache Society (IHS) as recurrent 
episodes of headache lasting from 4 to 72 hours, characterized by: unilateral 
localization, pulsating character, moderate or severe intensity, worsening with 
physical activity and association with nausea or photophobia and/or phonophobia.  
The IHS also classifies migraine according to the frequency of attacks: episodic 
migraine when the headache occurs less than 15 days a month, and chronic 
migraine, when the headache occurs 15 or more days a month for three months, 
and for at least 8 days a month with migraine headache characteristics. 4 
 
The subtypes of migraine with respect to its clinical presentation are: migraine with 
aura and without aura.4 Up to one third of migraine patients present with aura, with 
visual symptoms being the most frequent.5 
 
Four phases have been identified during migraine: prodromal phase, aura, 
headache, and postdrome.  The prodromal phase is characterized by premonitory 
symptoms hours before the headache, including difficulty concentrating, irritability, 
fatigue, repetitive yawning, neck stiffness and photophobia. 6 
 
Aura is characterized by recurrent episodes, lasting from 5 minutes to 60 minutes, 
with unilateral transient visual, sensory or other central nervous system symptoms, 
which develop progressively, usually preceding headache and migraine-associated 
symptoms.4 The genesis of aura is NMDA (N-methyl-D-aspartate) receptor 
activation and disseminated cortical depression. Disseminated cortical depression is 
an extreme depolarization of the cell membranes of glia and neurons that produces 
alteration of the ionic gradient, an increase in extracellular potassium concentrations, 
glutamate release, and a transient increase followed by a decrease in cerebral blood 
flow.6 
 
The pain phase of migraine is due to activation and sensitization of the 
trigeminovascular pain pathway which innervates intracranial structures, including 
the eye, dura mater, large brain cases and venous sinuses. It has been shown that 
it involves neuronal presynaptic activation by serotonin I receptorsD (5-HT 1D) 
results in the release of calcitonin gene (CGRP) and pituitary adenylate cyclase-
activating polypeptide (PACAP-38), which are neuroinflammatory peptides. The post 
synaptic effect on the meninges includes the activation of the arachidonic acid 
cascade which conditions inflammation and vasodilatation, stimulates nociceptive 
pain afferent to the first branch of the trigeminal nerve. 7 
 


 
11 
The diagnosis of migraine is clinical and must meet the criteria of the III edition of 
the International Classification of Headache Disorders (ICHD-III), which are for 
migraine without aura:  
At least five crises that meet criteria B-D.  
A. Headache episodes lasting 4 to 72 hours (untreated or unsuccessfully 
treated).  
B. The headache has at least two of the following four characteristics:  
1. Unilateral localization.  
2. Pulsatile character.  
3. Pain of moderate or severe intensity.  
4. Worsened by or conditioned by the abandonment of habitual physical 
activity  
(e.g., walking or climbing stairs).  
C. At least one of the following during headache:  
1. Nausea and/or vomiting.  
2. Photophobia and phonophobia.  
D. Without better explanation by another diagnosis of ICHD-III.  
 
Non-pharmacological treatment of migraine goes hand in hand with pharmacological 
treatment, one of which is to avoid the factors that trigger migraine attacks, and to 
make the respective lifestyle modifications. Pharmacological treatment is divided 
into abortive (that which is administered at the time of the headache) and 
prophylactic (that which is administered daily to reduce the probability of migraine 
episodes). 8 
 
The aim of prophylactic treatment is to reduce the frequency, duration and intensity 
of migraine attacks, improve response to acute treatment, improve functionality and 
reduce disability.9 
 
The American Academy of Neurology (AAN) recommends initiating prophylactic 
treatment in migraine patients with one or more of the following characteristics9 
1. Recurrent migraine, which interferes with the patient's activities of daily living 
and quality of life. 
2. Frequent headaches. 
3. Who have an inadequate response or contraindication to abortive treatment. 
4. Adverse events to abortive treatment. 
5. Infrequent migraine conditions: Ophthalmoplegic migraine, basilar migraine, 
hemiplegic, prolonged aura, migraine infarction. 
 
The IHS defines response to treatment as a decrease equal to or greater than 50% 
in 
the 
frequency 
of 
migraine 
days 
compared 
to 
baseline.10 
 
The American Academy of Neurology guideline for the prophylactic pharmacological 
treatment of episodic migraine classifies divalproate sodium, valproate sodium 
(VPA), topiramate, metoprolol and propranolol in level A (Drugs with established 
efficacy). 11 
 


 
12 
Valproic acid (2-propylpentanoic acid) was first synthesized in 1882 as an analog of 
valeric acid, which is naturally found in valerian. Valproic acid, sodium valproate or 
a mixture of the two (sodium divalproate), with mechanism of action characterized 
by increasing or enhancing γ-aminobutyric acid (GABA) neurotransmission, 
blockade of voltage-dependent sodium channels and T-type calcium channels.12 In 
2013 Cochrane conducted the review: Valproate for episodic migraine prophylaxis 
(Lindae et al)12 where they evaluated 10 clinical trials. Two crossover clinical trials 
for sodium Valproate demonstrated a significant reduction in headache frequency 
compared to placebo (MD -4.31 95% CI -8.32 to -0.30) which shows us in clinical 
terms an approximate reduction of four headaches per 28 days. The Jensen 1994 
study13 showed that sodium valproate is superior to placebo (OR 4.67; 95% CI 1.54 
- 14.14), suggesting that patients are three times more likely to have a reduction 
equal to or greater than 50% in the frequency of headaches compared to placebo.13 
The recommended dose for migraine is 500 to 1000 mg per day.11 The most frequent 
adverse effects are: asthenia, fatigue, dizziness/vertigo, nausea, tremor and weight 
gain. 12 
 
In recent years, there has been an increased interest in the use of glutamate receptor 
antagonists 
for 
migraine 
prophylaxis, 
such 
as 
Memantine. 
Within 
the 
pathophysiology of migraine, glutamate is involved in disseminated cortical 
depression, trigeminal-vascular activation.14 Other studies corroborate its role, 
reporting elevated glutamate levels in cerebrospinal fluid in patients with chronic 
migraine in the ictal period and elevated serum levels in patients with migraine. In 
addition, elevated levels of glutamate in the trigeminal-cervical complex have been 
evidenced after experimental stimulation in the structures of the dura mater and in 
the ventro-posteriomedial thalamic nucleus.  15 
 
In 2006 Charles and colleagues reported a case series with a total of 71 patients 
diagnosed with migraine refractory to prophylactic treatment. The headache 
frequency per month ranged from 4 to 30 (median =12.5) after treatment with 
Memantine for two months with a headache frequency per month of 0 to 22 (median 
=3.5). Only 54 patients answered the mailed survey of which 67% (n=37) presented 
a greater than 50% reduction in headache frequency.  However, this study had 
limitations such as being retrospective, without a control group and without blinding. 
Therefore, it only suggested Memantine as a possible treatment for migraine.16   
 
In 2008 Bigal and colleagues conducted the first open clinical trial, a pilot study to 
evaluate the efficacy and safety of memantine as a prophylactic treatment in patients 
diagnosed with refractory migraine. With a sample of 28 participants who presented 
a baseline frequency of headache days of 21.8 days per month, they received 
Memantine from 10 mg to 20 mg per day for three months. A decrease in the 
frequency of headache days was obtained to 16.1 (P<0.01). Whereby the authors 
concluded that Memantine as a prophylactic treatment is safe and effective in 
patients with refractory migraine.17 In 2015 Noruzzadeh and colleagues conducted 
the first randomized double-blind placebo-controlled clinical trial to evaluate the 
efficacy of Memantine as a prophylactic treatment of migraine without aura. The 


