Valproic Acid and Dihydroergotamine as Abortive Therapy in Pediatric Migraine

• Sponsor: Kimberly S Jones (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03885154
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 4
• Actual Duration (Months): 17.5
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The objective of this study is to compare clinical efficacy and tolerability of valproic acid (VPA) therapy versus dihydroergotamine (DHE) as abortive therapy in pediatric migraine.

Condition or Disease	Intervention/Treatment	Phase
Migraine in Children	Drug: Valproic Acid (VPA); Drug: Dihydroergotamine (DHE)	Phase 2

Detailed Description

The purpose of this study is to compare valproic acid (VPA) and dihydroergotamine (DHE) alone and sequentially in the treatment of pediatric migraines.

Inpatient pediatric migraine patients (based on International Classification of Headache Disorders, ICHD-II criteria) or those admitted to the University of Kentucky emergency department will receive standard of care acute headache management as per AAP/AAN guidelines. Those who fail to respond will be considered for further eligibility. Informed consent/assent will be obtained from the patients, parents or legal guardian.

Baseline labs will be collected prior to the start of the study.

1. Complete Blood Count (CBC)

2. Comprehensive Metabolic Panel (CMP)

3. Prothrombin Time/Activated Partial Thromboplastin Time/International Normalized Ratio (PT/APTT/INR)

4. Magnesium and phosphorous

Patients will initially be randomized into two groups (VPA or DHE) and treated for 24 hours. Those patients whose migraines resolve will end the study at 24 hours. Patients who are refractory to treatment will switch interventions and continue treatment for an additional 24 hours.

Intervention 1: VPA Intervention 2: DHE

Patients in Group 1 will be treated with VPA for 24 hours. They will be given an initial dose of IV VPA at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours; depending on drug levels they may also be checked at 8 and 12 hours. The target serum concentration is 100 (+/-10) ug/mL.

Patients in Group 2 will be treated with DHE for 24 hours. Dosing will be weight-based with no single dose >1mg and total 24 hour dose <3mg.

0 hour: 0.5 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.0 x (wt in kg) x (0.014) =Xmg

Patients will be assessed for migraine severity at baseline, 4, 8, 12, and 24 hours.

1. pain (using the standard 0-10 point VAS pain scale)

2. presence or absence of photophobia

3. presence or absence of phonophobia

4. presence or absence of nausea

The endpoint criterion is successful migraine resolution (improvement in VAS and resolution of photophobia, phonophobia, and nausea). Patients meeting this criterion will not continue forward in the study.

At 24 hours, those patients that are refractory to treatment will cross over to the alternate intervention, i.e. patients receiving VPA first will then get DHE, and patients receiving DHE first will then get VPA. Outcomes will be measured for the next 24 hour period as described above.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Valproic Acid and Dihydroergotamine as Abortive Therapy in Pediatric Migraine: An Open-Label Randomized Trial.
• Actual Study Start Date: Oct 3, 2017
• Actual Primary Completion Date: Mar 19, 2019
• Actual Study Completion Date: Mar 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Valproic Acid An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels.	Drug: Valproic Acid (VPA); IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours; Other Names: Depakene
Active Comparator: Dihydroergotamine Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours.	Drug: Dihydroergotamine (DHE); 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Active Comparator: Cross-Over to Dihydroergotamine An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours.	Drug: Valproic Acid (VPA); IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours; Other Names: Depakene ; Drug: Dihydroergotamine (DHE); 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Active Comparator: Cross-Over to Valproic Acid Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels.	Drug: Valproic Acid (VPA); IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours; Other Names: Depakene ; Drug: Dihydroergotamine (DHE); 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg

Outcome Measures

Primary Outcome Measures

1. Change in Pain Perception [Baseline to 24 hours]

   Change in pain perception measured by the 10-point visual analogue scale (VAS), where 0 is "no pain" and 10 is "pain as bad as it could be."

