Trial Information

Randomized Evaluation of Octreotide Versus Compazine for Emergency Department Treatment of Migraine Headache

A urine pregnancy test will be performed on women of child bearing age. After informed
consent is obtained, each patient will be placed in a dark private room and asked to grade
nausea, pain, and sedation on a 10 cm visual analog scale, using the left end as the zero
point for complaints and measurements. Patients will be instructed that a score of zero
signifies no pain and a score of 10 indicates severe pain. Each patient will be monitored
with continous pulse oximetry and have a 20-gauge IV catheter placed in the antecubital
fossa. Based on a computer generated random table, each subject will receive one of the
following: 2 cc containing 100ug octreotide, or 10 mg compazine over a 2 minute period,
followed by a 5 cc flush of saline solution. The above medication doses were chosen based on
previous literature. 6-8 Vital signs (blood pressure, heart rate, and respiratory rate) will
be recorded at 0, 30, and 60 minutes. At 60 minutes after the study injection, each
patient will be asked to regrade nausea, pain(VAS), and sedation on the same scale without
viewing the initial scores. Clinically important successful treatment will be defined as
achievement of the following criteria: patient satisfaction and either a decrease of 50% or
more in the pain score (compared with the initial score) or an absolute pain score of 2.5 cm
or less. Failure to achieve these criteria constitute treatment failure. The treating
physician will use an acceptable rescue medicine or group of medicines at treatment failure.
The 60 minute outcome was selected because of the route chosen (maximal absorption and
distribution within minutes) and because previous published data suggests that most
responders are identified during this interval. 9 Each patient will be contacted within 48
hours of discharge to define early relapse rate.

4.8 Inclusion criteria: Adults between the age of 18 and 65 years of age and diagnosis of
migraine with or without an aura who met the criteria of the International Headache Society,
and with at least one prior episode of a similar headache. 10 The International Headache
Society diagnosis criteria for migraine with and without aura is outlined in the below
table:

Migraine with AuraØ At least two attacks fulfilling the below characteristicsØ Headache has
at least three of the following four characteristics:1. 0ne or more fully reversible aura
symptoms indicating focal cerebral cortical and/or brain stem dysfunction2. At least one
aura symptom develops gradually over more than 4 minutes, or tow or more symptoms occur in
succession3. No aura symptom lasts more than 60 minutes; if more than one aura symptom is
present, accepted duration is proportionally increased4. Headache follows aura with a free
interval of less than 60 minutes (it may also begin before or simultaneously with the aura)
Migraine without AuraØ At least 5 attacks fulfilling the below characteristicsØ Headache
attacks lasting 4-72 hours (untreated or unsuccessfully treated)Ø Headache has at least two
of the following four characteristics:1. Unilateral location 2. Pulsating quality 3.
Moderate or severe intensity which inhibits or prohibits daily activities 4. Aggravated by
walking stairs or similar routine physical activityØ During headache at least one of the two
following symptoms occur:1. Nausea and/or vomiting2. Photophobia and phonophobia

4.9 Exclusion criteria: pregnancy and lactation, pre-medication within six hours of being
enrolled in the study, more than six prior headaches per month, allergy to the study drugs,
non-migraine headache, substance abuse, alcohol abuse, diabetes mellitus, or a coexisting
condition that might expose the patients to a disproportionately increased risk of a
significant adverse event: ischaemic heart disease, peripheral vascular disease,
cerebrovascular disease, uncontrolled hypertension (blood pressure >160/95), epilepsy, use
of cimetidine, dopamine agonist, cyclopsorin, or oral hypoglycemic agents, hepatic or renal
failure, and thyroid disorder.

4.10 Number of Subjects: TOTAL NUMBER OF SUBJECTS (nation-wide/study-wide) 56

5.0 Human Subject Protection

5.1 Recruitment: Patients presenting to the DACH ER with a complaint of headache will
interviewed by the physician. If they meet the inclusion and exclusion criteria, they will
be informed about the study by the treating physician, have to opportunity to ask questions,
and read the consent form.