 
13 
Memantine group had a greater reduction in migraine attack frequency compared to 
placebo, which was a difference of 2.3 attacks per month with a P<0.001. 14 
 
Based on two of the three clinical trials of prophylactic treatment with Memantine 
that have been conducted, memantine could be an effective new treatment 
alternative.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
14 
JUSTIFICATION 
 
The frequency of migraine attacks is a risk factor for progression from episodic 
migraine to chronic migraine, the recommendation is to initiate prophylactic 
treatment.13 The rate of adherence to prophylactic migraine treatment is low; 
adherence has been reported to range from 26% at 6 months to 17% at 12 months. 
18 The main causes of low adherence to prophylactic treatment are side effects and 
low efficacy of the treatment. 8  
 
In the review conducted in PubMed, Scopus and Web Science there is no clinical 
trial from 2000 - 2018 comparing the efficacy of memantine against sodium 
valproate, the latter being a first-line drug in prophylactic treatment. 
 
The study was presented and approved by the Research and Ethics Committees of 
the Central Hospital and was registered in Clinical Trials of the National Institutes of 
Health of the United States, being accepted and approved by all of them for its 
performance, with registration 74-19 in the HC and NCT04698525 for Clinical Trials. 
 
The Neurology service of the Central Hospital "Dr. Ignacio Morones Prieto" has a 
high prevalence of patients with migraine in the outpatient clinic, in 2018 there were 
about 600 consultations for primary headaches.  In addition, we have the support of 
the pharmacological company who will donate the corresponding treatment of 
memantine and sodium Valproate for 3 months.  
 
For this reason we propose this clinical trial to compare the efficacy of Memantine 
against sodium Valproate in the prophylactic treatment of migraine, and to consider 
it as a new drug for the prophylactic treatment of migraine.  
 
Unfortunately, due to the pandemic that we faced during the year 2020 when the 
patients were to be recruited for the study, we were unable to reach the goal set for 
patient inclusion. However, although the number of participants was lower, we were 
able to determine with them the difference between pre- and post-treatment for both 
drugs. In two population groups totally comparable in their demographic 
characteristics. 
 
 
 
 
 
 
 
 
 
 
 
 


 
15 
 
 
WORKING HYPOTHESIS 
 
The frequency of migraine attacks under prophylactic treatment with Memantine is 
equal to or less than that observed with sodium valproate for three months in adult 
patients with episodic migraine. 
 
 
OBJECTIVES 
 
A. General Objective 
1. To compare the efficacy in reducing the frequency of migraine attacks under 
prophylactic treatment with Memantine at a rate of 20 mg divided into two 
doses per day against sodium Valproate at a rate of 1000 mg divided into two 
doses per day for three months in adult patients with migraine.  
 
B. Specific objectives 
1. To evaluate the baseline frequency of migraine attacks in adult patients with 
migraine 28 days prior to the study.  
2. To evaluate the frequency of migraine attacks of the group - treatment with 
sodium Valproate for three months, in adult patients with migraine.  
3. To evaluate the frequency of migraine attacks of the group - treatment with 
Memantine for three months, in adult patients with migraine.  
 
C. Secondary objectives  
1.  Evaluate the response rate to treatment. 
2. Assess migraine disability using MIDAS (Migraine Disability Assessment) 
before and after treatment. 
3. To assess pain intensity in migraine attacks with the visual analog scale 
(VAS) before and after treatment. 
4. Identify adverse effects to sodium Valproate and Memantine. 
 
 
 
 
 
 
 
 
 


 
16 
 
 
SUBJECTS AND METHODS 
 
Site 
The study was conducted at the outpatient clinic of the Hospital Central Dr. Ignacio 
Morones Prieto, San Luis Potosí. 
 
Design 
Prospective, randomized, double-blind, controlled clinical trial. 
 
Inclusion criteria 
1. Men and women from 18 to 65 years old. 
2. Diagnosis of episodic migraine according to the ICHD-III of the IHS at least 
one year prior to the study.  
3. Must present at > 4 - < 8 migraine attacks per month. 
4. Not receiving prophylactic treatment for migraine headache.  
5. Sign informed consent 
 
Exclusion Criteria  
1. Pregnant or breastfeeding patients.  
2. Patients with other types of non-migraine headache. 
3. Allergy to Sodium Valproate and/or Memantine 
4. Being a carrier of systemic disease (infectious, immunological or metabolic 
processes) or cardiovascular disease (myocardial, coronary or valvular heart 
disease) that prevents participation in the study.  
 
Elimination Criteria  
1. Patients who do not tolerate the study drug during titration. 
2. Patients who voluntarily leave the study.  
3. Patients lost to follow-up.  
 
Variables 
 
Dependent´s 
1. Frequency of migraine attacks: Defined as the number of migraine attacks 
presented during the month. It is a continuous variable. 
2. Treatment response rate: Defined as a decrease equal to or greater than 50% 
in the frequency of days with migraine compared to the baseline situation. It 
is a continuous variable. 
3. Migraine disability: Numerically defined according to the MIDAS (Migraine 
Disability Assessment) survey, (where 0-5=no disability, 6-10 points mild 
disability, 11-20 points moderate disability, and >21=severe disability). It is an 
ordinal variable. 


 
17 
4. Pain intensity: Numerically defined according to the visual analog scale (VAS) 
the pain intensity of the migraine attack before and after prophylactic 
treatment where 0=no pain and 10=very severe pain). It is a continuous 
variable. 
5. Adverse treatment effects: Any response to a drug that is noxious, unintended 
and occurs at doses usual in our case for prophylactic treatment. The ICH 
Harminised Tripartite guideline classifies any of the following: non-severe and 
severe, severe being any that results in death, is life threatening, requires 
hospitalization, results in disability.   
 
 
Independent  
1. Treatment 
Group A: Memantine at a dose of 20 mg per day divided into two doses per 
day (morning and evening) for three months. 
Group B: Sodium valproate at a dose of 1000 mg per day divided into two 
doses per day (morning and evening) for three months. 
 
Confusers 
1. Age: years completed by the patient. Migraine is most prevalent from 25 to 
55 years of age, so it was expected that our patients would be young, and it 
was hoped that simple randomization would eliminate this bias. 
2. Gender: is the organic condition that distinguishes men from women. It is a 
qualitative, nominal variable. The prevalence in women is higher with a 3:1 
ratio between women and men, respectively. Therefore, a greater 
participation of women in the study was expected, 3 men in the Sodium 
Valproate group and 3 in the Memantine group participated and concluded 
the study. 
 
 
Randomization method 
 
By computer until the sample size is reached.  Randomization will be performed by 
computer. Computer generated numbers will be used for the creation of a 
randomization sequence.   
 
Method of follow-up. 
 
Double blind, the blindness is for the investigator who does not know the assigned 
medication (blindness 1) and for the patient (blindness 2) who does not know the 
assigned medication. At the end of the visit, a third person, who is part of the 
research team, will give the medication (tablets for 4 weeks) and will be the only one 
who could open the blindness security code if necessary.   
 
