Clinical trial NCT03185130
Conditions: Headache
Keywords: Headache Benign Headache
Sponsor: University Medical Center of Southern Nevada
Start date: 2017-05-16; Completion date: 2019-05-15
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Migraine headache has a 1-year period prevalence in the US of 11.7% and accounts for approximately 1.2 million migraine visits to US emergency departments per year . There are numerous studies that discuss treatment for migraine and other benign headaches within the emergency department (ED), however, there are very few that discuss specifically the use of intravenous fluids (IVF) for headache treatment. Many of these studies look at various options for treating migraine and other benign headaches: treatment options include dopamine antagonists, opioids, non-steroid anti-inflammatory drugs (NSAIDs), triptans, anti-epileptics and ergot derivatives. Comparisons have been done between many of these treatment options with dopamine antagonists appearing to be the most effective, compared to other treatments The dopamine antagonist with the most evidence and availability for benign headaches is prochlorperazine. Given that IVF administration is a common part of treatment regimen for benign headache patients in the emergency department and given the lack of randomized trials in adults, the investigators aim to study the use of IVF on pain reduction in headache patients in the adult ED. There has been one randomized trial in pediatrics that shows IVF may help in patients with migraines, whereas the adult literature has no randomized control trials and a review of data shows that fluids do not help relieve pain in migraine headache patients. This study will include both adult and pediatric patients presenting to the Emergency Department with complaint of benign headache.

Detailed description:
This will be a single center, prospective, single blinded randomized controlled trial on a convenience sample of patients presenting to the adult or pediatric ED with a chief complaint of headache. Subjects will only be enrolled when a physician or research assistant who is familiar with the study protocol is available to enroll patients. Written, informed consent will be obtained from each patient. Consent will include a discussion of the risks and benefits. In addition to parental informed consent in the pediatric population, age appropriate verbal assent will be obtained from pediatric subjects. After 30 minutes, the treating provider will be permitted to administer a "rescue medication" of their choice for further treatment. If there is an untoward event that requires the patient to know which IVF dose was administered, patient will unblinded and will not continue in the study.

Arms: arm 1: Standard Treatment Arm will receive: normal saline at 5 ml IV given over 1 hour, prochlorperazine 0.15 mg/kg up to 10 mg IV, diphenhydramine 1mg/kg (up to 50 mg) IV. arm 2: Study arm patients will receive: normal saline at 20 mL/kg (up to 1000 mL) given over 1 hour, prochlorperazine 0.15 mg/kg up to 10 mg IV, diphenhydramine 1mg/kg (up to 50 mg) IV.
Interventions: intervention 1: Normal Saline 5mL intervention 2: Normal Saline 20mL/kg intervention 3: Prochlorperazine 0.15 mg/kg up to 10 mg IV intervention 4: Diphenhydramine 1 mg/kg up to 50 mg IV
Intervention descriptions: intervention 1: Control arm subjects will receive Normal Saline 5 mL IV over 1 hour intervention 2: Study arm subjects will receive Normal Saline 20 mL/kg IV (up to 1000 mL) given IV over 1 hour, intervention 3: Standard Treatment Arm and Study Arm will receive prochlorperazine 0.15 mg/kg up to 10mg IV slow push intervention 4: Diphenhydramine dose 1 mg/kg up to 50 mg IV slow push

Protocol documents:
Prot_SAP_000.pdf: 
IVF Headache Protocol V7    3-15-2017      
 
 
 
 
 
 
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The I-FiBH Trial:  Intravenous Fluids in Benign Headaches Trial:  A Randomized Single 
Blinded Clinical Trial 
 
NCT 03185130 
 
March 15, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INTRODUCTION  
 
Migraine headache has a 1-year period prevalence in the US of 11.7% and accounts for 
approximately 1.2 million migraine visits to US emergency departments per year [1,2]. There are 
numerous studies that discuss treatment for migraine and other benign headaches within the 
emergency department, however, there are very few that discuss specifically the use of 
intravenous fluids (IVF) for headache treatment [3]. Many of these studies look at various 
options for treating migraine and other benign headaches: treatment options include dopamine 
antagonists, opioids, non-steroid anti-inflammatory drugs (NSAIDs), triptans, anti-epileptics and 
ergot derivatives [2]. Comparisons have been done between many of these treatment options 
with dopamine antagonists appearing to be the most effective, compared to other treatments [4, 
5, 6, 7]. The dopamine antagonist with the most evidence and availability for benign headaches 
is prochlorperazine [6, 7, 8 ,9, 10, 11, 12]. 
 
