Clinical trial NCT04112823
Conditions: Migraine
Sponsor: Montefiore Medical Center
Start date: 2019-12-22; Completion date: 2022-12-31
Enrollment: 209 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Dexamethasone is an evidence-based treatment of acute migraine. This is a randomized comparison of two different doses of dexamethasone for acute migraine.

All patients will also be treated with metoclopramide.

Detailed description:
Investigational medications. Medications in each study arm are as follows:

A. Metoclopramide 10mg IV drip over 15 minutes (for acute treatment)+ dexamethasone 4 mg IV B. Metoclopramide 10mg IV drip over 15 minutes (for acute treatment)+ dexamethasone 16 mg IV Assignment. Will be concealed. The research pharmacist will determine assignment based on a random number sequence. Randomization. Randomization will occur in blocks of 4 based on a random number generator. Blinding. Patients, clinicians, and research personnel will be blinded. Stratification. Subjects will be stratified by study site (Moses or Weiler) and baseline pain intensity (moderate or severe).

Follow-up phone calls will be performed 48 hours and 7 days after ED (emergency department) discharge. At the first call, the next follow-up phone call will be scheduled. Attempts to complete the follow-up calls successfully will be made every eight hours until deemed futile. At this point, questionnaires will be sent by express courier, and failing this, the investigator will perform a home visit.

At the 48-hour phone call, the focus will be assessments of pain, functional status, migraine associated features, adverse events, satisfaction with the medication received, and use of rescue medication. The focus of the seven day phone call will be on the total number of days with headache since ED discharge, the need for repeat ED visits, healthcare providers visited, days of work missed, and adverse medication effects.

Arms: arm 1: Dexamethasone 4mg, administered intravenously arm 2: Dexamethasone 16mg, administered intravenously
Interventions: intervention 1: Dexamethasone 4mg intervention 2: Dexamethasone 16mg
Intervention descriptions: intervention 1: Dexamethasone 4mg + metoclopramide 10mg, intravenously intervention 2: Dexamethasone 16mg + metoclopramide 10mg, intravenously

Protocol documents:
Prot_SAP_000.pdf: 
Dexamethasone for Migraine - Dose Comparison
Protocol ID: 2019-10562
NCT04112823


Dexamethasone for acute migraine. A randomized dose-comparison study. 
PI: Benjamin W. Friedman, MD, MS
Version date 07262019
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NCT#
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Aims
Migraine, a chronic, episodic headache disorder characterized by recurrent exacerbations, causes 1.2 million 
visits to US emergency departments (ED) annually.[1] Nearly 2/3rds of migraine patients experience worsening 
or recurrence of headache within 48 hours of ED discharge. About half of patients suffer more than two days of 
headache during the week following ED discharge.[2] Dexamethasone is an evidence-based treatment for 
migraine, with a number needed to treat of nine to decrease the frequency of moderate or severe headache 
within 72 hours of ED discharge.[3] The American Headache Society recommends dexamethasone for use in 
patients with acute migraine.[4] However, the optimal dose of dexamethasone is not known. Aggregated data do 
not reveal an association between dose of steroids and outcome. We therefore will perform a randomized dose-
finding study to determine whether high-dose dexamethasone affords more relief for patients with an acute 
migraine who present to an ED than low-dose dexamethasone. We hypothesize that dose of dexamethasone will 
be directly associated with the rate of sustained headache relief.
Methods.
Study design. This will be a randomized, double blind, comparative efficacy study conducted among patients 
who present to an ED with acute migraine. All participants will receive standard-of-care acute treatment, 
consisting of metoclopramide 10mg IV as the primary abortive medication. Additionally, all participants will 
receive a dose of dexamethasone IV. Because dexamethasone is an evidence-based therapy in these patients, 
there will be no placebo arm. Outcomes will be assessed by telephone 48 hours and seven days after the ED 
visit using a standardized instrument with a closed-question format. 
Population of interest. Eligible patients are those presenting to the ED for treatment of an acute migraine 
headache as defined by International Headache Society clinical criteria.[5] At the time of enrollment, the patient 
must rate the headache as moderate or severe in intensity and the ED treatment plan must include use of an 
intravenous medication. Adults aged at least 18 years will be eligible to participate. Patients are to be excluded 
for signs of secondary headaches including fever or objective neurologic findings on physical exam. Patients 
will also be excluded if already using corticosteroids, for contraindications or allergies to the investigational 
medications, or if pregnant or breastfeeding. Medication contra-indications are as follows:  pheochromocytoma, 
seizure disorder, Parkinson’s disease, use of MAO inhibitors, and use of anti-rejection transplant medications. 
Because patients will receive only one dose of dexamethasone, we will not exclude diabetics from participation.
Study setting. This study will be conducted in the Moses and Einstein EDs. 
Investigational medications. Medications in each study arm are as follows:
A. Metoclopramide 10mg IV drip over 15 minutes (for acute treatment)+ dexamethasone 4 mg IV
B. Metoclopramide 10mg IV drip over 15 minutes (for acute treatment)+ dexamethasone 16 mg IV
Assignment. Will be concealed. The research pharmacist will determine assignment based on a random number 
sequence. 
Randomization. Randomization will occur in blocks of 4 based on a random number generator. 
Blinding. Patients, clinicians, and research personnel will be blinded. 
Stratification. Subjects will be stratified by study site (Moses or Weiler) and baseline pain intensity (moderate 
or severe).
IRB NUMBER: 2019-10562
IRB APPROVAL DATE: 07/27/2022


