Clinical trial NCT02657031
Conditions: Headache
Keywords: Headache, Migraine
Sponsor: University Medical Center of Southern Nevada
Start date: 2016-03-17; Completion date: 2017-03-21
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares the efficacy of low dose Ketamine versus Compazine for the control of headache in patients presenting to the Emergency Department.

Detailed description:
After enrollment, each patient will randomized either to the standard treatment arm to receive prochlorperazine 10 mg IV along with diphenhydramine 25 mg IV, OR to the study arm to receive Ketamine 0.3 mg/kg along with ondansetron 4 mg IV. The diphenhydramine or ondansetron will be administered first, and immediately afterward the prochlorperazine or Ketamine will be administered. The prochlorperazine or Ketamine will be diluted in saline so that the total volume is 5 mL, and will be administered over 2 minutes. The diphenhydramine will be diluted in saline so that it is 2 mL (the same volume as the ondansetron). Both groups will also receive a 500 mL normal saline bolus after the study medications are administered. The ED pharmacist will be responsible for preparing the medications, using a double-blind protocol. He or she will record which arm the patient was randomized to. Only the pharmacist will have access to the randomization records and will not reveal the randomization until the end of the study. Emergency providers will be instructed not to administer any rescue medications for at least 30 minutes. The electronic medical record order will read "randomized study medication" (for the Ketamine or prochlorperazine) and "randomized add-on medication" (for the ondansetron or diphenhydramine).

Arms: arm 1: This arm uses standard of care treatment of prochlorperazine 10 mg IV along with diphenhydramine 25 mg IV plus Normal Sailine 500 cc bolus arm 2: This arm uses stud drug regime of Ketamine 0.3 mg/kg along with Ondansetron 4 mg IV plus Normal Saline 500 cc bolus.
Interventions: intervention 1: Prochlorperazine intervention 2: Ketamine intervention 3: Diphenhydramine intervention 4: Ondansetron intervention 5: Normal Saline
Intervention descriptions: intervention 1: prochlorperazine 10 mg IV intervention 2: Ketamine 0.3 mg/kg IV intervention 3: Diphenhydromine 25 mg IV intervention 4: Ondansetron 4 mg IV intervention 5: Normal Saline 500 cc IV Bolus

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 7 
CHECK Trial Protocol Version 4 
 
CLINICAL PROTOCOL 
 
 
The CHECK Trial:   
A Comparison of Headache Treatment in the Emergency Department:  
ProChlorperazine versus Ketamine   
 
 
INTRODUCTION 
 
In the emergency department (ED), one of the most common chief complaints is 
headache [1].   A number of prior studies have demonstrated the efficacy of a variety of 
medications for migraines and other benign headaches [2].  Some of the options for 
treating these types of headaches include dopamine antagonists, opioids, non-steroid anti-
inflammatory drugs (NSAIDs), triptans, anti-epileptics, and ergot derivatives [2].  
Amongst the available options, dopamine antagonists appear to be the most effective, 
with multiple studies demonstrating their superiority over opioids [3], NSAIDs [4], 
triptans [5], and anti-epileptics [6].  The dopamine antagonist that we use most 
frequently, and the one that has the most evidence to support its use for benign 
headaches, is prochlorperazine [5,6,7,8,9,10].  Although some data suggest that 
droperidol may be even more effective than prochlorperazine [11], the current national 
shortage limits its use.     
 
Despite the general effectiveness of dopamine antagonists and the variety of options for 
benign headache treatment, many patients who present to the ED still have headaches 24 
hours after treatment.  In one study by Friedman, 31% of patients still had moderate to 
severe headaches 24 hours after discharge [12].  Often we resort to opiates in refractory 
headaches despite evidence to suggest that opiates increase both length of stay and 
bounce backs [13]. 
 
