Clinical trial NCT05967442
Conditions: Migraine Headache
Keywords: magnesium migraine headache
Sponsor: Wake Forest University Health Sciences
Start date: 2019-08-23; Completion date: 2023-04-06
Enrollment: 157 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This investigation describes a proposed clinical trial that will evaluate the relative efficacy of intravenous magnesium sulfate for the treatment of migraine compared to intravenous metoclopramide (Reglan) and intravenous prochlorperazine (Compazine) in the treatment of acute headache and migraine in adult patients. The ultimate objective will be clinical application of these drugs in the emergency department for the treatment of acute headache and migraine.

The two phenothiazines (metoclopramide and prochlorperazine) have been routinely utilized in the treatment of acute headache and migraine in the emergency department setting. Per the 2017 American Headache Society guidelines, both intravenous metoclopramide and intravenous procholorperazine are recommended as "clinicians should offer" agents with level B evidence. Of note, there are no agents with level A evidence purported by this guideline for acute management of migraine. The same guideline offers "no recommendation can be made regarding the role of intravenous magnesium for adults who present to the ED with acute migraine. However intravenous magnesium may be of benefit to patients who present with migraine with aura." Multiple trials have evaluated intravenous magnesium's safety and efficacy in the management of acute migraine. These have demonstrated the tolerability of intravenous magnesium on a with breadth of patients. Most commonly the primary adverse event was flushing which self-resolved. No cases of hypotension were reported.

None of these study agents have been withdrawn from the market.

Detailed description:
Migraine or severe headache affected one-fifth of women and one-tenth of men in 2015 and is one of the leading causes of disability in the world. Over one million visits to emergency departments (ED) in the US are due to migraines. Migraine, previously believed to be a vascular disorder, is caused by inflammation due to vasodilation in the meninges secondary to the release of vasoactive neuropeptides by stimulation of the trigeminal nerve. This inflammation can result in symptoms such as headache, nausea, vomiting, dizziness, photophobia and phonophobia.

Despite migraine being a common disorder, there has yet to be a cure. Several classes of medications have been studied for the treatment of migraine. Recently, conventional therapy has shifted to the use of antidopaminergics including prochlorperazine, metoclopramide and haloperidol, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, and triptans, sumatriptan being the most commonly utilized. 5Although intravenous opioids have historically been the most common treatment for migraines, their use has fallen out of favor due to their association with increased recurrence of headaches and ED visits, abuse potential, and most recently severe intravenous opiate shortage. Alternative treatments include ketamine, propofol, dihydroergotamine and magnesium.

Magnesium is an intracellular cation that has been associated with both the function of serotonin and regulation of vascular tone, which are both mechanisms that implicate its role in the treatment of migraine. Intravenous magnesium sulfate has been studied as a treatment for migraine compared to placebo, metoclopramide and prochlorperazine. These studies have shown that magnesium is well-tolerated with a good safety profile and may be efficacious in the treatment of migraine. Metoclopramide, prochlorperazine and magnesium have been recommended in clinical practice guidelines and have become routine standard of care for treatment of migraine in this emergency department. However, no trial has evaluated these modalities simultaneously in the same population. The purpose of our study is to compare the relative efficacy for magnesium, metoclopramide, and prochlorperazine in the treatment of headache and migraine.

Via monthly block randomization, patients will be given one of three guideline recommended study drugs. Allocation will be concealed by a pharmacist (not participating in the rest of the study) solely designated to choose which drug will be the assigned study drug for each month. The pharmacists, physicians, and nurses participating in administration of the medications will be blinded to which drug is being administered during each month. Metoclopramide, prochlorperazine and magnesium have been recommended in clinical practice guidelines and have become routine standard of care for treatment of migraine in this emergency department. All three study drugs will be stored in the investigational medication refrigerator located in the main pharmacy. A pharmacist on duty in the emergency department will obtain the medication from the refrigerator and deliver it to the bedside nurse who is actively caring for the patient after an order from the physician.

The primary outcome of this study will be mean change in pain from baseline to 30 minutes after initiation of infusion (as defined on a 11-point Numeric Rating Scale. Secondary endpoints include mean change in pain from baseline to 60 minutes and 120 minutes after initiation of infusion (as defined on a 11-point Numeric Rating Scale), time to emergency department discharge, and adverse effects due to administration of study drug (hypotension, flushing, akathisia, dystonia, nausea, vomiting, dizziness, drowsiness, other self-reported adverse effects).