 
 
 


 
18 
Work Plan  
 
Recruitment was carried out from July 2019 to August 2020 in the outpatient service 
of Neurology, Referral and Emergency of the Central Hospital. Patients who met the 
inclusion criteria and signed the informed consent form participated in the study. At 
the time of recruitment, they will be randomized by computer by an external 
collaborator of wide experience, assigning them a number and an external 
collaborator will distribute them in one of the two groups. Double-blinding will be 
performed, both for the researcher and for the participant, the only one who knew 
which group they were assigned to was the one who performed the randomization.  
 
A total of 4 visits were made, with a time interval of one month for each visit.  
 
Visit 1 (Week 0): a clinical history was taken, a physical examination was performed, 
the informed consent form was signed (Annex 1), and the inclusion and exclusion 
criteria form (Annex 2) was filled out by the researcher. A "Migraine diary" (Annex 3) 
was provided to the patient where the migraine attacks were recorded to identify the 
baseline characteristics such as frequency, intensity, duration.  
 
Visit 2 (Week 4): the patient was given the medication assigned by the corresponding 
randomization. Memantine or VPA was prescribed as an oral tablet at night for one 
week and then increased in the second week to one tablet in the morning and at 
night. The baseline MIDAS survey was performed to identify migraine disability. The 
baseline "Migraine Diary" was collected and a new "Migraine Diary" was provided.  
 
Visit 3 (Week 8): Frequency of migraine attacks, adverse effects and tolerability of 
treatment were assessed by the investigator. The "Migraine Diary" was collected and 
a new "Migraine Diary" was provided. The corresponding medication was given for 
four weeks.  
 
Visit 4 (Week 12): Visit 3 (Week 8): Migraine attack frequency, adverse effects and 
tolerability of treatment were assessed by the investigator. The "Migraine Diary" was 
collected and a new "Migraine Diary" was provided. The corresponding medication 
was given for four weeks.  
 
Visit 5 (Week 16): Frequency of migraine attacks, adverse effects and tolerability of 
treatment were evaluated by the investigator. The "Migraine Diary" was collected. 
The MIDAS survey was performed again to assess post-treatment disability. 
 
Financing  
 
A donation of the pharmacological treatment Memantine and sodium Valproate was 
received from the Torrent Pharma Laboratory (Annex 5).   
 
 
 


 
19 
STATISTICAL ANALYSIS 
 
Sample size calculation 
Normal distribution model: x=Z(c /100 )2 r(100-r). n=N x /((N-1)E2 + x ) E=Sqrt[(N - n)x /n(N-1) ]. 
With a margin of error of 5%, a confidence level of 95%, with a prevalence of 
migraine in the general population of the State of San Luis Potosi of 271800 with a 
distribution response of 15%.19 The recommended sample size is 196 participants. 
Due to the fact that a pilot study will be conducted, 10% of the sample size will be 
taken to make it representative, a sample size of 20 participants for each group is 
decided.20 
 
Descriptive statistical analysis of the variables of interest will be performed. For 
continuous variables, analysis will be performed using the Student's t-test. The 
number of participants (n) and the final analysis was calculated using R (56). Alpha, 
the probability of type 1 error was set to 0.05 and the power was set to 0.8 which 
resulted in the probability of a type 2 error of 0.2, given that we limited to 20 
participants per treatment, delta was estimated with this restriction. 
 
 
 
 
ETHICS 
Risk category: Risk greater than minimal.  
Authorization will be requested from the Research Ethics Committee of the Hospital 
Central "Dr. Ignacio Morones Prieto". The study will be performed according to the 
Mexican Official Standard for the conduct of clinical studies in humans NOM-012-
SSA3-201221 , and international standards (Declaration of Helsinki22 and 
International Harmonized Guide (ICH) of Good Clinical Practices23 ) The diagnostic 
maneuvers that will be used are considered of higher than minimal risk because it is 
an interventional study according to article 17 of the regulations of the General Law 
of Health23 on Health Research.  
In addition, it is a priority to safeguard the physical and mental integrity of the 
patient, and privacy is respected by maintaining the confidentiality of the data at 
all times during the research, as well as the data obtained at the end of it. The 
consent of the legal subjects will be obtained through a document specifying the 
objective of the study, the duration, as well as the methods and medications that 
they will receive randomly. 
 
 
 
 


 
20 
RESULTS  
 
Eighty-seven patients were evaluated, of which only 33 patients were included in the 
study. In the Memantine group with 16 patients and 17 in the Sodium Valproate 
(VPA) group; only 27 patients concluded the study.  
 
Demographic data: In the Memantine group there were 13 women and three men, 
in the VPA group 13 women and four men. The average age of the patients in the 
Memantine group was 31.18 + 10.94 years and those in the VPA group 31.58 + 7.51 
years (Table 1). 
 
Migraine characteristics: In the Memantine group 62.5% (n=10) had a family 
history of migraine and in the VPA group 52% (n=9). The age of migraine onset in 
both groups was 18 years on average. Headache pain characteristics in the 
memantine group were pulsatile in 81.25% (n=13), hemicranial 87.5%% (n=14), 
disabling activities of daily living 93.75% (n=15), with photophobia in 87.50% (n=14), 
sonophobia 100% (n=16), disabling activities of daily living 93.75% (n=15), nausea 
and vomiting in 87.5% (n=14) in the VPA group was pulsatile in 76.47% (n=13), 
hemicranial 76.47% (n=13), disabling activities of daily living in 94.12% (n=16) with 
photophobia in 94.12% (n=16), sonophobia 58.82% (n=10), nausea and vomiting in 
100% (17). With respect to aura only present in three patients in the memantine 
group and in four in the VPA group. (Table  1: Migraine characteristics.) 
 
Primary objective: In the Memantine group with average migraine attacks before 
treatment of 5.31 (SD+1.54) per month in the three months before and after three 
months of treatment 0.93 (SD+1.49) per month, with a decrease of 4.21 (SD+1.76) 
migraine attacks p <<0.001 (Figure 1).Figure 1). In the VPA group with pretreatment 
mean migraine attacks of 5.35 (SD+1.11) and after three months of treatment of 0.77 
(SD+1.16) (Figure 2) with a decrease of 4.5 (SD+1.39) migraine attacks p <<0.001 
(Figure 3).  
 
 
 
0
2
4
6
8
10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Number of migraine attacks 
Patients
Figure 1. Frequency of migraine attacks in the Memantine 
group. 
PRETREATMENT
POST-TREATMENT


 
21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 . Baseline characteristics of both groups. 
 