Peripheral IVs and administration are common procedures and treatments within the ED. And 
while relatively safe, they are not without their own risks [13, 14, 15, 16]. Given that IVF 
administration is a common part of treatment regimen for benign headache patients in the 
emergency department and given the lack of randomized trials in adults, we aim to study the use 
of IVF on pain reduction in headache patients in the adult ED [3]. Given the specific definition 
of migraine headache, we have chosen to categorize our headaches as benign headaches, 
avoiding the difficulty of determining if a patient meets the specific criteria for migraine 
headache [17, 18]. There has been one randomized trial in pediatrics that shows IVF may help in 
patients with migraines, whereas the adult literature has no randomized control trials and a 
review of data shows that fluids do not help relieve pain in migraine headache patients [3, 19, 
20].  
 
We will design a single blinded randomized trial to study the effects of IVF on benign headaches 
There are numerous challenges using the International Headache Society guidelines for 
controlled drug trials in acute migraines, including having a patient population that knows the 
specifics of migraine headaches and meets the exact definition. In order to facilitate obtaining the 
necessary number of patients we will include all benign headache patients [17,18]. 
 
METHODS 
Study Design 
This will be a single center, prospective, single blinded randomized controlled trial on a 
convenience sample of patients presenting to the adult or pediatric ED with a chief complaint of 
headache.  Subjects will only be enrolled when a physician or research assistant who is familiar 
with the study protocol is available to enroll patients.   
 
Selection of Participants 


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Previous data have found that patients presenting to the ED with an undifferentiated headache 
improve with all the above-described headache medications regardless of whether or not they 
meet the definition of migraine, tension headache, or another primary headache disorder [7, 8, 
11].  Therefore, this study will enroll all patients between the ages of 10 and 65 who meet all of 
the inclusion criteria and do not meet any of the exclusion criteria, who present to the ED with a 
benign headache.   
 
Inclusion Criteria 
Patients who present to the ED with complaint of a headache with the following criteria:  
➢ Age 10 to 65 years 
➢ Temperature < 100.4 F 
➢ Normal neurologic exam and normal mental status 
 
Exclusion Criteria 
➢ Pregnant. 
➢ Meningeal signs are present 
➢ Acute angle closure glaucoma is suspected.   
➢ Head trauma within the previous two weeks 
➢ Lumbar puncture within the previous two weeks  
➢ Thunderclap onset of the headache 
➢ Known allergy to one of the study drugs. 
➢ History of intracranial hypertension. 
➢ Is a prisoner 
➢ Patient declined informed consent 
➢ Non-English speaking patient or parent/guardian for pediatric patients 
➢ Attending provider excludes patient   
➢ Severe dehydration 
 
Informed Consent 
Written, informed consent will be obtained from each patient.  Consent will include a discussion 
of the risks and benefits.  In addition to parental informed consent in the pediatric population, 
age appropriate verbal assent will be obtained from pediatric subjects. 
 
Risk/Benefit 
The risks are the side effects associated with each drug.  For prochlorperazine, this includes 
drowsiness, blurred vision, xerostomia, congestion, nausea, akathisia, tardive dyskinesia, NMS, 
and blood dyscrasias.  For Benadryl include sedation, tiredness, sleepiness, dizziness, 
constipation, dry mouth, blurred vision, nausea, and loss of appetite.  For normal saline, this 


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includes injection site swelling, redness, infection, venous thrombosis or phlebitis or 
hypervolemia. Personal benefits include intended reduction in headache symptoms and the 
satisfaction that the patient may be assisting investigators in determining a more effective 
headache treatment. 
 