Ketamine is a NMDA receptor antagonist that has both analgesic and dissociative 
properties [14].  Previous studies have demonstrated the effectiveness of ketamine for 
post-operative pain [15,16], pain in burn patients [17], and chronic pain [18].  New 
studies have also shown ketamine to be useful for acute pain in the ED by both the 
intranasal [19] and intravenous routes [20].  To our knowledge, there are no prospective 
studies that evaluate the effectiveness of ketamine for the treatment of benign headaches 
in the ED.    
 
We propose a double blind, randomized control study comparing ketamine to 
prochlorperazine for benign headaches in the ED.   
 
METHODS 
 
Study Design 
This will be a multicenter, prospective, double-blinded, randomized controlled trial on a 
convenience sample of patients presenting to the ED with a chief complaint of headache.  


Page 2 of 7 
CHECK Trial Protocol Version 4 
 
Subjects will only be enrolled when a pharmacist who is familiar with the study protocol 
is available to prepare medications.   
 
Exempt from FDA IND# 
This study meets the requirements in 21CFR312.2(b)Exemptions(1) to exclude this study 
drug from registration for FDA IND# .  
 
“21CFR312.2(b)Exemptions(1) The clinical investigation of a drug product that is 
lawfully marketed in the United States is exempt from the requirements of this part if all 
of the following apply: 
 
“(i)  The investigation is not intended to be reported to the FDA as a well-
controlled study in support of a new indication for use nor intended to be used to 
support any other significant change in the labeling for the drug; 
Investigators do not intend to report study data to the FDA to support label 
changes for Ketamine. 
 
“(ii)  If the drug that is under investigation is lawfully marketed as a prescription 
drug product, the investigation is not intended to support a significant change in 
the advertising for the product; 
Investigators do not intend to provide support for changes in advertising 
for Ketamine. 
 
“(iii)  The investigation does not involve a route of administration or dose level or 
use in a patient population or other factor that significantly increases the risk (or 
decreases the acceptability of the risks) associated with the use of the drug 
product; 
Investigators intend to administer Ketamine via the routine IV route at 
doses lower than typically ordered which will not alter the risk profile of 
the drug. 
 
“(iv)  The investigation is conducted in compliance with the requirements for 
institutional review set forth in part 56 and with the requirements for informed 
consent set forth in part 56; and 
This investigation will be conducted with UMC IRB approval with 
Written Informed Consent. 
 
“(v)  The investigation is conducted in compliance with the requirements of 
§312.7.”   
 
 
Study investigators will be compliant with 21CFR312.7  Which prohibits:  
“(a) promotion of an investigational new drug…,  (b) Commercial distribution of 
an investigational new drug…, (c)  prolonging an investigation…, (d) charging 
for and commercialization of investigational drugs…” 
 


Page 3 of 7 
CHECK Trial Protocol Version 4 
 
 
Selection of Participants 
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 [6,8,10].  Therefore, this study will enroll all patients between the ages 
of 18 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 18 to 65 years 
➢ Temperature < 100.4 F 
➢ Diastolic blood pressure < 104 mm Hg,  
➢ Normal neurologic exam and normal mental status 
 
Exclusion Criteria 
➢ Pregnant or breastfeeding. 
➢ 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 
➢ Weight more than 150 kg or less than 40 kg. 
➢ Known allergy to one of the study drugs. 
➢ History of schizophrenia or bipolar disorder. 
➢ History of intracranial hypertension. 
➢ Is a prisoner 
➢ Patient declined informed consent 
➢ Non-English speaking patient. 
➢ Attending provider excludes patient   
➢ Patient received any pain medication prior to enrollment 
 
Written, informed consent will be obtained from each patient.  Consent will include a 
discussion of the risks and benefits.  The risks are the side effects associated with each 
drug.  For compazine, this includes drowsiness, blurred vision, xerostomia, congestion, 
nausea, akasthisia, tardive dyskinesia, NMS, and blood dyscrasias.  For ketamine, this 
includes, sialorrhea, nausea/vomiting, elevation in blood pressure or heart rate, 
nystagmus/diplopia, fasciculations, hallucinations, bradycardia or hypotension, 
arrythmias, and respiratory depression.    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 randomized either to the standard treatment arm to 
receive prochlorperazine 10 mg IV along with diphenhydramine 25 mg IV, OR to the 