Variable 
 
Memantine 
 
Sodium Valproate 
Sex (%) 
                           Woman 
                       Man 
 
13 (81.25%) 
3 (18.75%) 
 
13 (76.47%) 
4 (23.52%) 
Average age 
31.18 + 10.94 
31.58 + 7.51 
Family history of migraine 
(%) 
10 (62.5%) 
9 (52.94%) 
Characteristics of migraine 
Type of pain (%) 
Pulsating 
Oppressive 
 
 
 
13 (81.25%) 
3 (18.75%) 
 
 
 
13 (76.47%) 
4 (23.52%) 
Pain location (%) 
Hemicranial 
Holocranean 
 
14 (87.5%) 
2 (12.5%) 
 
13 (76.47%) 
4 (23.52%) 
Photophobia No. (%) 
14 (87.50%) 
16 (94.12%) 
Sonophobia No. (%) 
16 (100%) 
10 (58.82%) 
Nausea and vomiting No. (%) 
14 (87.5%) 
17 (100%) 
Incapacitates activities of daily 
living 
15 (93.75%) 
16 (94.12%) 
Migraine without aura 
13 (81.25%) 
13 (76.47%) 
Migraine with aura 
3 (18.75%) 
4 (23.52%) 


 
22 
 
 
 
 
 
 
 
 
 
Secondary objectives. - Treatment response rate which is referred to as the 
decrease of equal or more than 50% of migraine days. In the Memantine group with 
pretreatment migraine days 4.3 (SD+ 1.93) and post treatment 0.23 (SD+ 0.44) with 
a mean decrease in migraine days of 3.9 (SD+ 1.89) p <<0.001. In the Sodium 
Valproate group with pretreatment migraine days 5.5 (SD+ 1.25) and post treatment 
0.27 with mean decrease of migraine days 4.88 with (SD+ 1.29) p <<0.001 (Figure 
0
2
4
6
8
1
2
3
4
5
6
7
8
9
10
11
12
13
Number of migraine attacks 
Patients
Frequency of migraine attacks in the sodium valproate 
group. 
PRETREATMENT
POST-TREATMENT
Memantina
VPA
Pretreatment
5.3125
5.352941176
Post-treatment
0.928571429
0.769230769
0
1
2
3
4
5
6
Frequency of migraine attacks
Frequency of migraine attacks pre- and post-treatment in 
both groups.
Pretreatment
Post-treatment


 
23 
4). In both groups the 27 patients presented a successful treatment response rate, 
in the Memantine group with a decrease in percentage of migraine days average 
94% (SD+ 9.95) and in the Sodium Valproate group 93.18% (SD+ 14.50). 
 
The intensity of migraine was evaluated with the Visual Analog Scale (VAS) pre and 
post treatment. In the Memantine group pre-treatment VAS 8.5 (SD+ 1.36) and post-
treatment 4.28 (3.65) p<0.00014. In the VPA group with pretreatment VAS 8.94(SD+ 
0.87) and post treatment 2.5 (SD+ 0.87) p <0.0000012. 
 
Migraine disability assessed with MIDAS in the Memantine group with MIDAS mean 
pretreatment 60.87 (SD+ 25.22) and post-treatment 15.57 (SD+ 14.32) p < 
0.000004. In the Sodium Valproate group with MIDAS pretreatment of 51.92 (SD+ 
22.67) and post treatment 10.53 (SD+ 19.97) p < 0.00002 (Figure 5). 
 
0
1
2
3
4
5
6
Memantina
VPA
Migraine days
Memantina
VPA
Pretreatment
4.36875
5.205882353
Post-treatment
0.237142857
0.27384615
Days with migraine pre- and post-treatment in both groups.
Pretreatment
Post-treatment


 
24 
 
 
Side effects: The side effects presented by the patients were not severe in their 
totality, eight patients in the Memantine group presented non-severe side effects and 
seven patients in the sodium valproate group (Table 2), the most frequent in both 
groups being somnolence. 
Table 2 . Side effects  
 
Memantine 
 
Sodium Valproate 
 
None 
 
 
Drowsiness  
 
 
Lack of concentration 
 
0 
Parasomnia 
0 
1 
Dizziness 
 
0 
Total 
 
 
 
DISCUSSION 
 
This is the first randomized double-blind pilot clinical trial comparing the efficacy and 
safety of memantine with a first-line treatment, sodium valproate. 
 
With the objective of recruiting 40 patients as a pilot study, the Neurology outpatient 
clinic was suspended due to the COVID-19 pandemic, we finally managed to recruit 
33 patients, 3 lost follow-up and 3 dropped out of the study due to COVID-19 and 
only 27 patients were included. 
 
0
10
20
30
40
50
60
70
Memantina
VPA
Score 
Memantina
VPA
Pretreatment
60.87
51.92
Post-treatment
15.57
10.53
Figure 5. MIDAS pre- and post-treatment in both groups. 


 
25 
Both groups were very homogeneous in terms of gender distribution, age, number 
of migraine attacks, duration of migraine attacks and clinical characteristics (pain 
location, type of pain, among others).  
In comparison with the Noruzzadeh and colleagues study, where the Memantine 
group had a baseline migraine frequency per month (pre-treatment) 5.4+ 2.5 and 
after 3 months of treatment the baseline migraine frequency was 1.9. In our study 
we found a similar response in the Memantine group with average migraine attacks 
before treatment of 5.31 and after 3 months of treatment 0.92 with a difference of 
4.39 migraine attacks p <<0.001. As in previous studies and reaffirming the reason 
why sodium Valproate is a drug of recommendation A, a decrease of 4.5 migraine 
attacks was obtained with p <<0.001.  
The migraine disability assessed by MIDAS initially showed severe disability (> 20 
points) in both groups, the patients presented scores higher than 50; after treatment, 
the Valproate group presented mild disability and the memantine group presented 
moderate disability.  
 
With respect to migraine intensity, a post-treatment decrease of > 50% was observed 
on the VAS scale. In view of the decrease in frequency, days and intensity, the 
impact of both treatments on the MIDAS scale that assesses migraine disability was 
demonstrated. Initially, severe disability (> 20 points) was observed in both groups, 
the patients presented scores higher than 50; after treatment, the Valproate group 
presented mild disability and the memantine group presented moderate disability. 
 
As in the only two clinical trials of memantine as a prophylactic treatment for 
migraine, side effects were not severe.  In the study by Noruzzadeh and colleagues, 
three patients had sedation, mild vertigo and nausea, the placebo group had one 
patient with nausea and a second patient had vertigo.  In the study by Bigal and 
colleagues the most frequent side effects were in seven patients reported 
drowsiness, three patients with anxiety and asthenia. In our study four patients 
reported somnolence, two reported lack of concentration and two reported dizziness. 
 
LIMITATIONS 
One of the limitations is the failure to include the required number of participants in 
the sample size. Since this clinical trial is a pilot study, new randomized double-blind 
clinical trials with a larger number of participants should be conducted.  
 
 
 
 
 
 
 
 
 


 
26 
CONCLUSIONS 
In this double-blind randomized clinical trial, so far (to our knowledge) the only pilot 
study comparing Memantine against sodium valproate, a first-line drug in the 
prophylactic treatment of migraine.  
 
The response in both groups was evident and significant (p<0.05) according to the 
treatment they received, with a clear decrease in the number of migraine attacks, 
days with migraine, disability and intensity.  
 
Memantine could be a new prophylactic treatment option in migraine, the study 
showed that there was no inferiority of Memantine compared to sodium Valproate 
as a prophylactic treatment for episodic migraine. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
27 
BIBLIOGRAPHY . 
 