Dexamethasone for acute migraine. A randomized dose-comparison study. 
PI: Benjamin W. Friedman, MD, MS
Version date 07262019
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Details of protocol. Patients who present to either of the study EDs with an acute headache will be referred by 
the attending emergency physician to the research staff for enrollment. Eligibility will be ascertained by 
research associates and verified by the site investigator. Capacity to consent to participate in this study will be 
assessed by the attending emergency physician and specifically documented. Prior to enrollment, patients with 
diabetes will be cautioned that the study medications may cause loss of glycemic control and that they will need 
to be attentive to their blood sugar during the week following ED discharge. Masked medication will be 
obtained from the pharmacy. The research associate will perform a baseline pain assessment. The ED nurse will 
then administer the research medication as described above. The research associates will return every 60 
minutes to perform an assessment of headache, associated features, and adverse events. The use of rescue 
medications to treat persistent pain will also be recorded. Prior to discharge, research associates will ascertain 
key socio-demographics and pertinent features of the headache history. A specific time to perform the first 
follow-up phone call will be scheduled. At the time of discharge, we will again caution diabetics to be attentive 
to their blood sugar.
    Follow-up phone calls will be performed 48 hours and 7 days after ED discharge. At the first call, the next 
follow-up phone call will be scheduled. Attempts to complete the follow-up calls successfully will be made 
every eight hours until deemed futile. At this point, questionnaires will be sent by express courier, and failing 
this, the investigator will perform a home visit. 
   At the 48-hour phone call, the focus will be assessments of pain, functional status, migraine associated 
features, adverse events, satisfaction with the medication received, and use of rescue medication. The focus of 
the seven day phone call will be on the total number of days with headache since ED discharge, the need for 
repeat ED visits, healthcare providers visited, days of work missed, and adverse medication effects. 
Measures and outcomes
Measures and outcomes used in this trial will utilize NINDS’s common data elements for headache and adhere 
to the International Headache Society’s clinical trials guidelines.[6] Exceptions to this will occur only for 
recommendations not relevant to ED-based studies.
Baseline variables of interest: Age, sex, duration of headache, use of medication prior to ED presentation (yes/ 
no), aura symptoms
 1) Headache intensity. We will assess headache intensity using the recommended four-item descriptive scale 
commonly used in headache clinical trials. Patients will be asked to describe their headache intensity as 
“severe,” “moderate,” “mild,” or “none.”[6]
2) Functional disability will be assessed using the recommended four-item scale: Severely impaired (“can't get 
out of bed”); Moderately impaired (“great deal of difficulty doing what I usually do”); Mildly impaired (“some 
difficulty doing what I usually do”); and Not impaired [6]
3) Headache days. We will ask how many days since ED discharge the patient had any headache, a moderate or 
severe headache, or an activity-impairing headache. For the purpose of this tabulation, a new day begins when 
the patient awakens to begin activities for the day and ends when the patient sleeps after ceasing all activities 
for the day. We will also ask patients to determine how often during their awake hours they experienced any 
headache using the following Likert scale: always, often, sometimes, rarely, never.
4) Medication preference. Preference for a specific medication is a highly patient centered outcome, in which an 
individual determines for herself the benefit of a particular drug versus the adverse effects experienced. We will 
include in this study a measure that has been used in multiple ED-based trials—“The next time you come to the 
IRB NUMBER: 2019-10562
IRB APPROVAL DATE: 07/27/2022