Page 4 of 7 
CHECK Trial Protocol Version 4 
 
study arm to receive ketamine 0.3 mg/kg along with ondansetron 4 mg IV.  The 
diphenhydramine or ondansetron will be administered first, and immediately afterward 
the prochlorperazine or ketamine will be administered.  The prochlorperazine or ketamine 
will be diluted in saline so that the total volume is 5 mL, and will be administered over 2 
minutes.  The diphenhydramine will be diluted in saline so that it is 2 mL (the same 
volume as the ondansetron).  Both groups will also receive a 500 mL normal saline bolus 
after the study medications are administered.  The ED pharmacist will be responsible for 
preparing the medications, using a double-blind protocol.  He or she will record which 
arm the patient was randomized to.   Only the pharmacist will have access to the 
randomization records and will not reveal the randomization until the end of the study.  
Emergency providers will be instructed not to administer any rescue medications for at 
least 30 minutes.  The electronic medical record order will read “randomized study 
medication” (for the ketamine or prochlorperazine) and “randomized add-on medication” 
(for the ondansetron or diphenhydramine). 
 
Safety 
After 30 minutes, the treating provider will be permitted to administer any medication 
they would like for further treatment.  If there is an untoward event that requires the 
treating provider to know which medication was administered, the pharmacist will 
unblind the randomization for that individual patient and the patient 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. 
 
 
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 15, 30, 45, and 60 minutes.  Time 
zero begins immediately after complete administration of the study drug.  Nausea (with a 
100 m VAS), vomiting, anxiety, restlessness (akathisia), heart rate, and blood pressure 
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 them to rate their satisfaction with the drug they received on a scale of 0-10, and to 


Page 5 of 7 
CHECK Trial Protocol Version 4 
 
ask if they are currently having a headache (yes or no).  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 
prochlorperazine and ketamine 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 
development of akathisia, rate of use of additional medications for headache, heart rate 
and blood pressure changes, headache resolution with telephone follow up, and patient 
satisfaction. 
 
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: 
 
A couple prior studies have used a 25-mm difference in mean VAS score reduction 
between groups to show a clinical benefit [6,9].  We define significant pain relief as an 
absolute decrease in the mean VAS score of 25 mm.   
 
Thirty-two patients will be needed in each group to find a 25-mm difference between the 
group means on the VAS at 60 min, with a power of 0.80 and an alpha of 0.05.  We will 
aim for 35 patients per group to account for about a 10% dropout rate.  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. 
 
 
References: 
 
[1]  Pitts SR, Niska RW, Xu J, Burt CW. National Hospital Ambulatory Medical Care 
Survey: 2006 emergency department summary. National health statistics reports; no 7. 
Hyattsville, MD: National Center for Health Statistics. 2008. 
 
[2]  Gelfand AA, Peter J. Goadsby PJ.  A Neurologist's Guide to Acute Migraine Therapy 
in the Emergency Room.  The Neurohospitalist 2012 2: 51 
 
[3] Cicek M, Karcioglu O, Parlak I, et al. Prospective, randomised, double blind, 


Page 6 of 7 
CHECK Trial Protocol Version 4 
 
controlled comparison of metoclopramide and pethidine in the emergency treatment of 
acute primary vascular and tension type headache episodes. Emerg Med J. 2004;21:323-
326. 
 
[4]  Friedman BW, Adewunmi V, Campbell C, et al.  A Randomized Trial of Intravenous 
Ketorolac Versus Intravenous Metoclopramide Plus Diphenhydramine for Tension-Type 
and All Nonmigraine, Noncluster Recurrent Headaches.  Annals of Emergency Medicine.  
2013:62(4):311-318. 
 