1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, 
and national incidence, prevalence, and years lived with disability for 354 diseases and 
injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global 
Burden of Disease Study 2017. Lancet 2018; 392: 1789-858. 
2. Bille B. A 40-year follow up of school children with migraine. Cephalalgia 1997; 17: 488-
91.  
3. Lipton R. Migraine: Epidemiology, Impact, and Risk Factors for Progression. Headache 
2005;45[Suppl 1]:S3-S13  
4. Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalalgia 2018; 38: 
1-211. 
5. Charles A, Hansen JM. Migraine aura: new ideas about cause, classification, and clinical 
significance. Curr Opin Neurol 2015; 28:255-260.  
6. Charles A. The pathophysiology of migraine: implications for clinical management. 
Lancet Neurol 2018; 17: 174-82.  
7. Dodick DW. Migraine. Lancet 2018; 391: 1315-30.  
8. Schwedt TJ. Preventive Therapy of Migraine. CONTINUUM (MINNEAP MINN) 
2018;24(4, HEADACHE):1052-1065.  
9. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache 
(an evidence-based review): report of the Quality Standards Subcommittee of the 
American Academy of Neurology. Neurology. 2000 Sep 26;55(6):754-62. 
10. Tassorelli C, Diener HC, Dodick DWSilberstein SD, Lipton RB, Ashina M et al. ; 
International Headache Society Clinical Trials Standing Committee. Guidelines of the 
International Headache Society for controlled trials of preventive treatment of chronic 
migraine in adults. Cephalgia 2018 Apr;38(5):815-832. 
11. Silberstein SD, Holland S, Dodick DW, Argoff C, Ashman E. Evidence-based guideline 
update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology 
2012;78:1337-1345.  
12. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Valproate (valproic acid or sodium 
valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. 
Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010611. 
13. Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine 
without aura: a triple-blind, placebo-controlled crossover study. Neurology 1994;44(4): 
647-51.  
14. Noruzzadeh R, Modabbernia A, Aghamollaii V, Ghaffarpour M, Harirchian 
MHMemantine for Prophylactic Treatment of Migraine Without Aura: A Randomized 
Double-Blind Placebo-Controlled Study. Headache. 2016 Jan;56(1):95-103. 
15. Chan K, MaassenVanDenBrink A. Glutamate Receptor Antagonists in the Management 
of Migraine. Drugs (2014) 74:1165-1176. 
16. Charles A, Flippen C, Romero Reyes M, Brennan K.C, Memantine for prevention of 
migraine: a retrospective study of 60 cases. J Headache Pain (2007) 8:248-250.  
17. Bigal M, Rapoport A, Sheftell F, Tepper D, Tepper S. Memantine in the preventive 
treatment of refractory migraine. Headache. 2008;48:1337-1342.  
18. Scher, A. I., Stewart, W. F., Ricci, J. A. & Lipton, R. B. Factors associated with the onset 
and remission of chronic daily headache in a population-based study. Pain 106, 81-89 
(2003). 


 
28 
19. Hepp Z, Dodick DW, Varon SF, et al. Adherence to oral migraine-preventive medications 
among 
patients 
with 
chronic 
migraine. 
Cephalalalgia 
2015; 
35(6):478-488. 
doi:10.1177/0333102414547138.  
20. Lang, Thomas & Secic, Michelle, How to Report Statistics in Medicine, American College 
of Physicians; (January 15, 1997), 367 pages 
21. Johanson G, Gordon B. Initial Scale Development: Sample Size for Pilot Studies. 
Educational and Psychological Measurement. 2010; 70(3):394 -400. 
22. Norma oficial Mexicana NOM-012-SSA3-2012 [On line]. That establishes the criteria for 
the execution of research projects for health in humans. Official Journal of the 
Federation. 
04 
Jan 
2013. 
[accessed: 
15 
Apr 
2019] 
Available 
at: 
http://dof.gob.mx/nota_detalle.php?codigo=5284148&fecha=04/01/2013 
23. WMA Declaration of Helsinski - Principles for Medical Research Involving Human 
Subjects. 64th General Assembly, Fortaleza, Brazil, October 2013.  
24. Ministry of Health, Official Gazette of the Federation. General Health Law, Ministry of 
Health, July 12, 2018. 
25. Stewart W F, et al. Validity of the Migraine Disability Assessment (MIDAS) score in 
comparison to a diary-based measure in a population sample of migraine sufferers. Pain 
2000;88(1):41-52. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
29 
ANNEX 1 
 
PATIENT INFORMED CONSENT DOCUMENT 
CENTRAL HOSPITAL "DR. IGNACIO MORONES PRIETO" CENTRAL 
HOSPITAL 
NEUROLOGY DEPARTMENT    
 
ADULT PATIENT 
TITLE OF THE RESEARCH PROTOCOL 
"Efficacy of memantine compared with sodium valproate in the prophylactic treatment of 
migraine". Randomized controlled clinical trial. 
 
REGISTRATION NUMBER OF THE 
PROTOCOL AUTHORIZED BY THE 
RESEARCH ETHICS COMMITTEE 
 
PERIOD OF EXECUTION OF THE 
AUTHORIZED PROTOCOL 
____________ 
___/___/____ - ___/___/____ 
 
PRINCIPAL INVESTIGATOR AND 
RESPONSIBLE AT THE HOSPITAL  
 
PRINCIPAL INVESTIGATOR'S 
AFFILIATION 
Dr. Ildefonso Rodríguez Leyva 
 
Department of Neurology  
Division of Internal Medicine  
Central Hospital "Dr. Ignacio Morones 
Prieto". 
Autonomous University of San Luis Potosi  
Professional license 763163 
CO-INVESTIGATOR 
CO-INVESTIGATOR'S AFFILIATION 
Dr. Damaris Daniela Vazquez Guevara 
Department of Neurology   
Division of Internal Medicine  
Central Hospital "Dr. Ignacio Morones 
Prieto". 
Autonomous University of San Luis Potosi 
Professional license 10045226 
 
DATE OF SUBMISSION OF INFORMED 
CONSENT 
 
 
PATIENT IDENTIFICATION NUMBER 
 
 
 
The Neurology Department of the Central Hospital Dr. Ignacio Morones Prieto is 
conducting a research study with the objective of comparing the efficacy of 
memantine versus sodium valproate in the prophylactic treatment of migraine.  This 
study will include 40 patients for 3 months each participant, from July 08 to October 


 
30 
30, 2019 and will be conducted in the Outpatient Referral Service, Emergency 
Outpatient and Neurology of the Central Hospital "Dr. Ignacio Morones Prieto".  
 
Patient information 
Migraine is a neurological disease characterized by headaches of variable duration, 
usually located in the middle of the head, although it can be located in the forehead 
or in the whole head. Most patients report that the pain is throbbing (like a heartbeat) 
and often accompanied by nausea, vomiting, discomfort, intolerance to light and 
noise. Some patients are warned of migraine prior to the headache with special 
symptoms such as blurred vision, flashes of light or stars, tunnel vision, which is 
known as aura.  
 
To know if your headache is migraine you should be evaluated by a doctor, because 
migraine headaches are very intense, migraine becomes incapacitating causing 
missing work, school or not being able to perform activities of daily living, is one of 
the reasons why you should go to a neurologist who will make the diagnosis and 
assess whether you are a candidate for treatment. The treatment of migraine is 
divided into two types: acute, which is given at the time of the migraine attack, and 
prophylactic, which is given to prevent new migraine attacks and reduce their 
intensity. The complications of migraine is that it becomes a chronic disease, which 
implies migraine attacks more than 15 days a month.  
 
You have been invited to participate in this study because you have been diagnosed 
with migraine and are a candidate for prophylactic treatment. In this research study 
we will compare the efficacy of two types of treatment, one known as sodium 
valproate already known as a treatment for migraine and another that could be a 
new treatment for migraine which is Memantine.   
 