Secondary Outcome Measures

1. Percentage of Participants With Presence of Photophobia [Baseline, 4, 8, 12 and 24 hours]

   Presence of absence of photophobia

2. Percentage of Participants With Presence of Phonophobia [Baseline, 4, 8, 12 and 24 hours]

   Presence of absence of phonophobia

3. Percentage of Participants With Presence of Nausea [Baseline, 4, 8, 12 and 24 hours]

   Presence or absence of nausea

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• acute migraine as per ICHD-II criteria

• pediatric (age 10-18)

Exclusion Criteria:

For Valproic Acid (VPA)

• Pregnancy

• Liver disease (Acute or Chronic)

• Urea Cycle Disorder

• Mitochondrial Disease

For Dihydroergotamine (DHE)

• Pregnancy

• Peripheral vascular disease, coronary heart disease

• History of cerebrovascular event

• Severe or poorly controlled hypertension

• Impaired liver or renal function

• Triptan given in last 24 hours

• Hemiplegic migraine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kentucky	Lexington	Kentucky	United States	40536

Sponsors and Collaborators

• Kimberly S Jones

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Nov 27, 2018

More Information

Publications

None provided.

• Responsible Party: Kimberly S Jones, Assistant Professor of Neurology and Pediatrics, University of Kentucky
• ClinicalTrials.gov Identifier: NCT03885154
• Other Study ID Numbers: 44243
• First Posted: Mar 21, 2019
• Last Update Posted: Oct 7, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Kimberly S Jones, Assistant Professor of Neurology and Pediatrics, University of Kentucky: Migraine; Headache; Valproic acid; Dihydroergotamine; Pediatric
• Additional relevant MeSH terms: Migraine Disorders; Dihydroergotamine; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Valproic Acid	Dihydroergotamine	Cross-Over to Dihydroergotamine	Cross-Over to Valproic Acid
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Period Title: Overall Study
STARTED	12	10	0	2
COMPLETED	12	10	0	2
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Valproic Acid	Dihydroergotamine	Cross-Over to Dihydroergotamine	Cross-Over to Valproic Acid	Total
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Total of all reporting groups
Overall Participants	12	10	0	2	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.6 (1.2)	14.1 (2.0)	16.0 (1.4)	15.0 (1.6)
Sex: Female, Male (Count of Participants)
Female	8 66.7%	5 50%	2 Infinity	15 750%
Male	4 33.3%	5 50%	0 NaN	9 450%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 NaN	0 0%
Asian	0 0%	0 0%	0 NaN	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 NaN	0 0%
Black or African American	0 0%	0 0%	0 NaN	0 0%
White	0 0%	0 0%	0 NaN	0 0%
More than one race	0 0%	0 0%	0 NaN	0 0%
Unknown or Not Reported	12 100%	10 100%	2 Infinity	24 1200%
Region of Enrollment (participants) [Number]
United States	12 100%	10 100%	2 Infinity	24 1200%

Outcome Measures

1. Primary Outcome

Title	Change in Pain Perception
Description	Change in pain perception measured by the 10-point visual analogue scale (VAS), where 0 is "no pain" and 10 is "pain as bad as it could be."
Time Frame	Baseline to 24 hours

Outcome Measure Data

Analysis Population Description

No participants were enrolled in the cross-over to dihydroergotamine arm. Participants were analyzed on a per-arm basis. Data were not collected for DHE only for the two participants who crossed over to Valproic Acid; only the combination of treatments.

Arm/Group Title	Valproic Acid	Dihydroergotamine	Cross-Over to Dihydroergotamine	Cross-Over to Valproic Acid
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Measure Participants	12	10	0	2
Mean (Standard Deviation) [change in score on a scale]	-6.2 (3.6)	-5.8 (2.9)	-5 (1.4)

2. Secondary Outcome

Title	Percentage of Participants With Presence of Photophobia
Description	Presence of absence of photophobia
Time Frame	Baseline, 4, 8, 12 and 24 hours

Outcome Measure Data

Analysis Population Description

No participants were enrolled in the cross-over to dihydroergotamine arm. Participants were analyzed on a per-arm basis. Data were not collected for DHE only for the two participants who crossed over to Valproic Acid; only the combination of treatments.