Interventions 
After enrollment, each patient will be randomized either to the standard treatment arm to receive 
prochlorperazine 0.15 mg/kg up to 10 mg IV along with diphenhydramine 1mg/kg (up to 50 mg) 
IV and normal saline at 5 mL/h IV OR to the study arm to receive prochlorperazine along with 
diphenhydramine IV and normal saline at 20 mL/kg (up to 1000 mL) given IV over 1 hour.  The 
diphenhydramine will be administered first, and immediately afterward the prochlorperazine will 
be administered.  The patient will then be connected to normal saline on an IV pump and 
randomized to 5 cc over an hour or 20 cc/kg (maximum 1000 cc) over one hour. The IV bag and 
pump will be covered so that the patient will not know how much fluid they are receiving.  
Patients will undergo simple randomization to either the fluid bolus group or the control group. 
The treating physician will consult a folder that contains a list specifying the group assignment. 
Each row of the list corresponded to a patient, and will be covered by a small slip of opaque 
paper that will be removed at the time of enrolment to reveal the group assignment. This list was 
constructed at the beginning of the study using a random number generator by a research staff.  
Randomization in the pediatric ED and adult ED will be separate to ensure equal numbers of 
pediatric patients in both the experimental and control arms (blocking).  Emergency providers 
will be instructed not to administer any rescue medications for at least 30 minutes.   
 
Safety 
After 30 minutes, the treating provider will be permitted to administer a “rescue medication” of 
their choice for further treatment.  If there is an untoward event that requires the patient to know 
which IVF dose was administered, patient will unblinded and will not continue in the study.  
 
Reportable Events 
Anticipated side effects are those listed on the manufacturer’s package insert and are treated as 
routine non-urgent or non-emergent events are not reportable events. 
Adverse Events are those unanticipated side effects that require interventions or anticipated side 
effects that do not respond to intervention. 
Serious Adverse Events are those side effects that require Advanced Life Support measures to 
control symptoms. 
AEs and SAEs will be reported to the IRB within 5 days of the event. 
 


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Methods of Measurement 
Enrolled patients will fill out a brief data collection form to include age, sex, race, phone 
number, and baseline headache severity using a 100-mm visual analog scale (VAS).  Repeat 
headache severity scores will be measured at 30 and 60 minutes.  Time zero begins immediately 
after complete administration of the study drug.  Nausea (with a 100 mm VAS) and vomiting 
will also be assessed at these time intervals.  The need for rescue medications will be extracted 
from the patient’s chart at a later time.   
 
Trained research assistants will call the patient 24-48 hours post-discharge by phone to ask if 
they are currently having a headache (yes or no) and to rate their current pain (0-10). If the 
patient is admitted, the patient will be approached in the hospital by an investigator or research 
assistant for follow up.      
 
Outcome Measures 
The primary outcome measure will be the difference in pain scores between the 5 cc over an 
hour and 20 mg/kg (up to 1000 cc) over an hour groups measured as the absolute difference 
between the means at 60 min.  Secondarily, we will measure the difference between the rates of 
decline in pain scores, rate of admission, nausea scores, rate of vomiting, rate of use of additional 
medications for headache, and headache resolution with telephone follow up. 
 
Privacy and Security 
In order to protect the privacy of the research subjects and to maintain the confidentiality of data, 
all data will be managed only by trained research assistants or investigators and will be stored in 
the locked Emergency Medicine research offices and electronic data will be stored on a password 
protected computer in the locked Emergency Medicine research office.  All research assistants 
and investigators are HIPAA- trained, CITI trained and credentialed by UMC IRB, and oriented 
to the study protocol. 
 
Data Analysis: 
Assuming a SD of 22 (based on prior data from our institution), we calculated that we would 
need 45 patients in each group to find a clinically important difference in pain score reduction 
(13 mm) between groups at 60 min with at least 80% power and an alpha of 0.05. 
 
The groups will be compared using a t -test on gender, race, and age; and a chi (with Yates 
correction)-squared test on severity of presenting headache, to determine if they are similar.  The 
individual VAS measurements will be compared using a repeated measures analysis of variance 
(ANOVA) test. 


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