To perform this study, patients will be included in two groups at random, each group 
will have 20 participants. One group will receive sodium Valproate and the other will 
receive Memantine, however, it is important that neither you nor the physician will 
know which drug treatment you will be receiving for 3 months.  
 
Procedures to be undergone by the patient 
Your participation in this research study is completely voluntary and if you agree to 
participate, we will ask you to carefully read this informed consent document and to 
ask all the necessary questions to the responsible research physician, Dr. Ildefonso 
Rodriguez Leyva, so that he can resolve your doubts. When you no longer have 
any doubts regarding what will be done in this study, we will ask you to sign your 
acceptance to participate at the end of this document, and we will ask you to provide 
us with general information such as your name, age, weight, height; your medical 
history; in an interview of approximately 45 minutes, which will be conducted by Dr. 
Damaris Daniela Vazquez Guevara in the outpatient area of this hospital, so it will 
not be necessary to review your clinical record. At the end of this first medical 
assessment, you will be given a migraine diary where you can record your migraine 
attacks and their characteristics.  To keep your data anonymous, you will be 
assigned a code with which only the research physicians participating in this study 


 
31 
will be able to know your identity. 
 
Medical evaluations will be performed every 4 weeks on 5 occasions in total at the 
Neurology outpatient clinic of the Central Hospital by Dr. Damaris Daniela Vazquez 
Guevara. From the second visit on, she will be asked again about the frequency of 
migraine attacks, if she tolerates the medication and possible adverse effects. In 
addition, at visits 2, 3, and 4 the research team will provide you with the medication 
at no cost randomly assigned for 4 weeks, and at each visit you will be given a new 
migraine diary which will be collected at the next visit. At all visits you will be given a 
survey to assess the intensity of your migraine attack pain. While you are receiving 
the drugs you will have medical attention by the team for possible adverse effects. 
 
Your doctor has explained to you in detail what your disease consists of and the 
importance of having a prophylactic treatment in order to reduce the frequency of 
your migraine attacks.  
 
Patient benefits: 
You may benefit from having a favorable response to the treatment and decrease 
the frequency of migraine attacks. However, you will be collaborating with the 
research area of the Neurology Department of the Central Hospital "Dr. Ignacio 
Morones Prieto" and we will not know which drug you will be receiving.  This study 
is intended to evaluate a new prophylactic treatment for migraine that seems to be 
well tolerated by patients.  
 
Benefits for society: 
This research study will help to evaluate a new drug for the prophylactic treatment 
of migraine, although there are already drugs indicated for migraine, sometimes 
patients do not tolerate it or have no response, which is why this new drug is 
proposed.  
 
Potential risks for the patient: 
The potential risks involved in your participation are greater than minimal as it is an 
interventional study. You may experience side effects from the medications such as: 
nausea, vomiting, weight gain, tremor, hair loss.  
 
However, in the remote case that you feel any other discomfort generated by the 
research drug, it is necessary to immediately notify Dr. Damaris Daniela Vazquez 
Guevara who will provide you with the necessary attention, which will not generate 
any cost for you.  
 
You should be aware that in the event of a side effect or adverse drug reaction 
requiring hospitalization or treatment, expenses will be covered by the principal 
investigator.  
 
It is important to note that you will not receive any payment for participating in the 
study and you will be given a copy of this informed consent document signed by the 
responsible investigators. 


 
32 
 
Confidentiality: 
The personal and medical information obtained from you in this study is confidential 
and will be used only by the research team of this project to analyze and complement 
the results obtained and will not be available for any other purpose.  This information 
will be combined with that of other participants to carry out the present study. In order 
to maintain anonymity, you will be assigned a code for the use of your data.  
 
If you so choose, the investigators responsible for this study may inform your treating 
physician that you have agreed to participate in this study, so that the information 
obtained may be included in your clinical record. For this purpose, we will ask you to 
indicate at the end of this document whether or not you agree to the above. 
 
The results of this study may be published for scientific purposes in special journals 
directed to medical personnel, nurses, chemists and researchers related to the 
health area in order to make them aware of the possibility of a new prophylactic 
treatment for migraine. The results of this study may also be presented at scientific 
meetings where new findings obtained from this and other studies related to the 
health and treatment of patients with the same diagnosis are discussed. The clinical 
data of all participants will be presented anonymously and in such a way that you or 
any of the patients participating in this study cannot be identified. 
 
In accordance with the General Law for the Protection of Personal Data in 
Possession of Obligated Subjects and the Law for the Protection of Personal Data 
of the State of San Luis Potosi, your personal data may not be processed, 
transferred or used for purposes not expressly described in this document, unless it 
is strictly necessary for the exercise and fulfillment of the powers and obligations 
expressly provided for in the rules governing the actions of the researchers 
responsible for the study; it is in compliance with a legal mandate; it is necessary for 
reasons of public safety, public order, public health or safeguarding the rights of third 
parties. 
 
Any other use required for the use of your data or analysis or handling of your 
samples and/or results of the analyses described in this document, must be informed 
and requested with due justification to the Research Ethics Committee of this 
Hospital, who will determine the relevance of the request and, if applicable, will 
authorize a different use for your data, samples and/or products derived from your 
samples and/or results. Always in compliance with national and international 
legislative guidelines and norms and for the benefit and protection of the integrity of 
the participating actors. 
 
There are Mexican institutions or organizations such as the Ministry of Health, the 
Federal Commission for Protection against Health Risks (COFEPRIS), the National 
Bioethics Commission (CONBIOETICA) or even the Research Ethics Committee 
(CEI) of this hospital, which are responsible for monitoring the proper handling of 
personal and medical data that you and other patients have authorized to be used 
in the conduct of research studies such as this one. These institutions or 


 
33 
organizations may request at any time to the researchers of this study, the review of 
the procedures that are performed with your information and measurements, in order 
to verify that a correct and ethical use is made of them; so they may have access to 
this information that has been previously assigned with an identification code, when 
required. 
 
Participation or withdrawal: 
Your participation in this study is absolutely voluntary and you have been invited to 
participate because of the characteristics of your disease, and you are a candidate 
to receive prophylactic treatment for migraine.   
 
You are free to refuse to participate in this research study; but if you decide to 
participate, at any time and without explanation, you may revoke or cancel the 
consent you are now signing. Your decision whether or not to participate will in no 
way affect the medical treatment you receive at the institution for your illness. If you 
decide to terminate your participation in this study, you must communicate it to Dr. 
(a) Dr. Damaris Daniela Vazquez Guevara who will provide you with a very simple 
document (format) in which you will put some of your data and indicate that you no 
longer wish to participate in the study. Your decision to participate or not, will not 
affect in any way the medical treatment you receive in the institution for your disease.  
 
You will be given a copy of this informed consent form, which includes the contact 
information of the person in charge of this study and of the hospital's Research Ethics 
Committee, in order to clarify any doubts that may arise.  
 
Ethical Considerations: 
This study is considered to be of greater than minimal risk as it is an intervention 
study and will be randomized between 2 interventions, because the investigators 
responsible for this study will make decisions regarding treatment for 3 months.  
 
We will not ask for your authorization to review your medical record, we will only ask 
you a few questions, as we have already explained. 
 