Dexamethasone for acute migraine. A randomized dose-comparison study. 
PI: Benjamin W. Friedman, MD, MS
Version date 07262019
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ER for treatment of migraine, do you want to receive the same medication again?”[7] Patients will be asked to 
choose among “Yes,” “No,” or “Not sure”. 
5) Adverse outcomes will be assessed using an open-ended format. Patients will be asked to grade the specific 
adverse events they list as “mild,” “moderate,” or “severe.”
Outcomes. 
Efficacy analysis. The primary outcome for this study will be sustained headache relief for 48 hours: achieving 
a headache intensity = “none” or “mild” within two hours of medication administration and maintaining this 
level, without requiring additional headache medication, for the entire 48 follow-up period
Secondary efficacy endpoints. 
1) Two hours headache relief (achieving a headache level = mild or none within two hours of medication 
administration without requiring rescue medication 2) Number of headache days during the week after ED 
discharge 3) Patient preference for receiving the same medication for a subsequent headache, measured at the 
48 follow-up phone call 4) Use of additional headache medication in the ED 5) Use of additional headache 
medical after ED discharge
Safety endpoints. 1) Frequency of adverse events in the ED; 2) Frequency of adverse events developing within 
48 hours following ED discharge. 
Both during the ED visit and at the 48 hour follow-up, we will ask the following question: Did any new 
symptoms begin after you received the study medication. An affirmative response will be followed with open-
ended queries to categorize these symptoms. Affirmative responses will be tabulated. The open-ended queries 
will be used to categorize specific adverse events.
Analysis. Efficacy. For the primary analysis, we will report the rate of sustained headache freedom in each 
group as n/N (%, 95%CI). Random assignment will be stratified to ensure balance among the study arms with 
regard to study site and baseline pain intensity. Asymmetry with regard to the other important baseline variables 
discussed above will be addressed using multivariable regression techniques. We will address discrepant 
baseline variable by building a multivariate linear regression model in which the dependent variable in number 
of headache days, the primary predictor variable is investigational medication, and all discrepant important 
baseline variables are included in the model.
Dichotomous secondary outcomes will be reported as simple proportions, relative risk, and odds ratios with 
95%CI. Absolute risk reduction will be calculated and reported with 95%CI.
Safety analysis. We will perform simple pairwise comparisons of specific adverse events. 
Sample size calculation. In a recently completed study performed here at Montefiore, the rate of sustained 
headache relief after administration of metoclopramide 10mg IV +dexamethasone 10mg IV was 37%. In this 
type of research, a clinically important difference has been defined as an approximate 15% absolute risk 
reduction (between group difference). Assuming a primary outcome rate of 30% in the high dose group and 
45% in the low dose group, we calculated the need for 163 patients in each arm, using an alpha =0.05 and beta= 
0.20. To this we added a 10% margin to account for protocol violations and patients lost to follow-up. 
Therefore, we hope to enroll 360 patients.
We anticipate that we can enroll 250 patients/ year.
IRB NUMBER: 2019-10562
IRB APPROVAL DATE: 07/27/2022