Arm/Group Title	Valproic Acid	Dihydroergotamine	Cross-Over to Dihydroergotamine	Cross-Over to Valproic Acid
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Measure Participants	12	10	0	2
Baseline	100 833.3%	100 1000%	100 Infinity
4 hours	58 483.3%	42 420%	50 Infinity
8 hours	17 141.7%	17 170%	0 NaN
12 hours	0 0%	17 170%	0 NaN
24 hours	0 0%	17 170%	0 NaN

3. Secondary Outcome

Title	Percentage of Participants With Presence of Phonophobia
Description	Presence of absence of phonophobia
Time Frame	Baseline, 4, 8, 12 and 24 hours

Outcome Measure Data

Analysis Population Description

No participants were enrolled in the cross-over to dihydroergotamine arm. Participants were analyzed on a per-arm basis. Data were not collected for DHE only for the two participants who crossed over to Valproic Acid; only the combination of treatments.

Arm/Group Title	Valproic Acid	Dihydroergotamine	Cross-Over to Dihydroergotamine	Cross-Over to Valproic Acid
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Measure Participants	12	10	0	2
Baseline	100 833.3%	92 920%	50 Infinity
4 hours	42 350%	25 250%	0 NaN
8 hours	8 66.7%	8 80%	0 NaN
12 hours	8 66.7%	0 0%	0 NaN
24 hours	0 0%	0 0%	0 NaN

4. Secondary Outcome

Title	Percentage of Participants With Presence of Nausea
Description	Presence or absence of nausea
Time Frame	Baseline, 4, 8, 12 and 24 hours

Outcome Measure Data

Analysis Population Description

No participants were enrolled in the cross-over to dihydroergotamine arm. Participants were analyzed on a per-arm basis. Data were not collected for DHE only for the two participants who crossed over to Valproic Acid; only the combination of treatments.

Arm/Group Title	Valproic Acid	Dihydroergotamine	Cross-Over to Dihydroergotamine	Cross-Over to Valproic Acid
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Patients who do not respond to VPA after 24 hours will be given Dihydroergotamine (DHE) for the next 24 hours. Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg	Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Patients who do not respond to DHE after 24 hours will be given Valproic Acid (VPA) for the next 24 hours. An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
Measure Participants	12	10	0	2
Baseline	100 833.3%	100 1000%	100 Infinity
4 hours	58 483.3%	58 580%	0 NaN
8 hours	8 66.7%	33 330%	0 NaN
12 hours	8 66.7%	33 330%	0 NaN
24 hours	0 0%	25 250%	0 NaN

Adverse Events

Time Frame	Participants were assessed at baseline, 4 hour, 8 hour, 12, 24 hours per intervention.
Adverse Event Reporting Description	No participants were enrolled in the cross-over to dihydroergotamine arm so there was no risk for all-cause mortality.
Arm/Group Title	Valproic Acid		Dihydroergotamine
Arm/Group Description	An initial dose of Valproic Acid (VPA) will be given IV at 20mg/kg, followed by continuous infusion of 1mg/kg/hour for 24 hours. Serum levels of VPA will be checked at 4 and 24 hours, with additional timepoints possible at 8 and 12 hours based on drug levels. Valproic Acid (VPA): IV VPA load 20mg/kg, followed by continuous infusion of 1mg/kg/hr for 24 hours		Dihydroergotamine (DHE) will be given as weight-based dosing, with no single dose >1mg and not exceeding 3mg over 24 hours. Dihydroergotamine (DHE): 0 hour: 0.50 x (wt in kg) x (0.014) =Xmg 8 hour: 0.75 x (wt in kg) x (0.014) =Xmg 24 hour: 1.00 x (wt in kg) x (0.014) =Xmg
All Cause Mortality
	Valproic Acid		Dihydroergotamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/12 (0%)
Serious Adverse Events
	Valproic Acid		Dihydroergotamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Valproic Acid		Dihydroergotamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		3/12 (25%)
Cardiac disorders
Tightness in chest	0/14 (0%)		2/12 (16.7%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/14 (0%)		1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.