Amitriptyline to Prevent Headache After Traumatic Brain Injury

Study Description

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Brief Summary:

The investigators propose to conduct a 2-arm, open-label pilot study to determine if early treatment with amitriptyline will decrease the frequency and severity of headaches after mild traumatic brain injury (TBI). Amitriptyline is a tricyclic antidepressant that is commonly available and inexpensive. It is used as a first-line drug for primary headache prevention in a very low dose range of 10-50 mg.

• Specific Aim 1 is to conduct a 2-arm open-label study to examine the effect of preventive treatment with amitriptyline on the frequency and severity of headache after mild TBI.
• Specific Aim 2 is to collect data needed for design of a Phase 3 study, including an estimate of effect size, headache variability, and desirable drug treatment start date.
• Specific Aim 3 is to examine the feasibility of using headache diaries with individuals with mild TBI.
• Specific Aim 4 is to establish the safety and tolerability of amitriptyline for the prevention of headache after mild TBI.

The investigators hypothesize that early preventive treatment with amitriptyline will avert the development of chronic post-traumatic headache (PTH) as compared to rates of headache from a recent natural history study on PTH after mild TBI.

The investigators propose to enroll inpatient subjects from a Level I trauma center as well as from outpatient clinics and from the general community with a diagnosis of mild TBI. Subjects will be screened for current headache. After baseline assessment, 72 subjects with current headache will be randomized to one of 2 groups. Group 1 will immediately begin amitriptyline and or Group 2 will be followed and begin amitriptyline at Day 30. All subjects will be asked to complete a daily headache diary beginning on Day 1 of the study. A detailed medical history and headache survey will be completed. Subjects will have a scheduled stepped increase in the drug dosage every week for 3 weeks to the maximum study dosage of 50 mg. Weekly telephone calls will monitor for adverse events and compliance with the drug and headache diary. Clinic visits will occur at 30, 60 and 90 days. The 30 day clinic visit will include cognitive testing to assess for differences between groups and initiation of drug treatment for Group 2. Both 30 and 60 day visits will include review of headache diary, potential adverse effects, and pill counts. The 90 day visit will be for outcome assessment. In addition, the headache survey will be repeated by telephone at Day 180.

Condition or disease	Intervention/treatment	Phase
Brain Injuries; Post-Traumatic Headache	Drug: Amitriptyline	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	50 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Amitriptyline to Prevent Headache After Traumatic Brain Injury
Study Start Date :	April 2013
Actual Primary Completion Date :	February 2016
Actual Study Completion Date :	February 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Amitriptyline Immediate; The Amitriptyline Immediate group will begin study drug immediately after enrollment. Immediate Drug participants will be started on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.	Drug: Amitriptyline; Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), Day 30 and Day 60 (to monitor compliance and distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until their Day 30 visit. Those in group 2 who report headache at Day 30 will receive their initial dosage container and will then be reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).; Other Name: Elavil
Experimental: Amitriptyline Delayed; The Amitriptyline Delayed group will start the study drug at the Day 30 visit on one 10 mg capsule each evening. The dosage will be adjusted upwards to 25 mg daily for Week 2 to a maximum of 50 mg daily by Week 3.	Drug: Amitriptyline; Participants with headache will be enrolled within the first 12 weeks after injury and will be randomly assigned to 2 groups (see Table 1 for summary of protocol). Group 1 will be assessed within 3 months of injury (baseline, Day 0) (when they will receive their initial ramp-up dosage containers; see Table 2 for dosing), Day 30 and Day 60 (to monitor compliance and distribute study drug), and for final outcome on Day 90. Group 2 will be assessed within 3 months of injury (baseline, Day 0) but will not receive medication until their Day 30 visit. Those in group 2 who report headache at Day 30 will receive their initial dosage container and will then be reassessed at Day 60 (to monitor compliance and distribute study drug) and Day 90 (final outcome).; Other Name: Elavil

Outcome Measures

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Primary Outcome Measures :

1. Frequency of Headaches [ Time Frame: 90 days ]
   Number of subjects reporting an average of at least one headache per week
2. Severity of Headache [ Time Frame: 90 days ]
   Number of subjects with headache reporting an average pain of at least 6 on a 0-10 scale with 0=no pain and 10=worst pain.