You will be given a copy of this informed consent, signed by the responsible 
investigator, which includes his or her contact information and the contact 
information of the Research Ethics Committee of this hospital to clarify any doubts 
that may arise. 
Commitment to answer questions and doubts: 
For any questions, doubts or clarifications about this double-blind Randomized 
Clinical Trial study to compare the efficacy of Memantine versus Sodium Valproate 
in the prophylactic treatment of Migraine, or about any adverse reaction related to 
the medication that you are taking as treatment and that has been prescribed by 
your treating physician, you may contact: 
 
Dr. Ildefonso Rodríguez Leyva 
Department of Neurology   
Central Hospital "Dr. Ignacio Morones Prieto". 


 
34 
Av. Venustiano Carranza 2395, Col. Zona Universitaria, San Luis Potosí, S.L.P., 
C.P. 78290, Tel. 6643759438   
 
Dr. Damaris Daniela Vazquez Guevara 
Department of Neurology   
Central Hospital "Dr. Ignacio Morones Prieto". 
Av. Venustiano Carranza 2395, Col. Zona Universitaria, San Luis Potosí, S.L.P., 
C.P. 78290, Tel. 6643759438   
 
If you have any questions regarding your rights as a participant in the research study, 
you may also contact a person not involved with the research team for this study: 
 
Dr. Emmanuel Rivera López 
Chairman of the Research Ethics Committee 
Central Hospital "Dr. Ignacio Morones Prieto". 
Venustiano Carranza Av. 2395,  
Col. Zona Universitaria, San Luis Potosi, S.L.P., C.P. 78290,  
Tel. (52-444) 8 34 27 01, Ext. 1710 
 
 
 
Acceptance of the Informed Consent Document  
If you wish to voluntarily participate in this research, please provide your name, 
signature and date this document in the spaces provided below. Your signature 
signifies your agreement to the following: 
 
1. I have been given complete and adequate information verbally and in writing about 
the purpose of the study, explained that the risks are greater than minimal because 
it is an interventional study, and the benefits of participating in clear language. 
I have been informed that I may withdraw my consent and terminate my participation 
in this study at any time without affecting my right to receive medical care. 
3. It is my responsibility to ask questions to clarify any points I do not understand 
regarding my participation in this study. I have asked all questions of the person 
conducting the consent process and have received satisfactory answers. 
4. I have not concealed or misrepresented any current medical condition or any 
medical history related to my health. I have answered all questions regarding my 
health accurately and truthfully. 
5. I am of legal age and legally capable of giving this consent.  
6. I agree to participate in this study on a voluntary basis without duress or coercion. 
I understand that my refusal to participate or discontinuation of participation at any 
time will not result in penalty or loss of benefits to which I am otherwise entitled. 
7. I understand and agree that the information obtained from the present study may 
be used for publication of these results for academic purposes as part of scientific 
dissemination and in support of clinical practice, but that at all times an assigned 
code will be used to maintain my anonymity and the confidentiality of my data. 
8. I have had it explained to me that the personal and clinical information I have 
consented to provide will retain my privacy and will be used only for purposes arising 
from this study.  


 
35 
9. The investigators participating in this project have agreed to provide me with 
updated information obtained during the study at the time I request it and will provide 
me with a copy of this informed consent document. 
 
By means of this informed consent document I agree to participate in the medical 
study entitled "Efficacy of memantine compared to sodium valproate in the 
prophylactic treatment of migraine". Randomized controlled clinical trial, free 
and voluntary. 
 
Authorization for use of clinical data 
 
You are asked to indicate your agreement or disagreement that the investigators 
responsible for this project may use the clinical data, anonymously for the conduct 
of this research protocol, whose objectives and procedures have been explained to 
you and that you have freely and voluntarily provided them, Mark your answer with 
an X:  
 
____ I give my permission to the investigators participating in this project to use the 
clinical data that I have provided to them in the research that they have explained to 
me.  
 
____ I do not give my permission to the investigators participating in this project to 
use the clinical data I have provided in the research they have explained to me.  
Authorization to inform my treating physician of my participation in this 
research study and to have my results included in my medical record. 
 
You are requested to indicate your agreement or disagreement for the investigators 
responsible for this research study to inform your treating physician, Dr. (a) 
___________________________________________, that you have agreed to 
participate in this study with the registration number ___________ before the IRB of 
this hospital and for the results obtained from the measurements of blood flow in the 
arteries of your brain, which you have consented to be performed, to be included in 
your clinical record so that they can be used as a reference for your treatment by 
your treating physician. Please mark your answer with an X:  
 
____ I give my authorization to the investigators to inform my treating physician of 
my participation in this research study and to include my results in my file, in 
accordance with the above and as explained to me.  
____I do not give my authorization to the investigators to inform my treating 
physician of my participation in this research study and to include my results in my 
file, in accordance with the above and as explained to me. 
 


 
36 
By means of this informed consent document I agree to participate in the research 
study entitled "Efficacy of memantine compared to sodium valproate in the 
prophylactic treatment of migraine". Randomized controlled clinical trial, on a 
free and voluntary basis.  
 
PATIENT'S NAME 
PATIENT'S SIGNATURE OF 
ACCEPTANCE 
 
 
 
 
 
DATE INFORMED CONSENT OBTAINED 
 
 
NAME OF LEGAL REPRESENTATIVE (if necessary) 
ACCEPTANCE SIGNATURE OF THE 
LEGAL REPRESENTATIVE 
 
 
 
 
DATE INFORMED CONSENT OBTAINED 
RELATIONSHIP 
 
 
ADDRESS / CONTACT PHONE NUMBER  
 
 
 
 
NAME OF WITNESS 1 
SIGNATURE OF WITNESS 1 
 
 
 
 
DATE 
RELATIONSHIP 
 
 
ADDRESS / CONTACT TELEPHONE NUMBER OF WITNESS 1 
 
 
 
 
 
NAME OF WITNESS 2 
SIGNATURE OF WITNESS 2 
 
 
 
 
DATE 
RELATIONSHIP 
 
 
ADDRESS / CONTACT TELEPHONE NUMBER OF WITNESS 2 
 
 
 
 


 
37 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr. Ildefonso Rodríguez Leyva 
  
 
 
 
Dr. Damaris Daniela Vazquez Guevara 
PRINCIPAL INVESTIGATOR AND 
RESPONSIBLE 
OF THE RESEARCH PROTOCOL 
Department of Neurology  
Autonomous University of San Luis Potosi  
PROFESSIONAL LICENSE 763163 
 
CO-INVESTIGATOR 
 
Department of Neurology   
Autonomous University of San Luis Potosi  
PROFESSIONAL LICENSE 10045226 
 
REVOCATION OF INFORMED CONSENT 
 
I declare to the Principal Investigator, Dr. (a) ___________________ that it is my will 
to revoke the informed consent that I have accepted on _______________, to 
participate in the research protocol entitled "Efficacy of memantine compared to 
sodium valproate in the prophylactic treatment of migraine". Randomized 
controlled clinical trial. It is my right to request that my clinical and personal data, 
as well as the results of the tests that have been performed on me so far, be removed 
from this research and no longer be included in the final results and reports or 
publications that will be generated from this research study. 
 