[5]  Kostic MA, Gutierrez FJ, Rieg TS, Moore TS, Gendron RT.  A Prospective, 
Randomized Trial of Intravenous Prochlorperazine Versus Subcutaneous Sumatriptan in 
Acute Migraine Therapy in the Emergency Department.  Annals of Emergency Medicine.  
2009.   
 
[6] Tanen DA, Miller S, French T, Riffenburgh RH.  Intravenous Sodium Valproate 
Versus Prochlorperazine for the Emergency Department Treatment of Acute Migraine 
Headaches: A Prospective, Randomized, Double-Blind Trial.  Ann Emerg Med. 
2003;41:847-853.   
 
[7] Jones J, et al. Randomized double-blind trial of intravenous prochlorperazine for the 
treatment of acute headache. JAMA.1989;261:1174-1176. 
 
[8] Friedman BW, Esses D, Solorzano C, et al.  A Randomized Controlled Trial of 
Prochlorperazine Versus Metoclopramide for Treatment of Acute Migraine.  Annals of 
Emergency Medicine 2008: 52(4): 399-406. 
 
[9] Callan JE, Kostic MA, Bachrach EA, Rieg TS.  Prochlorperazine versus 
Promethazine for Headache Treatment in the Emergency Department:  A Randomized 
Controlled Trial.  J Emerg Med. 2008; 35:247-253.   
 
[10] Coppola M, Yealy DM, Leibold RA.  Randomized, Placebo-Controlled Evaluation 
of Prochlorperazine Versus Metoclopramide for Emergency Department Treatment of 
Migraine Headache.  Annals of Emergency Medicine 1995.      
 
[11] Miner JR, et al. Droperidol vs. prochlorperazine for benign headaches in the 
emergency department. Acad Emerg Med. 2001;8:873-879. 
 
[12]  Friedman BW, Hochberg ML, Esses D, et al.  Recurrence of primary headache 
disorders after Emergency Department discharge:  frequency and predictors of poor pain 
and functional outcomes.  Ann Emerg Med.  2008 Dec:52(6):696-704. 
 
[13]  McCarthy LH, Cowan RP.  Comparison of parenteral treatments of acute primary 
headache in a  large academic emergency department cohort.  Cephalalgia.  2015 
Aug;35(9):807-15. 
 
[14]  Adams HA.  Mechanisms of action of ketamine.  Anaesthesiol Reanim.  


Page 7 of 7 
CHECK Trial Protocol Version 4 
 
1998;23(3):60-3. 
 
[15] Eghball MH, Taregh S, Amin A, Sahmeddini MA.  Ketamine Improves 
Postoperative Pain and Emergence Agitation Following Adenotonsillectomy in Children:  
A Randomized Clinical Trial.  M.E.J. ANESTH 22 (2), 2013.   
 
[16]  Weinbroum AA. A single small dose of postoperative ketamine provides rapid and 
sustained improvement in morphine analgesia in the presence of morphine-resistant pain. 
Anesth Analg 2003;96:789–795. 
 
[17]  McGuinness SK, Wasiak J, Cleland H, et al. A systematic review of ketamine as an 
analgesic agent in adult burn injuries. Pain Med 2011;12:1551–1558. 
 
[18] Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based 
review. Anesth Analg 2003;97:1730–1739. 
 
[19]  Andolfatto G, Willman E, Joo D, et al.  Intranasal Ketamine for Analgesia in the 
Emergency Department: A Prospective Observational Series.  Acad Emerg Med.  
2013;20(10):1050-1054.   
 
[20]  Motov S, Rockoff B, Cohen V, et al.  Intravenous Subdissociative-Dose Ketamine 
Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled 
Trial.  Ann of Emerg Med.  2015;66(3):222-229.   
 
[21]  Miner JR, Smith SW, Moore J, et al. Sumatriptan for the treatment of 
undifferentiated primary headaches in the ED. Am J Emerg Med. 2007;25:60-64.