Secondary Outcome Measures :

1. Number of Participants With Adverse Events Possibly Related to Study Medication [ Time Frame: Day 1 through Day 90 ]
   The number and types of treatment related adverse events will be monitored on a weekly basis and will be divided by severity if differing.
2. Rey Auditory Verbal Learning Test (Total) [ Time Frame: 30 days ]
   The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug. Scoring is based on the total number of words recalled from a list of 15 across 5 trials (max score of 75) with higher score indicating better learning.
3. Rey Auditory Verbal Learning Test (Short) [ Time Frame: 30 days ]
   The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug. Scoring is based on the total number of words recalled from the original list of 15 after a new list of 15 is given (used as distraction). Higher scores indicate better short-term memory.
4. Rey Auditory Verbal Learning Test (Long) [ Time Frame: 30 days ]
   The Rey Auditory Verbal Learning Test will be administered at 30 days to detect potential changes in cognitive function due to study drug. Scoring is based on the total number of words recalled from the original list of 15 after a 30 minute time delay. Higher scores indicate better long-term memory.
5. Trail Making Test (A) [ Time Frame: 30 days ]
   Trail Making Test will be given at 30 days to detect any impact of study drug on cognition. This is a test of visual attention and is scored by the number of seconds it takes to complete the task of making a trail through letters.
6. Trail Making Test (B) [ Time Frame: 30 days ]
   Trail Making Test will be given at 30 days to detect any impact of study drug on cognition. This is a test of visual attention and task switching and is scored by number of seconds it takes to complete the task (switching from letters to numbers in order).
7. Wechsler Adult Intelligence Scale (WAIS) IV Digit Symbol [ Time Frame: 30 days ]
   The WAIS IV Digit Symbol test will be given to detect any effect of study drug on cognition. This test assesses processing speed and new learning and requires an individual to substitute the relevant digit for a symbol and are given a time limit. The total number of correct digits are summed and converted to a scaled score (range 1-20 with 10 being at the 50th percentile) with higher scores indicating better performance.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Acute mild TBI (Glasgow Coma Scale of 13-15 on emergency department evaluation, any period of loss of consciousness (LOC) < than 30 minutes, alteration of consciousness or post-traumatic amnesia (not to exceed 24 hours)
• Ability to give consent
• Ages 18-60
• Access to a telephone
• Current headache (new headache or headache worse than prior to injury)

Exclusion Criteria:

• Does not speak English
• Diagnosed seizure disorder
• Myocardial infarction in prior 6 months
• Cardiac arrhythmia requiring medication treatment
• Prolonged Q-T interval on electrocardiogram
• Psychosis
• Intoxication on hospital admission sufficient enough to cloud the diagnosis of mild TBI
• Incarceration or homelessness
• Allergy to amitriptyline
• Current treatment with amitriptyline or other tricyclic antidepressant
• Currently taking any medication not recommended for use with amitriptyline due to the potential for Q-T interval prolongation. Examples of this include: Class I, I-A or II antiarrhythmics, TCA's, MAOI's, selected fluoroquinolones (gatifloxacin, moxifloxacin), selected antipsychotic medications (haloperidol, risperidone, quetiapine), selected antiretroviral medications, cisapride, chloroquine, chlorpromazine, prochlorperazine, promethazine, citalopram, fluoxetine, erythromycin, methadone
• History of glaucoma
• History of prostate disease or current urinary retention

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Washington
Harborview Medical Center
Seattle, Washington, United States, 98109

Sponsors and Collaborators

University of Washington

Investigators

Principal Investigator:	Jeanne M Hoffman, PhD	University of Washington

More Information

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Additional Information:

University of Washington TBI Model Systems website 

Responsible Party:	Jeanne Hoffman, Professor, University of Washington
ClinicalTrials.gov Identifier:	NCT01856270 History of Changes
Other Study ID Numbers:	STUDY00001333
First Posted:	May 17, 2013
Results First Posted:	December 22, 2017
Last Update Posted:	January 23, 2018
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Jeanne Hoffman, University of Washington:

Traumatic brain injury; Post-traumatic headache; Drug therapy

Additional relevant MeSH terms:

Wounds and Injuries; Brain Injuries; Brain Injuries, Traumatic; Headache; Post-Traumatic Headache; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Pain; Neurologic Manifestations; Signs and Symptoms; Headache Disorders, Secondary; Headache Disorders

Amitriptyline; Amitriptyline, perphenazine drug combination; Antidepressive Agents, Tricyclic; Antidepressive Agents; Psychotropic Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic Agents