 
PATIENT'S NAME 
PATIENT SIGNATURE 
 
 
 
 
DATE OF REVOCATION OF INFORMED CONSENT 
 
 
 
NAME OF WITNESS 1 
SIGNATURE OF WITNESS 1 
 
 
 
 
DATE OF REVOCATION OF INFORMED CONSENT 
 
 
NAME OF WITNESS 2 
SIGNATURE OF WITNESS 2 
 
 
 
 
 
 
 
 
Dr. Damaris Daniela Vazquez Guevara 
(name and signature of the person obtaining informed 
consent) 
RESEARCHER PARTICIPATING IN THE PROTOCOL 


 
38 
DATE OF REVOCATION OF INFORMED CONSENT 
 
 
 
 
 
 
 
Dr. Ildefonso Rodríguez Leyva 
  
 
 
 
Dr. Damaris Daniela Vazquez Guevara 
PRINCIPAL INVESTIGATOR AND 
RESPONSIBLE 
OF THE RESEARCH PROTOCOL 
Department of Neurology  
Autonomous University of San Luis Potosi  
PROFESSIONAL LICENSE 763163 
 
CO-INVESTIGATOR 
 
Department of Neurology   
Autonomous University of San Luis Potosi  
PROFESSIONAL LICENSE 10045226 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MIDAS SURVEY 
 
Answer the following questions about all the headaches you have had in the last 
3 months.  
 
 
1. How many days did you miss work or school in the last 3 months 
due to your headache (if not going to school or work indicate 0)?  
 


 
39 
2. How many days did your productivity at work or school decrease by 
half or less in the last 3 months because of your headache? (Do not 
include the days you checked in question 1 for missed work. If you 
do not go to school or work, mark 0) ______ 
 
3. How many days did you not do your household chores in the last 3 
months because of your headache?  
 
4. How many days did your productivity in household chores decrease 
by half or less in the last 3 months because of your headache? (Do 
not include the days you already counted in question 3 for not having 
done your chores).  
 
5. How many days were you unable to participate in family, social and 
fun activities in the last 3 months because of your headache?  
 
 
A. How many days did you have a headache in the last 3 months (if an attack 
lasted more than one day, count each day)?  
 
B. On a scale of 0 to 10, how intense were those headaches on 
average (0: no pain, 10: worst pain imaginable)?  
 
 
 
 
 
 
 
 
 
 
 
Stewart W F, et al. Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a 
diary-based measure in a population sample of migraine sufferers. Pain 2000;88(1):41-52.  
ANNEX 5 
 
 
 
 
 
 
 
 
 
 
 
Score 
Degree of Disability MIDAS 
0-5 points  
No or minimal disability  
6-10 points 
Mild disability 
11-20 points 
Moderate disability 
>21 points 
Severe disability 


 
40 
 
 
 
  
 
 
 
 
 
 
To whom it may concern:  
 
 
 
 
We hereby inform you that the drug used in the clinical trial: "Efficacy of memantine compared to 
sodium valproate in the prophylactic treatment of migraine", a randomized controlled clinical trial, 
conducted by Dr. Ildefonso Rodriguez Leyva, was donated by Laboratorios Torrent to support clinical 
research. 
 
 
Under no circumstances did Torrent Pharma participate in the study, nor do we have access to any 
information about the patients, doses, or results. 
 
 
 
 
 
SINCERELY 
 
 
Laboratorios Torrent S. A. de C. V. 

SAP_005.pdf: 
"Efficacy of Memantine compared to sodium Valproate as 
prophylactic treatment for Episodic Migraine" A controlled 
randomized pilot clinical trial 
A controlled randomized clinical trial 
NCT04698525  
ID 74-19 
Study Protocol document date: February 15, 2019.       
Statistical Analysis Plan document date: January 15, 2020. 
Informed Consent Form document date: February 15, 2019. 


 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Sample size calculation 
Normal distribution model: x=Z(c /100 )2 r(100-r). n=N x /((N-1)E2 + x ) E=Sqrt[(N - n)x /n(N-1) ]. 
With a margin of error of 5%, a confidence level of 95%, with a prevalence of migraine in 
the general population of the State of San Luis Potosi of 271800 with a distribution 
response of 15%.19 The recommended sample size is 196 participants. Because a pilot 
study will be conducted, 10% of the sample size will be taken to make it representative, 
a sample size of 20 participants for each group is decided.20 
 
Descriptive statistical analysis of the variables of interest will be performed. For 
continuous variables, analysis will be performed using the student’s t-test. The number of 
participants (n) and the final analysis was calculated using R (56). Alpha, the probability 
of type 1 error was set to 0.05 and the power was set to 0.8 which resulted in the 
probability of a type 2 error of 0.2, given that we limited to 20 participants per treatment, 
delta was estimated with this restriction. 
 
 
The aim of this study was to assess the efficacy of memantine and compared sodium valproate 
in the prophylactic treatment of migraine. 
 
Study design  
A single center, doble-blinded, controlled, randomized pilot clinical trial. 
The present study was designed as a randomized, double-blind, controlled pilot trial. It was 
authorized by the Research and Ethic Committee in February 2019, with the ID 74-19 and 
register in Clinical Trials from INH with the NCT04698525. 
The study was conducted from July 2019 to November 2020 at Neurology service at Hospital 
Central Dr. Ignacio Morones Prieto, San Luis Potosí, México.  
 
Inclusion criteria 
Men and women from 18 to 65 years old. 
Diagnosis of migraine according to the ICHD-III of the IHS at least one year before the study. 
To have at least 4-14 migraine attacks per month. 
Not receiving prophylactic treatment for migraine 
Sign informed consent 
 
 
 
 


Exclusion criteria 
Pregnant or lactating patients. 
Patients with another type of non-migraine headache. 
Allergy to Sodium Valproate and/or Memantine 
Being a carrier of systemic disease (infectious, immunological, or metabolic processes) or 
cardiovascular (myocardial, coronary, or valvular disease) prevents their participation in the 
study. 
 
Primary outcomes 
 The primary outcome was the difference in change from baseline in the monthly attack 
frequency at week 12 between the two groups (using migraine diary).  
 
Secondary outcomes  
1. Evaluate the response rate to treatment. 
2. Evaluate migraine disability using MIDAS (Migraine Disability Assessment) before and after 
 
treatment. 
3. Identify adverse effects to sodium valproate and memantine. 
Statical analysis. 
 
Statistical analysis 
Descriptive statistical analysis of the variables of interest will be carried out.  
For continuous variables, their research will be analyzed using the t-student test.  
First, the number of participants (n) and the final analysis were calculated using R (56).  
Alpha, the probability of a type 1 error was set to 0.05. 
The power was set to 0.8, resulting in a type 2 error of 0.2.  
Since we were limited to 20 participants per treatment, the delta was estimated with this 
restriction. 
Since we were limited to 20 participants per treatment, the delta was estimated with this 
restriction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Results 
 
PRIMARY OUTCOME 
 


Secondary outcome 
 
Evaluate the response rate to the treatment 
 
 
Adverse Events 
 
 
Conclusions 
 
This double blind randomized clinical trial is the only pilot study where Memantine is compared 
to Sodium Valproate as prophylactic treatment for migraine.  
The response of both groups was dramatic and significant (p< 0.05) to the management they 
received, with a clear difference in the number of attacks, duration of four, intensity (EVA), and 
disability caused by the attack (MIDAS) 
Memantine could be considered as a prophylactic treatment option in migraine. 
The adverse events were frequent but mild and transient for both groups. 
Grade 1-Mild 
Grade 1-Mild 
Grade 1-Mild 
Grade 1-Mild