5.2 Benefits: Patients participating in this study will have the potential benefit of
having their headache pain resolved. They will be part of an effort to find a treatment for
migraine headaches that will hopefully be effective and with a lower side effect profile.

5.3 Risks: The risks of this study include treatment failure and an allergic reaction to
one of the study medicines. Each medicine cares its own specific risk to the patient due to
its unique make-up and mechanism of action.

Octreotide has been shown to inhibit gallbladder contractility and decrease bile secretion
in normal volunteers. In clinical trials, the incidence of biliary tract abnormalities was
63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). Less than 2%
of patients treated with octreotide for 1 month or less developed gallstones. Octreotide
alters the balance between the counter-regulatory hormones, insulin, glucagon and growth
hormone, which may result in hypoglycemia (3%) or hyperglycemia (16%). Studies have also
demonstrated that octreotide suppress thyroid stimulating hormone (12%). Pancreatitis,
bradycardia, poor dietary fat and B12 absorption have also been reported. Most reports are
in patients with acromegaly who are prone to the before mentioned problems and the true
incidence in the non-acromegaly population is not known.

Compazine has been shown to cause orthostatic hypotension and extrapyramidal symptoms. Of
the extrapyramidal symptoms, akathisia (25-60% after single dose) and dystonic reactions (4%
after single dose) are the most commonly encountered. These reactions can be minimized by
the rate of administration and the concurrent use of diphenhydramine. Due to the study
design, diphenhydramine will not be used but a slow rate of administration with 50 ml normal
saline bag that will be given over 5 minutes. This slower rate of administration will
decrease risk of extrapyramidal symptoms. Irreversible tardive dyskinesia and neuroleptic
malignant syndrome have been described with compazine. These complications are extremely
rare and the true incidence is unknown

5.4 Safeguards for Protecting Subjects: Data collection sheets will be available to the
treating physician and PI only. The PI and AIs will obtain the follow up information for
all participants. Adverse reaction to any of the medications will be managed in the
emergency department depending on the specific reaction.

5.5 Risk:Benefit Assessment: The medications used in this study are currently being used
to treat headaches. Octreotide has been studied in this setting and side effect profile has
been minimal. The risks are minimal with the current exclusion criteria. Benefit of relief
of headache outweighed the risk of the side effects of any one of these medications.

5.6 Alternatives: Other medications have been used to treat migraines to include
morphine, reglan, magnesium. Alternative is also to not to participate in this study.

6.0 Data Analysis: In this study, the independent variables are treatment (octreotide,
comparzine, demerol) and time (0, 30, 60 minutes). The dependent variable is pain measured
on a numerical rating scale (1 to 10). The null hypothesis is that there will be no
difference in pain between treatments. The alternative hypothesis is that there will be a
greater decrease in pain with octreotide. The investigator expects the pain at baseline to
be 6 +/- 2. A 30% difference in pain between treatments will be clinically significant.
This is a 0.3 * 6 / 2 = 0.9 effect size. The appropriate test is a two-factor ANOVA
(treatment, time) with repeated measures on one factor (time) followed by one-tailed t-tests
corrected for multiple comparisons. Six post hoc comparisons on a one-tailed test are
appropriate for this design, so we made a maximum Bonferroni correction of p = 0.05 / 6 =
0.0083 ~ 0.005. I used a look-up table based on employing the method of Kraemer and
Thiemann (1988) to obtain an initial estimate of the sample size, which was confirmed with
1000 iterations of a Monte Carlo simulation until the power was between 80% and 85% with a
level of confidence of 95%. According to this method, a sample size of 32 per group (96
total) is needed to detect a clinically significant difference with the desired level of
confidence and power. If two treatments (octreotide, comparzine) are used, a sample size of
28 per group (56 total) is needed.