Comparative Study Between Valproate and Memantine in the Prophylactic Management of Episodic Migraine.

Sponsor

Universidad Autonoma de San Luis Potosí (Other)

Overall Status

Completed

CT.gov ID

NCT04698525

Collaborator

(none)

Enrollment

Location

Arms

Actual Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Migraine Headache	Drug: Valproate Sodium Drug: Memantine	Phase 3

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:

Unilateral location.
Pulsatile character.
Pain of moderate or severe intensity.
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:

Nausea and vomiting.
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

Recurrent migraine, which interferes with the patient's daily life and quality of life.
Frequent headaches.
That they have an inadequate response or contraindication to abortive treatment.
Adverse events to abortion treatment.
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

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

A double-blind study with two groups. One using VPA and the other one using memantine in subjects with a diagnosis of episodic migraine.A double-blind study with two groups. One using VPA and the other one using memantine in subjects with a diagnosis of episodic migraine.

Masking:

Single (Investigator)

Masking Description:

The clinician will make an evaluation and if the patient has the criteria for inclusion will be by randomization in one group or another. Neither the clinician and the patient will not know the administrated treatment.

Primary Purpose:

Treatment

Official Title:

Efficacy of Memantine Compared With Sodium Valproate in the Prophylactic Treatment of Episodic Migraine.

Actual Study Start Date :

Aug 1, 2019

Actual Primary Completion Date :

Aug 30, 2020

Actual Study Completion Date :

Nov 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Valproate group This is a well know antiepileptic drug with efficacy as a preventive tic treatment in episodic migraine	Drug: Valproate Sodium Comparison between two actives Other Names: Diwali
Active Comparator: Memantine This is a possible preventive treatment in episodic migraine	Drug: Memantine Memantine Other Names: Ezagun

Arm

Intervention/Treatment

Active Comparator: Valproate group

This is a well know antiepileptic drug with efficacy as a preventive tic treatment in episodic migraine

Drug: Valproate Sodium

Comparison between two actives

Other Names:

Diwali

Active Comparator: Memantine

This is a possible preventive treatment in episodic migraine

Drug: Memantine

Memantine

Other Names:

Ezagun

Outcome Measures

Primary Outcome Measures

Reduction in days of headache pain with treatment of memantine as well as valproate in the preventive management of episodic migraine. [Three months]
In a double-blind clinical trial, we compare two active drugs (mamantine vs. Valproate) in three months, looking for reductions in the presentation days of migraine attacks by month.
The change in the intensity of the pain in a migraine attack will be measured by a visual analog scale (VAS). [Three months]
The possible reduction in the average in visual analog scale (0-10) before and after three months of treatment with the drugs will be measure in both arms of the study.
The Migraine Disability Assessment MIDAS scale will measure before and after the treatment to improve the quality of life in both groups after three months of treatment. [Three months.]
To compare the average of Memantine against the group that receives Valproate before and after starting preventive treatment. Using the Migraine Disability Assessment scale (The score is the sum of days missed from work or school, days of housework missed, days of missed non-work activities, and days of work or school plus days of housework in which productivity in the last three months) to compare punctuation changes.The MIDAS score is divided into four degrees: Grade I (0-5 points): Slight limitations and few treatment needs in patients. Grade II (6-10 points): Moderate limitations and moderate treatment needs. Grade III (11-20 points) and IV (21 or more points): severe and great punctuation treatment needs.

Secondary Outcome Measures

Measure changes in weight with the administration of active drugs. [Three months]
To realize a comparison between the average weight group in both arms before and after Valproate and Memantine administration.The weight will be measured in kilograms and the initial against the final will be compared.

Other Outcome Measures

The number of adverse events and the safety in the use of memantine in the prophylaxis of episodic migraine is comparable to valpoate. [Three months]
The number of adverse events and the safety of the use of memantine in the prophylaxis of episodic migraine is comparable to valpoate. Evaluated according to CTCAE v5.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
You must 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.