Dexamethasone for acute migraine. A randomized dose-comparison study. 
PI: Benjamin W. Friedman, MD, MS
Version date 07262019
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Data collection and processing. Data acquisition will be performed using REDCap (Research Electronic Data 
Capture), a secure, web-based application designed specifically to support data capture for research studies. The 
REDCap project  (http://project-redcap.org/) is an international project, with more than 70 institutional partners 
from CTSA and GCRC funded institutions. Paper consent documents will be maintained in locked research 
cabinets.
Data monitoring committee and interim analysis. This committee will be headed by Dr. Carlo Lutz, MD MS, 
and include Dr. Esses, MD, the interim chair of the Department of Emergency Medicine. The committee will 
meet every month with the PI and co-investigators to monitor:  1) adverse events; and, 2) recruitment and 
enrollment. 
We will perform an interim analysis after 200 patients have been enrolled, slightly past the halfway point. At 
this point, we will halt the study for futility, clear superiority, or a large discrepancy in adverse medication 
events. Futility will be defined as < 10% between-group difference, as continuing the study beyond this point 
would be unlikely to result in a statistically significant difference between the groups. Clear superiority will be 
defined as >20% between-group difference. A large discrepancy in adverse events will be defined as >20% 
between-group difference in the overall rate of participants who suffer any adverse event.
Registration. The study will be registered at http://www.clinicaltrials.gov.
Consent. Informed consent will be obtained when patients present to the ED.  As part of our consent process, 
we will offer to help patients call a family member or friend and discuss the study with them if they wish.  We 
will also have the patient’s attending physician confirm that the patient has the capacity to consent to participate 
in the study at the time they are asked to provide consent.
Risks/Benefits
Anti-dopaminergics such as metoclopramide can cause extra-pyramidal side effects including tardive 
dyskinesia. Corticosteroids can cause irreversible boney necrosis and short-term side effects including mood 
swings, nightmares, loss of glycemic control, and an increased propensity for infections. Of note, the 
irreversible side effects listed above have never been reported after a single standard dose of any of the 
investigational medications administered in this study. The investigational medications can also cause a variety 
of nuisance side effects including dizziness, drowsiness, and palpitations. As with any clinical study, there is a 
risk that the patient’s personal identifiers and private health data may be seen by non-study personnel. It is clear 
that a great many migraine patients continue to suffer from headache after ED discharge. This protocol is 
specifically designed to inform the ED-based treatment of acute migraine.
Data Storage & Confidentiality
Data will be stored and maintained securely in REDCap. Data analysis initially de-identifies patients, and is 
done only on password-protected computers behind an institutional firewall, protected with professionally 
maintained anti-viral software. Consent documents will be maintained in locked research cabinets in 
inaccessible areas. Only study personnel will have access to the data and consent documents.
IRB NUMBER: 2019-10562
IRB APPROVAL DATE: 07/27/2022


Dexamethasone for acute migraine. A randomized dose-comparison study. 
PI: Benjamin W. Friedman, MD, MS
Version date 07262019
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References:
1.
Friedman, B.W., et al., Current management of migraine in US emergency departments: An analysis of 
the National Hospital Ambulatory Medical Care Survey. Cephalalgia, 2015. 35(4): p. 301-9.
2.
Friedman, B.W., et al., Recurrence of primary headache disorders after emergency department 
discharge: frequency and predictors of poor pain and functional outcomes. Annals of emergency 
medicine, 2008. 52(6): p. 696-704.
3.
Colman, I., et al., Parenteral dexamethasone for acute severe migraine headache: meta-analysis of 
randomised controlled trials for preventing recurrence. BMJ, 2008. 336(7657): p. 1359-61.
4.
Orr, S.L., et al., Management of Adults With Acute Migraine in the Emergency Department: The 
American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache, 2016. 
56(6): p. 911-40.
5.
Olesen, J., et al., The International Classification of Headache Disorders, 3rd edition (beta version). 
Cephalalgia : an international journal of headache, 2013. 33(9): p. 629-808.
6.
Tfelt-Hansen, P., et al., Guidelines for controlled trials of drugs in migraine: third edition. A guide for 
investigators. Cephalalgia : an international journal of headache, 2012. 32(1): p. 6-38.
7.
Friedman, B.W., P.E. Bijur, and R.B. Lipton, Standardizing emergency department-based migraine 
research: an analysis of commonly used clinical trial outcome measures. Academic emergency 
medicine : official journal of the Society for Academic Emergency Medicine, 2010. 17(1): p. 72-9.
IRB NUMBER: 2019-10562
IRB APPROVAL DATE: 07/27/2022