Arms: arm 1: Magnesium Sulfate 2gm in 50ml D5W over 20 minutes arm 2: Metoclopramide 10mg in 50ml D5W over 20 minutes arm 3: Prochlorperazine in 50ml D5W over 20 minutes
Interventions: intervention 1: Magnesium Sulfate intervention 2: Metoclopramide 10mg intervention 3: Prochlorperazine (Compazine) Injection
Intervention descriptions: intervention 1: Magnesium Sulfate 2gm in 50ml D5W over 20 minutes intervention 2: Metoclopramide 10mg in 50ml D5W over 20 minutes intervention 3: Prochlorperazine 10mg in 50ml D5W over 20 minutes

Protocol documents:
Prot_SAP_002.pdf: 
Official Title:  A Randomized, Placebo-Controlled, Double-Blind Study of the Effects of Magnesium 
Compared to Conventional Therapy on Acute Migraine  
NCT05967442
Date:  9/10/2020


Study Protocol and Statistical Analysis Plan
Study Design and Setting
This study was a single-center, prospective, double-blinded, randomized-controlled,
three-armed trial comparing magnesium, metoclopramide, and prochlorperazine for the
treatment of migraine. This trial was conducted in a large, level 1 trauma, tertiary-care medical
center ED near Chicago, Illinois from August of 2019 through March of 2020.
Selection of Participants
Patients greater than or equal to 18 years of age presenting to the ED with a chief complaint of
migraine or headache while an ED pharmacist was present were eligible for inclusion in this
study. Migraine diagnosis was determined by an ED physician after thorough examination to
rule out migraine mimics or headache conditions where traditional migraine therapy would be
deemed inappropriate. Patients were required to have the ability to provide informed consent.
Exclusion criteria included
pregnancy, a stated history of renal impairment, allergy or sensitivity to
any of the study drugs, or receipt of any of the study drugs prior to
Enrollment.
Interventions
Following assessment for study eligibility, patients were consented by the ED pharmacist.
Patients were randomized to receive one of three study drugs (magnesium sulfate 2 g,
metoclopramide 10 mg, or prochlorperazine 10 mg) via computer randomization. Study drug
randomization and preparation was the responsibility of the IV room pharmacist who was not
part of the study. The ED pharmacists, physicians, and nurses participating in administration of
the medications were blinded to which drug was selected. Magnesium sulfate 2 g/50 mL D5W,
prochlorperazine 10 mg/50 mL D5W, or metoclopramide 10 mg/50 mL D5W was then
administered as an IV infusion over 20 min.
Measurements and outcomes
The primary outcome of this study was change in pain from baseline to 30 min after initiation of
infusion. Pain was assessed by the ED pharmacist using the 11-point Numeric Rating Scale
(NRS) and recorded on a data collection tool. NRS is a validated tool commonly used to
measure different types of pain [15]. Secondary endpoints included change in pain score from
baseline to 60 min and 120 min after initiation of infusion (as defined on a 11-point NRS), ED
length of stay, and necessity for rescue analgesia at any time following the study drug
administration. Safety endpoints included monitoring for common adverse effects related to the
study drugs—primarily hypotension, flushing, akathisia, dystonia, nausea, vomiting, dizziness,
drowsiness, or other self-reported adverse effects [16-18]. Patient baseline characteristics were
also collected, which included patient-reported past medical history and analgesic use prior to
presenting to the ED.
Analysis


A sample size of 264 subjects (88 subjects per treatment arm) was calculated to detect a
difference of 1.4 points in the NRS between groups to achieve a power of 80% [19]. Statistical
significance was defined a priori as p < 0.05, and normality was assessed using the
Shapiro-Wilk test. Descriptive statistics were used for nominal data, while ordinal and
categorical data were evaluated using Mann-Whitney U and Pearson's χ2 , respectively.
Between-group comparisons were made using one-way ANOVA and Kruskal-Wallis, as
appropriate for all continuous data. A post hoc non-inferiority analysis of the primary endpoint
was conducted using Welch's t-test with a non-inferiority margin of 1.4. Data analysis was
performed through SAS software for Windows (Version 9.4).